Publications by authors named "Henk-Jan Aanstoot"

40 Publications

Residual C-peptide secretion and hypoglycemia awareness in people with type 1 diabetes.

BMJ Open Diabetes Res Care 2021 09;9(1)

Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Introduction: This study aimed to assess the association between fasting serum C-peptide levels and the presence of impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes.

Research Design And Methods: We performed a cross-sectional study among 509 individuals with type 1 diabetes (diabetes duration 5-65 years). Extensive clinical data and fasting serum C-peptide concentrations were collected and related to the presence or absence of IAH, which was evaluated using the validated Dutch version of the Clarke questionnaire. A multivariable logistic regression model was constructed to investigate the association of C-peptide and other clinical variables with IAH.

Results: In 129 (25%) individuals, residual C-peptide secretion was detected, while 75 (15%) individuals reported IAH. The median (IQR) C-peptide concentration among all participants was 0.0 (0.0-3.9) pmol/L. The prevalence of severe hypoglycemia was lower in people with demonstrable C-peptide versus those with absent C-peptide (30% vs 41%, p=0.025). Individuals with IAH were older, had longer diabetes duration, more frequently had macrovascular and microvascular complications, and more often used antihypertensive drugs, antiplatelet agents and cholesterol-lowering medication. There was a strong association between IAH and having a severe hypoglycemia in the preceding year. In multivariable regression analysis, residual C-peptide, either continuously or dichotomous, was associated with lower prevalence of IAH (p=0.040-0.042), while age at diabetes onset (p=0.001), presence of microvascular complications (p=0.003) and body mass index (BMI) (p=0.003) were also independently associated with the presence of IAH.

Conclusions: Higher BMI, the presence of microvascular complications and higher age at diabetes onset were independent risk factors for IAH in people with type 1 diabetes, while residual C-peptide secretion was associated with lower risk of this complication.
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http://dx.doi.org/10.1136/bmjdrc-2021-002288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444236PMC
September 2021

Hypoglycaemia and diabetes-specific quality of life in adolescents with type 1 diabetes.

Diabet Med 2021 Aug 12;38(8):e14565. Epub 2021 Apr 12.

Department of Psychology, University of Southern Denmark, Odense, Denmark.

Aims: To examine whether frequency, perceived severity and fear of hypoglycaemia are independently associated with diabetes-specific quality of life in adolescents with type 1 diabetes.

Methods: Cross-sectional self-reported data on demographics, frequency and perceived severity of both self-treated and severe hypoglycaemia, fear of hypoglycaemia (Hypoglycaemia Fear Survey-Child version) and diabetes-specific quality of life (Pediatric Quality of Life Diabetes Module; PedsQL-DM) were obtained from the project 'Whose diabetes is it anyway?'. Hierarchical regression analyses were performed for the total scale and recommended summary scores of the PedsQL-DM as dependent variables; independent variables were entered in the following steps: (1) age, gender and HbA , (2) frequency of hypoglycaemia, (3) perceived severity of hypoglycaemia and (4) fear of hypoglycaemia.

Results: Adolescents (12-18 years; n = 96) completed questionnaires. In the first three steps, female gender (p < 0.05), higher HbA (p < 0.05), higher frequency of severe hypoglycaemia (p < 0.05) and higher perceived severity of severe (p < 0.05) and self-treated hypoglycaemia (p < 0.001) were significantly associated with lower diabetes-specific quality of life (β ranging from 0.20 to 0.35). However, in the final model only fear of hypoglycaemia was significantly associated with QoL (p < 0.001). Adolescents with greater fear reported lower diabetes-specific quality of life, with 52% explained variance. This pattern was observed across subdomains of diabetes-specific quality of life.

Conclusions: Fear of hypoglycaemia was the only factor independently associated with diabetes-specific quality of life, whereas frequency and perceived severity of hypoglycaemia were not. These findings highlight the importance of awareness and assessment of fear of hypoglycaemia in clinical practice.
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http://dx.doi.org/10.1111/dme.14565DOI Listing
August 2021

Depression and anxiety in adolescents with type 1 diabetes and their parents.

Pediatr Res 2021 Mar 4. Epub 2021 Mar 4.

Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic disorders (CoRPS), Tilburg University, Tilburg, The Netherlands.

Background: Longitudinal studies including parental distress when examining adverse health outcomes in adolescents with type 1 diabetes are lacking. This study examined whether parental depression and anxiety predict adolescent emotional distress and glycated hemoglobin A (HbA) 1 year later and whether a relation between parental distress and HbA is mediated by the level of parental involvement in diabetes care and by treatment behaviors.

Methods: Longitudinal path modeling was applied to data from 154 adolescents and parents from diabetes centers participating in the Longitudinal study of Emotional problems in Adolescents with type 1 diabetes and their Parents/caregivers (Diabetes LEAP). At baseline and 1-year follow-up, participants completed measures of depression and anxiety. HbA was extracted from medical charts. Responsibility and treatment behavior questionnaires were completed by adolescents at baseline.

Results: Baseline parental depressive and anxiety symptoms were not associated with 1-year adolescent depressive symptoms, anxiety symptoms, and HbA. Responsibility division and treatment behaviors did not mediate associations between parental emotional distress and 1-year HbA.

Conclusions: Parental depressive and anxiety symptoms did not predict adolescent health outcomes 1 year later. Future studies may determine whether the link is present in case of mood/anxiety disorders or severe diabetes-specific distress, or whether adolescents are resilient in the face of parental distress.

Impact: Adolescents with T1D are a vulnerable group in terms of psychological and health outcomes. Whether parental emotional distress (i.e., depressive and anxiety symptoms) is prospectively associated with adolescent emotional distress and/or HbA has been understudied. Our results show that parental distress was not related to adolescent distress or HbA 1 year later. Responsibility division and treatment behaviors did not mediate associations between parental emotional distress and 1-year HbA. Future studies could determine whether these links are present in case of mood/anxiety disorders or severe diabetes-specific distress, or whether adolescents are resilient in the face of parental distress.
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http://dx.doi.org/10.1038/s41390-021-01392-yDOI Listing
March 2021

The division and transfer of care responsibilities in paediatric type 1 diabetes: A qualitative study on parental perspectives.

J Adv Nurs 2021 Apr 16;77(4):1968-1979. Epub 2021 Feb 16.

Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic disorders [CoRPS], Tilburg University, Tilburg, The Netherlands.

Aim: To determine which factors other than child age play a role in the division and transfer of diabetes care responsibilities between parents and children with type 1 diabetes.

Design: Qualitative focus group study.

Methods: Across four sites in the Netherlands, 18 parents (13 mothers) of children (9-14 years) with type 1 diabetes participated in four focus groups in 2015-2016, as part of the research project 'Whose diabetes is it anyway?'. Qualitative content analysis and the constant comparison method were used to analyse the data.

Results: According to parents, the transfer process included both direct and indirect tasks, had different levels (remembering, deciding, performing), was at times a difficult and stressful process, and showed large variation between families. A large number of child, parent and context factors were identified that affected the division and transfer of diabetes care responsibilities according to parents. Both positive and negative consequences of the transfer process were described for parental and child health, behaviour and well-being. Parental final evaluations of the division and transfer of diabetes care responsibilities appeared to be dependent on parenting values.

Conclusion: How families divide and transfer diabetes care tasks appeared to be affected by a complex interplay of child, parent and context characteristics, which had an impact on several parent and child domains.

Impact: Parents struggle with the right timing of transfer, which calls for more support from diabetes nurses. The identified factors can be used as input for integrating a more family-based approach into current age-based guidelines, to improve regular care.
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http://dx.doi.org/10.1111/jan.14781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048668PMC
April 2021

Prevalence and course of mood and anxiety disorders, and correlates of symptom severity in adolescents with type 1 diabetes: Results from diabetes LEAP.

Pediatr Diabetes 2021 06 16;22(4):638-648. Epub 2021 Mar 16.

Department of Medical and Clinical Psychology, Center of Research on Psychological and Somatic disorders (CoRPS), Tilburg University, Tilburg, The Netherlands.

Objectives: We aim to determine the prevalence and the course of anxiety and mood disorders in Dutch adolescents (12-18 years old) with type 1 diabetes, and to examine correlates of symptom severity, including parental emotional distress.

Methods: Participants were 171 adolescents and 149 parents. The Diagnostic Interview Schedule for Children-IV was used to assess current, past year and lifetime anxiety and mood disorders in adolescents. Symptom severity and diabetes distress were measured with validated questionnaires. Correlates of these symptoms were examined using hierarchical regression analyses and included demographics (adolescent sex and age), clinical factors (diabetes duration, treatment modality, most recent glycated hemoglobin A ; all extracted from medical charts), adolescent diabetes distress, and parent emotional distress.

Results: Twenty-four (14%) adolescents met the criteria for ≥1 disorder(s) in the previous 12 months. Anxiety disorders were more prevalent than mood disorders (13% vs. 4%). Lifetime prevalence of anxiety and mood disorders was 29% (n = 49). The presence of any of these disorders earlier in life (from 5 years old up to 12 months prior to assessment) was associated with disorders in the past 12 months (OR = 4.88, p = 0.001). Higher adolescent diabetes distress was related to higher symptoms of anxiety (b = 0.07, p = 0.001) and depression (b = 0.13, p = 0.001), while demographics, clinical characteristics, and parental emotional distress were not related.

Conclusions: Anxiety and mood disorders are common among adolescents and related to earlier disorders. Higher diabetes distress was related to higher symptom severity. Clinicians are advised to address past psychological problems and remain vigilant of these problems.
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http://dx.doi.org/10.1111/pedi.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251968PMC
June 2021

Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide-for type 1 diabetes.

Lancet Diabetes Endocrinol 2020 06 5;8(6):470-472. Epub 2020 May 5.

Immunomodulation and Regenerative Cell Therapy, Leiden University Medical Center, 2333 ZA Leiden, Netherlands; Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute at City of Hope, Duarte, CA, USA.

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http://dx.doi.org/10.1016/S2213-8587(20)30104-2DOI Listing
June 2020

Precision Dosing of Rapid-Acting Insulin Matters.

Diabetes Technol Ther 2020 05 3;22(5):346-351. Epub 2020 Mar 3.

Eli Lilly and Company, Utrecht, the Netherlands.

Despite several molecular and technological advances in insulin therapy and insulin delivery, global evidence highlights inadequate glycemic control in populations with type 1 diabetes (T1D) and type 2 diabetes (T2D). In this review, we discuss the importance of more precise dosing of insulin as one of the approaches to improve glycemic control while reducing hypoglycemic events. This report is based on the expert opinion of authors and literature search of articles relevant to the past and present insulin delivery devices in diabetes management, especially half-unit insulin pens. We describe the various factors that facilitate better glycemic control, focusing on the impact of appropriate insulin delivery device selection on diabetes management. Precision dosing of insulin is a lesser-studied factor that contributes toward better glycemic control. Insulin pens have consistently outperformed syringes as delivery devices due to their greater accuracy and precision of dosing, ease-of-use, and patient preference. These advantages make them better suited to administer insulin in hypoglycemia-prone insulin-sensitive people with T1D, particularly younger children and geriatric patients. Half-unit insulin pens further extend this benefit by delivering half-unit doses of insulin accurately. They may contribute to better management of diabetes by allowing flexible dosing for mealtimes and physical activities even in erratic diet situations or illnesses by offering corrective doses in small increments. They are ideal delivery devices for insulin-sensitive people with T1D who require greater accuracy and precision in insulin delivery to achieve more stringent glycemic control.
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http://dx.doi.org/10.1089/dia.2019.0374DOI Listing
May 2020

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes.

Diabetologia 2020 02 21;63(2):351-361. Epub 2019 Nov 21.

Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

Aims/hypothesis: Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study.

Methods: Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively.

Results: Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading.

Conclusions/interpretation: Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.
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http://dx.doi.org/10.1007/s00125-019-05032-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946733PMC
February 2020

Study protocol of Diabetes LEAP: a longitudinal study examining emotional problems in adolescents with type 1 diabetes and their parents/caregivers.

BMC Pediatr 2019 10 24;19(1):377. Epub 2019 Oct 24.

Department of Psychology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.

Background: Type 1 diabetes (T1D) is a chronic metabolic condition requiring intensive daily self-care to avoid both high and low blood glucose levels. Self-care and glycemic outcomes are particularly problematic in adolescence, a period known for its increased risk of emotional problems. However, the true scope of mood and anxiety disorders in adolescents with T1D is unknown. Earlier studies are limited by a small sample size, lack of diagnostic interview data, a focus on depression only, non-adolescent specific estimates, lack of information about parental emotional problems and/or a cross-sectional design. Diabetes LEAP is a two-year prospective observational cohort study examining (a) the prevalence and course of depression and anxiety in adolescents with T1D and their parents/caregivers, (b) the risk factors predicting the presence of these emotional problems, (c) their longitudinal relation with diabetes outcomes, and (d) the psychosocial care currently in place.

Methods: Adolescents (12-18 years) from 8 Dutch pediatric diabetes clinics are interviewed using the DISC-IV to establish the presence of mood and anxiety disorders in the previous 4 weeks, the previous 12 months, and lifetime. They also complete questionnaires, including CDI-2, GAD-7, and PAID-T. Parents/caregivers complete PHQ-9, GAD-7, and PAID-PR. Follow-up assessments take place after 1 and 2 years.

Discussion: This longitudinal study with diagnostic interviews in a large cohort of adolescents with T1D in the Netherlands will provide much needed information regarding the prevalence and course of depression and anxiety in this group, thereby opening avenues for proper recognition, prevention and timely treatment.
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http://dx.doi.org/10.1186/s12887-019-1743-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813041PMC
October 2019

Losing Track of Lipids in Children and Adolescents with Type 1 Diabetes: Towards Individualized Patient Care.

Exp Clin Endocrinol Diabetes 2021 Jul 4;129(7):510-518. Epub 2019 Jul 4.

Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, The Netherlands.

Aim: To assess 1) the prevalence of children and adolescents with type 1 diabetes (T1D) changing from low-risk into borderline-high-risk lipid levels or from borderline-high-risk into high-risk lipid levels ('lose track of lipids') and 2) the power of a risk score including the determinants HbA1c, body mass index (BMI), gender, age, diabetes duration and ethnicity in predicting which patients lose track of lipids.

Methods: 651 children and adolescents with T1D were included in this longitudinal retrospective cohort study. Lipid dynamics and the impact of the risk score on losing track of lipids were evaluated. Kaplan-Meier analysis was used to estimate screening intervals.

Results: 31-43% percent of the patients had lost track of one or more lipids at the next lipid measurement. This happened more frequently in patients with a low-risk lipid level at start. Depending on the lipid parameter, 5% of patients with low-risk lipid levels lost track of lipids after 13-23 months. The risk score based on concomitant information on the determinants was moderately able to predict which patients would lose track of lipids on the short term.

Conclusions: A considerable number of children and adolescents with T1D loses track of lipids and does so within a 2-year screening interval. The predictive power of a risk score including age, BMI, gender, HbA1c, diabetes duration and ethnicity is only moderate. Future research should focus on another approach to the determinants used in this study or other determinants predictive of losing track of lipids on the short term.
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http://dx.doi.org/10.1055/a-0950-9677DOI Listing
July 2021

Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer.

Diabetologia 2018 12 3;61(12):2516-2519. Epub 2018 Oct 3.

Department of Radiology and Nuclear Medicine, Radboud university medical centre, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.

In this issue of Diabetologia, Alavi and Werner ( https://doi.org/10.1007/s00125-018-4676-1 ) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as 'futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a 'futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.
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http://dx.doi.org/10.1007/s00125-018-4745-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223852PMC
December 2018

Parental Diabetes Behaviors and Distress Are Related to Glycemic Control in Youth with Type 1 Diabetes: Longitudinal Data from the DINO Study.

J Diabetes Res 2017 10;2017:1462064. Epub 2017 Dec 10.

Department of Medical Psychology, VU University Medical Center, De Boelenlaan 1117, 1081 HV Amsterdam, Netherlands.

Objective: To evaluate (1) the longitudinal relationship between parental well-being and glycemic control in youth with type 1 diabetes and (2) if youth's problem behavior, diabetes parenting behavior, and parental diabetes-distress influence this relationship.

Research Design And Methods: Parents of youth 8-15 yrs (at baseline) ( = 174) participating in the DINO study completed questionnaires at three time waves (1 yr interval). Using generalized estimating equations, the relationship between parental well-being (WHO-5) and youth's HbA1c was examined. Second, relationships between WHO-5, Strength and Difficulties Questionnaire (SDQ), Diabetes Family Behavior Checklist (DFBC), Problem Areas In Diabetes-Parent Revised (PAID-Pr) scores, and HbA1c were analyzed.

Results: Low well-being was reported by 32% of parents. No relationship was found between parents' WHO-5 scores and youth's HbA1c ( = -0.052, = 0.650). WHO-5 related to SDQ ( = -0.219, < 0.01), DFBC unsupportive scale ( = -0.174, < 0.01), and PAID-Pr ( = -0.666, < 0.01). Both DFBC scales (supportive = -0.259, = 0.01; unsupportive = 0.383, = 0.017), PAID-Pr ( = 0.276, < 0.01), and SDQ ( = 0.424, < 0.01) related to HbA1c.

Conclusions: Over time, reduced parental well-being relates to increased problem behavior in youth, unsupportive parenting, and parental distress, which negatively associate with HbA1c. More unsupportive diabetes parenting and distress relate to youth's problem behavior.
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http://dx.doi.org/10.1155/2017/1462064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742467PMC
August 2018

Hvidoere Smiley Faces: International diabetes quality of life assessment tool for young children.

Pediatr Diabetes 2018 05 22;19(3):553-558. Epub 2017 Nov 22.

Clinique Pediatrique/CHL, Diabetes & Endocrine Care CP, Luxembourg.

Background: Few diabetes-specific quality of life (QOL) tools are available for young children.

Objectives: To design and evaluate, a new age-specific QOL questionnaire and its associations with treatment regimens and metabolic control.

Methods: Clinical, demographic data and centrally analyzed HbA1c were collected on 1133 children <11 years (girls 48%; mean ± SD age 8.0 ± 2.1 years; diabetes duration ≥1 year) from 18 centers (Europe, Japan, North America and Australia). Children completed the 10-item Smiley Faces QOL questionnaire constructed for the study, and children ≥7 years also completed the KIDSCREEN-10 Index.

Results: In total, 1035 children completed the new Smiley Faces questionnaire which was well understood by 993 (70% ≥4 years and 96% ≥5 years, respectively). Internal consistency and reliability were good (Cronbach's α = .73). Inter-item correlation ranged r = 0.047 to 0.451 indicating each item measures separate aspects of children's satisfaction construct. Convergent validity assessed by comparison to the HrQOL KIDSCREEN-10 Index showed moderate correlation coefficient 0.501. Factor analysis revealed 3 factors explaining 51% of the variance. Children reported good QOL with most items positive, mean values between 1 and 2 on a 5-point scale (lower scores indicating greater QOL). Diabetes satisfaction was unrelated to age, diabetes duration, HbA1c, or severe hypoglycemia. Girls were more satisfied than boys. Children on intensive regimens reported better QOL (P < .02). Main dissatisfaction related to insulin injections and blood sugar testing.

Conclusions: The Smiley Faces questionnaire enables QOL assessment in young children and identification of areas of dissatisfaction and other clinically relevant items relating to diabetes management.
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http://dx.doi.org/10.1111/pedi.12602DOI Listing
May 2018

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes.

Pediatr Diabetes 2018 05 20;19(3):559-565. Epub 2017 Nov 20.

Clinique Pediatrique/CHL, Diabetes & Endocrine Care CP, Luxembourg, Luxembourg.

Objective: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes.

Research Design And Methods: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring.

Results: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac.

Conclusions: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.
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http://dx.doi.org/10.1111/pedi.12606DOI Listing
May 2018

Skin autofluorescence is increased in young people with type 1 diabetes exposed to secondhand smoking.

J Diabetes 2017 Mar 1;9(3):308-310. Epub 2016 Dec 1.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Skin autofluorescence is increased in diabetes, rises with age, and predicts diabetes-related complications. Exposure to secondhand smoke, because one or more family members are smokers, further increases skin autofluorescence in children and young adults with type 1 diabetes. Elimination of passive smoking should be a goal in diabetes education. Association between age and skin autofluorescence (SAF), in arbitrary units (AU), in young people with type 1 diabetes exposed (black dots) and not exposed (open dots) to secondhand smoke. Regression lines show correlations between these parameters in exposed (solid line) and not exposed (dashed line) patients.
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http://dx.doi.org/10.1111/1753-0407.12498DOI Listing
March 2017

Increased skin autofluorescence of children and adolescents with type 1 diabetes despite a well-controlled HbA1c: results from a cohort study.

BMC Endocr Disord 2016 Sep 9;16(1):49. Epub 2016 Sep 9.

Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Blaak 6, 3011, TA, Rotterdam, Netherlands.

Background: Early identification of children and adolescents with type 1 diabetes at high risk for development of complications is important, as early intervention may prevent further deterioration. Here we investigate the applicability of assessing skin advanced glycation end products (sAGEs) by skin autofluorescence (SAF) as a potential surrogate risk marker.

Methods: This study included a cross-sectional analysis of SAF in 77 patients with type 1 diabetes mellitus and 118 healthy controls across age categories (11-12, 13-14, 15-16, and 17-19 years old). In patients, the impact of current and historical glycated hemoglobin (HbA1c) values, age, and duration of diabetes on SAF was studied in a retrospective cohort study and analyzed with multivariable analyses.

Results: SAF was significantly and similarly higher in patients when compared with controls across all age categories (P ≤0.009). For patients, age, duration of diabetes, and current and historical HbA1c were associated with SAF in univariate analysis. Multivariate analysis showed no association between HbA1c and SAF. A subgroup of patients with a HbA1c-within-target (≤7.5 %/59 mmol/mol) were observed to have high SAF.

Conclusion: Children and adolescents with type 1 diabetes show higher SAF than controls. The presumed correlation of high HbA1c with high SAF does not exist in all patients. Thus, use of this non-invasive measure may provide a surrogate marker for diabetic complications, additional to HbA1c.
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http://dx.doi.org/10.1186/s12902-016-0129-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017065PMC
September 2016

Disturbed eating behaviors in adolescents with type 1 diabetes. How to screen for yellow flags in clinical practice?

Pediatr Diabetes 2017 08 30;18(5):376-383. Epub 2016 Jun 30.

Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands.

Background: Adolescents with type 1 diabetes are at an increased risk of disturbed eating behaviors (DEBs).

Objective: The aims of this study are to (i) explore the prevalence of DEBs and associated 'yellow flags', and (ii) establish concordance between adolescents-parents and adolescents-clinicians with respect to DEBs.

Methods: Adolescents (11-16 yr) and parents completed questionnaires. A stepwise approach was used to assess DEBs: only adolescents whose answers raised psychological yellow flags for DEBs completed the Diabetes Eating Problems Scale - Revised and questions from the AHEAD study. Parents and clinicians shared their observations regarding possible DEBs. Kruskal-Wallis tests, post hoc Mann-Whitney U test, and chi-squared tests were utilized to examine clinical yellow flags. Cohen's kappa was used to assess concordance.

Results: Of 103 adolescents participated (51.5% girls), answers of 47 (46.5%) raised psychological yellow flags, indicating body and weight concerns. A total of 8% scored above cut-off for DEBs. Clinical yellow flags were elevated glycated hemoglobin A1c (p = 0.004), older age (p = 0.034), dieting frequency (p = 0.001), reduced quality of life (p = 0.007), less diabetes self-confidence (p = 0.015), worsened diabetes management (p < 0.001), and body dissatisfaction (p < 0.001). Body Mass Index (BMI) z-scores and gender were no yellow flags. Concordance between parents and adolescents was slight (k = 0.126 and 0.141), and clinicians and adolescents was fair (k = 0.332).

Discussion: Half of the adolescents reported body and weight concerns, less than 1 in 10 reported DEBs. Screening for yellow flags for DEBs as a part of clinical routine using a stepwise approach and early assistance is recommended to prevent onset or deterioration of DEBs.
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http://dx.doi.org/10.1111/pedi.12400DOI Listing
August 2017

GADA persistence and diabetes classification.

Lancet Diabetes Endocrinol 2016 07;4(7):563-4

Diabetes Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam 3011TA, Netherlands. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(16)30103-6DOI Listing
July 2016

Do traditional cardiovascular risk factors solely explain intima-media thickening in youth with type 1 diabetes?

J Diabetes Complications 2016 08 31;30(6):1137-43. Epub 2016 Mar 31.

Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, Netherlands.

Aims: The aim of this study was to assess age-specific carotid intima-media thickness (cIMT) in children and adolescents with type 1 diabetes and to investigate associations between cIMT, age, classical cardiovascular disease (CVD) and other risk factors.

Methods: This study included a cross-sectional analysis of cIMT in 178 patients with type 1 diabetes and 208 healthy controls across age categories. In patients, the impact of gender, socio-economic status, ethnicity, current and historical body mass index, blood pressure, hemoglobin A1c, high-density lipoprotein, and low-density lipoprotein cholesterol on cIMT was studied in a retrospective follow-up cohort study.

Results: Median cIMT was equally greater in patients versus controls across all age categories (P≤0.03). Regression models in patients confirmed a lack of association between cIMT and classical CVD risk factors.

Conclusions: Children and adolescents with type 1 diabetes showed greater cIMT than controls in all age categories. Increased cIMT did not seem to be consistently associated with classical adult CVD risk factors, adding to the current debate in pediatrics about the impact on classical CVD risk factors to the development of subclinical atherosclerosis in type 1 diabetes. Future studies are warranted to determine if cIMT could assist in predicting macrovascular complications of type 1 diabetes.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.03.030DOI Listing
August 2016

The relationship between parenting stress and parent-child interaction with health outcomes in the youngest patients with type 1 diabetes (0-7 years).

Eur J Pediatr 2016 Mar 5;175(3):329-38. Epub 2015 Oct 5.

Center of Research on Psychology in Somatic diseases (CoRPS), Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands.

Unlabelled: To test whether parenting stress and the quality of parent-child interaction were associated with glycemic control and quality of life (QoL) in young children (0-7 years) with type 1 diabetes (T1DM), we videotaped 77 families with a young child with T1DM during mealtime (including glucose monitoring and insulin administration). Parent-child interactions were scored with a specifically designed instrument. Questionnaires assessed general and disease-related parenting stress and (diabetes-specific (DS)) QoL. HbA(1c) (glycemic control) was extracted from the medical records. Both general and disease-related parenting stress were associated with a lower (DS)QoL (r ranged from -0.39 to -0.70, p < 0.05), but not with HbA(1c) levels. Furthermore, with regard to the parent-child interaction, emotional involvement of parents (r = 0.23, p < 0.05) and expressed discomfort of the child (r = 0.23, p < 0.05) were related to suboptimal HbA(1c) levels. There was no clear pattern in the correlations between parent-child interaction and (DS)QoL.

Conclusion: The results support the notion that diabetes does not only affect the child with T1DM: T1DM is a family disease, as parenting factors (like stress and parent-child interactions) are associated with important child outcomes. Therefore, it is important for health-care providers to not only focus on the child with T1DM, but also on the family system.
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http://dx.doi.org/10.1007/s00431-015-2631-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757610PMC
March 2016

Diabetes IN develOpment (DINO): the bio-psychosocial, family functioning and parental well-being of youth with type 1 diabetes: a longitudinal cohort study design.

BMC Pediatr 2015 Jul 15;15:82. Epub 2015 Jul 15.

Department of Medical Psychology, VU University Medical Center, De Boelenlaan 1117, 1081, HV, Amsterdam, The Netherlands.

Background: Strict glycemic control during adolescence decreases the risk of developing complications later in life, even if this level of control is not maintained afterwards. However, the majority of adolescents with type 1 diabetes (T1D) are in poor control and so far medical or psychological interventions have shown limited success. Adolescence is characterized by major biological, psychosocial, cognitive and parent-child relationship changes and the complex interaction between these developmental trajectories, and its impact on health outcomes is still poorly understood. A specific topic of interest in this context is the timing of diagnosis. The longitudinal study DINO (Diabetes IN develOpment) aims to examine: 1) If and how the onset of T1D before vs. during puberty results in different outcomes of glycemic control, self-management, psychological functioning and diabetes-related quality of life. 2) The timing of onset of disturbed eating behavior, its risk factors and its prospective course in relation to glycemic and psychological consequences. 3) If and how the onset of T1D before vs. during puberty results in different family functioning and parental well-being. 4) If and how the cognitive development of youth with T1D relates to glycemic control and diabetes self-management.

Methods/design: DINO, a longitudinal multi-center cohort study is conducted in youth with T1D in the age range 8-15 years at baseline. Participants will be divided into two subgroups: pre-pubertal and pubertal. Both groups will be followed for 3 years with assessments based on a bio-psychosocial model of diabetes, scheduled at baseline, 12 months, 24 months and 36 months examining the biological, psychosocial -including disturbed eating behaviors- and cognitive development, family functioning and parental well-being.

Discussion: A better understanding of how the different trajectories affect one another will help to gain insight in the protective and risk factors for glycemic outcomes and in who needs which support at what moment in time. First results are expected in 2016.
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http://dx.doi.org/10.1186/s12887-015-0400-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502615PMC
July 2015

Comment on Malik. Which test for diagnosing early human diabetic neuropathy? Diabetes 2014;63:2206-2208.

Diabetes 2015 Feb;64(2):e1

Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, the Netherlands.

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http://dx.doi.org/10.2337/db14-1472DOI Listing
February 2015

Achilles tendons in people with type 2 diabetes show mildly compromised structure: an ultrasound tissue characterisation study.

Br J Sports Med 2015 Aug 13;49(15):995-9. Epub 2015 Jan 13.

MOVEFIT-Sports Medicine, Department of Rehabilitation Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background: Musculotendinous overuse injuries are prevalent in people with type 2 diabetes. Non-enzymatic glycosylation of collagen resulting in tendon stiffening may play a role. In this case-control study we determined whether patients with diabetes had poorer ultrasonographic structure in their Achilles tendons compared to age-matched controls.

Methods: People with type 1 diabetes or type 2 diabetes, and age-matched controls, had computerised ultrasound tissue characterisation of both Achilles tendons. In contiguous ultrasonographic images of the tendon, echopatterns were quantified and categorised into four echo-types. Tendon abnormality was quantified as sum of echo-types III+IV. Furthermore, skin autofluorescence (AF) of the forearm (AF-value) was gathered.

Results: Twenty four type 2 diabetes patients, 24 controls, 24 type 1 diabetes patients and 20 controls were included. AF-value was higher in type 1 diabetes (1.55±0.17) than in their controls (1.39±0.18, p<0.001) and in type 2 diabetes (2.28±0.38) compared to their controls (1.84±0.32, p<0.001) Achilles tendons of type 2 diabetes patients contained more echo-types III+IV (14.1±7.9%) than matched controls (8.0±5.4%, p<0.001). There was a trend towards a difference in echo-types III+IV between type 1 diabetes patients (9.5±5.3%) and their controls (6.5±3.7%, p=0.055). In a stepwise linear regression analysis, body mass index (BMI) was moderately associated with tendon abnormality in patients with diabetes and controls (β=0.393, p<0.001).

Conclusions: Type 2, and possibly type 1, diabetes patients showed poorer ultrasonographic Achilles tendon structure that may be a risk factor for tendinopathy. Although markers for accumulation of advanced glycation end products were elevated in both diabetes populations, only BMI was associated with these abnormalities.

Trial Registration Number: NTR2209.
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http://dx.doi.org/10.1136/bjsports-2014-093696DOI Listing
August 2015

ISPAD Clinical Practice Consensus Guidelines 2014. Other complications and diabetes-associated conditions in children and adolescents.

Pediatr Diabetes 2014 Sep;15 Suppl 20:270-8

Diabetes Centre for Children and Adolescents, Children's Hospital auf der Bult, Hannover, Germany.

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http://dx.doi.org/10.1111/pedi.12183DOI Listing
September 2014

Qualitative observation instrument to measure the quality of parent-child interactions in young children with type 1 diabetes mellitus.

BMC Pediatr 2014 Jun 10;14:145. Epub 2014 Jun 10.

Center of Research on Psychology in Somatic diseases (CoRPS), Department of Medical and Clinical Psychology, Tilburg University, PO Box 90153, Tilburg LE 5000, The Netherlands.

Background: In young children with type 1 diabetes mellitus (T1DM), parents have complete responsibility for the diabetes-management. In toddlers and (pre)schoolers, the tasks needed to achieve optimal blood glucose control may interfere with normal developmental processes and could negatively affect the quality of parent-child interaction. Several observational instruments are available to measure the quality of the parent-child interaction. However, no observational instrument for diabetes-specific situations is available. Therefore, the aim of the present study was to develop a qualitative observation instrument, to be able to assess parent-child interaction during diabetes-specific situations.

Methods: First, in a pilot study (n = 15), the observation instrument was developed in four steps: (a) defining relevant diabetes-specific situations; (b) videotaping these situations; (c) describing all behaviors in a qualitative observation instrument; (d) evaluating usability and reliability. Next, we examined preliminary validity (total n = 77) by testing hypotheses about correlations between the observation instrument for diabetes-specific situations, a generic observation instrument and a behavioral questionnaire.

Results: The observation instrument to assess parent-child interaction during diabetes-specific situations, which consists of ten domains: "emotional involvement", "limit setting", "respect for autonomy", "quality of instruction", "negative behavior", "avoidance", "cooperative behavior", "child's response to injection", "emphasis on diabetes", and "mealtime structure", was developed for use during a mealtime situation (including glucose monitoring and insulin administration).

Conclusions: The present study showed encouraging indications for the usability and inter-rater reliability (weighted kappa was 0.73) of the qualitative observation instrument. Furthermore, promising indications for the preliminary validity of the observation instrument for diabetes-specific situations were found (r ranged between |.24| and |.45| for significant correlations and between |.10| and |.23| for non-significant trends). This observation instrument could be used in future research to (a) test whether parent-child interactions are associated with outcomes (like HbA1c levels and psychosocial functioning), and (b) evaluate interventions, aimed at optimizing the quality of parent-child interactions in families with a young child with T1DM.
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http://dx.doi.org/10.1186/1471-2431-14-145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086281PMC
June 2014

Assessing diabetes-related quality of life of youth with type 1 diabetes in routine clinical care: the MIND Youth Questionnaire (MY-Q).

Pediatr Diabetes 2012 Dec;13(8):638-46

Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands.

Aim: It is recommended to assess health-related quality of life (HRQoL) in teenagers with diabetes as part of their ongoing medical care. Here, we describe the development and psychometric evaluation of the Monitoring Individual Needs in Diabetes Youth Questionnaire (MY-Q), a multi-dimensional self-report HRQoL questionnaire designed for use in pediatric diabetes care.

Design And Methods: In expert meetings, characteristics and domains of interest were defined. Existing questionnaires were reviewed, topics selected, and new items added, resulting in the 36-item MY-Q. To test face validity, we interviewed 22 teenagers. In addition, 84 teenagers with type 1 diabetes (age 10-18 yr) completed the MY-Q and Pediatric Quality of Life Inventory (PedsQL) generic and diabetes-modules to examine psychometric properties. Hemoglobin A1c (HbA1c) values were obtained by chart audit.

Results: The MY-Q consists of seven subscales (social impact, parents, diabetes control perceptions, responsibility, worries, treatment satisfaction, and body image and eating behavior) as well as general HRQoL and emotional well-being. Cronbach's alpha for the total scale was 0.80. Strong correlations between MY-Q total and PedsQL generic and diabetes-module scores (r = 0.58 and r = 0.71, p < 0.001) confirmed concurrent validity. Higher HbA1c was associated with lower diabetes control perceptions (r = -0.35, p = 0.001), worries (r = -0.24, p = 0.029), and body image and eating behavior (r = -0.26, p = 0.019) scores. Younger age was associated with higher diabetes control perceptions (r = -0.26, p = 0.020) and body image and eating behavior (r = -0.23, p = .038), and lower responsibility (r = 0.25, p = 0.027) scores.

Conclusion: The MY-Q is the first HRQoL questionnaire designed for use in clinical care. It has acceptable measurement properties and seems suitable for implementation in routine care of teenagers with diabetes.
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http://dx.doi.org/10.1111/j.1399-5448.2012.00872.xDOI Listing
December 2012

Quality of life of children with type 1 diabetes: a systematic review.

Curr Diabetes Rev 2012 Nov;8(6):434-43

Developmental Psychology/Tilburg University, Room number: P 707, P.O. Box 90153, 5000 LE Tilburg, The Netherlands.

Introduction: Children with type 1 diabetes mellitus (T1DM) have to deal with a complex and demanding daily treatment regime which can have a negative impact on the quality of life (QoL) of these patients. The objective of the present study is to review studies that have compared generic quality of life of children and adolescents with T1DM with that of healthy peers. In addition, we will examine whether QoL differs between boys and girls, and across different developmental stages.

Methods: A systematic literature search using PubMed was conducted for the years 2000 through May 2012. 17 studies were eligible for the current review. Effect sizes were computed to estimate the effects of having T1DM on QoL in children and adolescents.

Results: Although individual studies reported small to moderate effect sizes on the distinct QoL-domains, the weighted effect sizes across all studies indicated no differences in QoL-domains between children and adolescents with T1DM and healthy controls. However, disease-specific problems were certainly present. Girls with T1DM reported lower generic and disease-specific QoL than boys with T1DM. Relationships between age and generic or disease-specific QoL remained unclear.

Conclusions: Although children and adolescents with T1DM have to live with a demanding treatment regime, overall results revealed that their generic QoL is not impaired compared to healthy peers. However, disease-specific QoL problems, including a negative impact of diabetes on daily functioning, and diabetes-related worries were certainly present. Longitudinal research is needed in order to provide tailored care for children of all ages with T1DM.
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http://dx.doi.org/10.2174/157339912803529850DOI Listing
November 2012

[Metformin in adolescents and adults with type 1 diabetes mellitus: not evidence-based].

Ned Tijdschr Geneeskd 2011 ;155(39):A3166

Isala Klinieken, Diabetescentrum, Zwolle, the Netherlands.

Objective: Adolescents with type 1 diabetes mellitus (DM1) often have problems in achieving optimal glycaemic control. We investigated whether there is evidence of the beneficial effect of the addition of metformin to insulin therapy in adolescents with DM1.

Design: Systematic literature study.

Method: Medline and Embase were searched for randomised double-blind trials in adolescents with DM1 up to May 2011 inclusive. Two reviewers selected relevant articles based on title, summary and, if necessary, the full text. The quality of the methodology was also assessed.

Results: We found 2 studies in adolescents, of limited scope and duration. On this basis, it was decided that the search of the literature should be extended to adults with DM1, whereby 4 studies were found. All six trials were of good methodological quality, and included 196 patients in total. Clinical and statistical heterogeneity precluded pooling the results in a meta analysis. In one study in adolescents metformin treatment showed a reduction of HbA1c by 0.6% (95% CI: -1.16-0.04) and a slight decrease in daily total insulin dose. However, the treatment groups were not comparable at baseline. In the other studies, no significant changes in HbA1c were found. All studies showed decreased daily insulin dose; in four studies this was significant. Two studies showed a beneficial effect on weight or BMI. No serious side effects were recorded. One study showed an increase in hypoglycaemic episodes during metformin treatment.

Conclusion: The possible benefit of adding metformin to insulin in adolescents and adults with type 1 diabetes remains unclear. A well-designed double-blind randomised trial carried out over a longer time period is required to assess whether metformin is of added value.
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December 2011

Quality of the parent-child interaction in young children with type 1 diabetes mellitus: study protocol.

BMC Pediatr 2011 Apr 14;11:28. Epub 2011 Apr 14.

Center of Research on Psychology in Somatic diseases [CoRPS], Department of Medical Psychology and Neuropsychology, Tilburg University, Tilburg, the Netherlands.

Background: In young children with type 1 diabetes mellitus (T1DM) parents have full responsibility for the diabetes-management of their child (e.g. blood glucose monitoring, and administering insulin). Behavioral tasks in childhood, such as developing autonomy, and oppositional behavior (e.g. refusing food) may interfere with the diabetes-management to achieve an optimal blood glucose control. Furthermore, higher blood glucose levels are related to more behavioral problems. So parents might need to negotiate with their child on the diabetes-management to avoid this direct negative effect. This interference, the negotiations, and the parent's responsibility for diabetes may negatively affect the quality of parent-child interaction. Nevertheless, there is little knowledge about the quality of interaction between parents and young children with T1DM, and the possible impact this may have on glycemic control and psychosocial functioning of the child. While widely used global parent-child interaction observational methods are available, there is a need for an observational tool specifically tailored to the interaction patterns of parents and children with T1DM. The main aim of this study is to construct a disease-specific observational method to assess diabetes-specific parent-child interaction. Additional aim is to explore whether the quality of parent-child interactions is associated with the glycemic control, and psychosocial functioning (resilience, behavioral problems, and quality of life).

Methods/design: First, we will examine which situations are most suitable for observing diabetes-specific interactions. Then, these situations will be video-taped in a pilot study (N = 15). Observed behaviors are described into rating scales, with each scale describing characteristics of parent-child interactional behaviors. Next, we apply the observational tool on a larger scale for further evaluation of the instrument (N = 120). The parents are asked twice (with two years in between) to fill out questionnaires about psychosocial functioning of their child with T1DM. Furthermore, glycemic control (HbA1c) will be obtained from their medical records.

Discussion: A disease-specific observational tool will enable the detailed assessment of the quality of diabetes-specific parent-child interactions. The availability of such a tool will facilitate future (intervention) studies that will yield more knowledge about impact of parent-child interactions on psychosocial functioning, and glycemic control of children with T1DM.
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http://dx.doi.org/10.1186/1471-2431-11-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098161PMC
April 2011

Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection.

Viral Immunol 2010 Feb;23(1):99-104

Department of Medical Microbiology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.

Previous studies have shown that enteroviral RNA can be detected in blood at the onset of type 1 diabetes (T1D). The infection may play a role in triggering T1D and genetic host factors may contribute to this process. We investigated (1) whether enterovirus is present at the onset of T1D in peripheral blood mononuclear cells (PBMC), plasma, throat, or stool, and (2) whether enteroviral presence is linked with HLA-DR type and/or polymorphisms in melanoma differentiation-associated gene 5 (MDA5) and 2'-5' oligoadenylate synthetase 1 (OAS1), factors of antiviral immunity. To this end, PBMC, plasma, throat, and stool samples from 10 T1D patients and 20 unrelated controls were tested for the presence of enteroviruses (RT-PCR), for HLA-DR type, and polymorphisms in MDA5 and OAS1. Enterovirus RNA was detected in PBMC of 4/10 T1D patients, but none of 20 controls. Plasma was positive in 2/10 T1D patients and none of 20 controls, suggesting that enteroviruses found at the onset of T1D are mainly present in PBMC. All throat samples from positive T1D patients were virus-negative and only 1 fecal sample was positive. The negative results for all throat and most stool samples argues against acute infection. Enterovirus presence was linked with HLA-DR4, but not with polymorphisms in MDA5 or OAS1.
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http://dx.doi.org/10.1089/vim.2009.0072DOI Listing
February 2010
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