Motivational interviewing from the paediatricians' perspective: assessments after a 2-day training for physicians caring for adolescents with chronic medical conditions (CMCs).

BACKGROUND: Counselling adolescents with chronic medical conditions (CMCs) can be challenging regarding suitable interviewing skills and clinicians' attitudes toward the patient. Successful communication can be a key element of treatment. Motivational Interviewing (MI) is broadly applicable in managing behavioural problems and diseases by increasing patient motivation for lifestyle changes. However, data concerning the applicability, feasibility and implementation of MI sessions in everyday practice are missing from the physicians' point of view. METHOD: The present study was conducted as a mixed methods design. Twenty paediatricians were randomized to a 2-day MI course followed by MI consultations. Data were collected through a questionnaire one year after MI training. Factors for effective training and possible barriers to successful use of MI were examined. RESULTS: Completed questionnaires were returned by 19 of 20 paediatricians. The paediatricians' experiences with MI demonstrate that MI is regarded as a valuable tool when working with adolescents with CMCs. 95% of all respondents reported that they found MI education necessary for their clinical work and were using it also outside the COACH-MI study context. 73.7% percent saw potential to strengthen the connection to their patients by using MI. The doctors were already using more MI conversation techniques after a 2-day MI course. Obstacles were seen in the short training, the lack of time and missing undisturbed environment (interruptions by telephone, staff, etc.) during clinical flow. CONCLUSIONS: MI techniques are not yet a regular part of medical training. However, a 2-day MI course was rated effective and provided a lasting impact by physicians caring for children and adolescents with chronic medical conditions (CMCs), although booster sessions should be offered regularly. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00014043) on 26/04/2018.

Interleukin-7 and soluble Interleukin-7 receptor levels in type 1 diabetes - Impact of IL7RA polymorphisms, HLA risk genotypes and clinical features.

High soluble IL-7 receptor (sIL-7R) serum levels and associated single nucleotide polymorphisms in the IL7RA gene were found in autoimmune diseases including type 1 diabetes. Further determinants on sIL-7R and IL-7 availability as well as changes during type 1 diabetes disease course remain elusive. Here we performed multiparameter analysis to identify influential genetic and disease-associated factors on sIL-7R and IL-7 serum levels during type 1 diabetes disease course (239 children) and in healthy controls (101 children). We found higher sIL-7R serum concentrations at type 1 diabetes onset and decreasing levels during therapy whereas IL-7 was only higher in long term patients as compared to controls. Multiple linear regression analyses revealed several factors, including IL7RA SNP rs6897932 and HLA risk haplotypes, influencing sIL-7R levels but not IL-7, which was solely associated with the sIL-7R. This study revealed unexpected complexity in the regulation of the sIL-7R but not for IL-7.

Interleukin-7-dependent nonclassical monocytes and CD40 expression are affected in children with type 1 diabetes.

The important role of IL-7 in the generation of self-reactive T-cells in autoimmune diseases is well established. Recent studies on autoimmunity-associated genetic polymorphisms indicated that differential IL-7 receptor (IL-7R) expression of monocytes may play a role in the underlying pathogenesis. The relevance of IL-7-mediated monocyte functions in type 1 diabetes remains elusive. In the present study, we characterized monocyte phenotype and IL-7-mediated effects in children with type 1 diabetes and healthy controls with multicolor flow cytometry and t-distributed Stochastic Neighbor-Embedded (t-SNE)-analyses. IL-7R expression of monocytes rapidly increased in vitro and was boosted through LPS. In the presence of IL-7, we detected lower monocyte IL-7R expression in type 1 diabetes patients as compared to healthy controls. This difference was most evident for the subset of nonclassical monocytes, which increased after IL-7 stimulation. t-SNE analyses revealed IL-7-dependent differences in monocyte subset distribution and expression of activation and maturation markers (i.e., HLA-DR, CD80, CD86, CD40). Notably, monocyte CD40 expression increased considerably by IL-7 and CD40/IL-7R co-expression differed between patients and controls. This study shows the unique effects of IL-7 on monocyte phenotype and functions. Lower IL-7R expression on IL-7-induced CD40high monocytes and impaired IL-7 response characterize monocytes from patients with type 1 diabetes.

CD5-expressing CD8+ T-cell subsets differ between children with type 1 diabetes and controls.

Different lymphocyte subsets are involved in autoimmune pathogenesis of type 1 diabetes (T1D). Previous studies suggested a role of CD5-expressing T and B cells including rare unconventional lymphocytes with combined T- and B-cell features [dual expressing (DE) cells]. We performed algorithm-supported multiparameter flow cytometry and quantitative PCR to investigate immune cell subsets and DE cells in children with T1D (n = 20) and matched controls (n = 20). Comparisons of conventional immune cells detected increased proportions of CD3+ T cells in T1D patients, whereas CD19+ B-cell proportions were comparable to controls. Self-organizing maps for flow cytometry analyses (FlowSOM) showed highly similar CD5-expressing B-cell subsets and no differences for DE cells were detected between the study groups by flow cytometry or specific quantitative PCR. Notably, differences in CD8+ T cells were indicated by FlowSOM and similarity-based t-distributed stochastic neighbor embedding (tSNE) analyses. Study group comparisons confirmed significantly reduced CD8+ T-cell proportions with moderate or low CD5 expression in T1D patients. Finally, in vitro experiments showed stable CD5 expression differences of CD8+ T cells after T-cell activation, cytokine stimulation and culture. We observed differences of T-cell coreceptor CD5 expression in T1D patients with potential relevance for immune regulation of CD8+ T-cell activation.

Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes.

BACKGROUND: Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. METHODS: We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). RESULTS: We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. CONCLUSIONS: Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.

Dominant TNFα and impaired IL-2 cytokine profiles of CD4+ T cells from children with type-1 diabetes.

Aberrantly activated CD4+ T memory cells play a central role in the development of type-1-diabetes. Interleukin-7 promotes generation of autoimmune memory T cells and increased Interleukin-7 availability is associated with type-1-diabetes susceptibility. T-cell-mediated immune pathology at onset of type-1-diabetes is well defined, but characteristics of long-term symptomatic disease stages remain largely elusive. In the present study, memory CD4+ T-cell activation and cytokine expression as well as sensitivity to Interleukin-7 in vitro were compared between patients with type-1-diabetes at clinical onset (n=25), long-term symptomatic disease (median duration 4.5 years, n=19) and matched healthy controls (n=21). T-cell responses of type-1-diabetes patients were characterized by higher frequencies of cytokine and activation marker expressing CD4+ memory T cells as compared to healthy controls. Notably, correction for individual cytokine expression levels revealed qualitative differences of cytokine profiles characterized by significantly increased TNFα and decreased IL-2-expressing T-cell proportions in long-term type-1-diabetes patients. IL-7-mediated T-cell co-stimulation induced quantitative and qualitative cytokine expression differences highly similar to type-1-diabetes-specific profiles. In addition, CD4+ memory T cells from children with long-term type-1-diabetes were more sensitive to in vitro IL-7 co-stimulation. Global transcriptome analysis revealed IL-7 induced expression differences of CD4+ T cells, including increased IL-2R expression and effects on subsequent T-cell receptor activation. We conclude that long-term symptomatic type-1-diabetes patients differed in memory T-cell cytokine profiles and Interleukin-7 co-stimulation. Regulation of IL-2 expression and sensitivity are affected with possible consequences for disease course and severity at long-term type-1-diabetes stages.

Graves' disease in children with Down syndrome.

While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves' disease (GD) is rare (ranges 0.6-3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients' medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51-4.30), free triiodothyronine, free thyroxine (mean ± s.d .), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5-8.1), 50.2 ± 18.7 pmol/L (NR 12.6-20.9), and 17.0 (2.89-159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was 'block and replace' in ten patients and 'dose titration' in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.

The Impact of COVID-19 Pandemic on Mental Health of Adolescents With Chronic Medical Conditions: Findings From a German Pediatric Outpatient Clinic.

PURPOSE: The impact of the COVID-19 pandemic on the mental health of adolescents is of great concern, especially in the vulnerable group of adolescents with chronic medical conditions. The aim of this study was to examine this impact on the mental health of adolescents with chronic medical conditions treated in a German pediatric outpatient clinic. METHODS: Changes in the mental health status of adolescents with chronic medical conditions treated in a German pediatric outpatient clinic during the COVID-19 pandemic were explored via validated screening tools for anxiety and depression. RESULTS: The relative risk for adolescents with chronic medical conditions to develop clinically relevant symptoms of anxiety or depression was significantly higher (odds ratio 1,78 [confidence interval 1.06-3.04]) during the pandemic. DISCUSSION: This study identifies the COVID-19 pandemic as a potential additional risk for adolescents with chronic medical conditions to develop clinically relevant signs of anxiety or depression.

Subjective burden of government-imposed Covid-19 restrictions in Switzerland: Evidence from the 2022 LINK Covid-19 survey.

BACKGROUND: While a large literature has quantified the health and economic impact of COVID-19, estimates on the subjective losses in quality of life due to government imposed restrictions remain scarce. METHODS: We conducted a nationally representative online survey in Switzerland in February 2022 to measure average self-reported quality of life with government restrictions. We used a discrete choice experiment to compute average willingness to pay for avoiding specific restrictions and time-trade-off questions to quantify the relative quality of life under restrictions. RESULTS: A total of 1299 Swiss residents completed the online survey between February 9th and 15th, 2022. On average, respondents valued life under severe restrictions at 39% of their usual life (estimated relative utility 0.39 [0.37, 0.42]). Willingness to pay for avoiding restrictions was lowest for masks (CHF 663 [319, 1007]), and highest for schools and daycares (CHF 4123 [3443, 4803]) as well as private parties (CHF 4520 [3811, 5229]). We estimate that between March 2020 and February 2022 a total of 5.7 Million QALYs were lost due to light, moderate and severe restrictions imposed by the governments. CONCLUSIONS: The quality of life losses due to government restrictions are substantial, particularly when it comes to the closure of schools and daycares, as well as the prohibition of private gatherings. Future policies should weigh these costs against the health benefits achievable with specific measures.

Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype.

The highest genetic type 1 diabetes risk is conferred by HLA class II haplotypes defined by alleles at the HLA-DR and -DQ loci. The combination of HLA-DQA1*03:01 and DQB1*03:02 alleles (summarized as 'HLA-DQ8') is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. This classification is based on conventional genotyping of exon 2 of the DQ gene locus and excludes exon 3. In this study, HLA genotyping on the type 1 diabetes susceptibility loci HLA-DRB1, DQA1 and DQB1 was performed using a high-resolution next generation sequencing method. In addition to the routinely examined exon 2, exon 3 was also sequenced. Samples from 229 children with type 1 diabetes were included and compared to a cohort of 9,786 controls. In addition to previously described HLA-DQ haplotypes in type 1 diabetes patients, we found that as well as HLA-DQA1*03:01,HLA-DQA1*03:03 also contributed to HLA-DQ8. HLA-DQA1*03:03 differs from HLA-DQA1*03:01 by one nucleotide substitution in exon 3 at position 160, leading to a single amino acid replacement. DRB1*04:05 was exclusively associated with DQA1*03:03 whereas the DRB1*04:01 haplotype comprised either DQA1*03:01 or DQA1*03:03. Significantly increased type 1 diabetes risk was confirmed for all these haplotypes with only minor differences between DQA1*03:01 and DQA1*03:03 alleles. This study identified the HLA-DQA1*03:03 allele as an addition to the already known type 1 diabetes risk haplotypes, and can contribute to more precise HLA genotyping approaches.

Motivational Interviewing as a tool to enhance access to mental health treatment in adolescents with chronic medical conditions and need for psychological support (COACH-MI): study protocol for a clusterrandomised controlled trial.

BACKGROUND: This cluster-randomised monocentric controlled trial focuses on improving the uptake symptoms of mental health care in adolescents with chronic medical conditions who have been identified by screening to have depression or anxiety. The study aims to determine the efficacy of motivational interviewing (MI) delivered by trained physicians to increase 12- to 20-year-old adolescents' utilisation of psychological health care for symptoms of anxiety or depression. METHODS/DESIGN: In this single-centre approach, n = 1,000 adolescents will be screened (using PHQ-9 and GAD-7), and adolescents with results indicative of anxiety or depressive symptoms (n = 162) will be advised to seek psychological health care in clusters from treating physicians in specialised outpatient departments. Participants who screen positive will receive either two sessions of MI or treatment as usual (TAU; regarded as the typical daily clinical practice), which is focused on recommending them to seek psychological health care for further evaluation. MI efficacy will be compared to the current TAU as the control condition. The primary outcome is the utilisation rate of psychological health care after counselling by an MI-trained physician vs. an untrained physician. Additionally, reasons for not claiming psychological support and changes in disease-related parameters will be evaluated in a 6-month follow-up session. DISCUSSION: This trial will evaluate the feasibility of MI as a way to improve the utilisation of mental health-care services by adolescents who need further support other than that provided by standard care for chronic diseases. Physicians offering MI to adolescents may serve as a model for optimising health-care management in daily clinical practice, which may improve adolescents' long-term well-being by improving adherence to medical treatment and preventing negative lifelong consequences into adulthood. TRIAL REGISTRATION: German Trials Register (DRKS), DRKS00014043 . Registered on 26 April 2018. Düsseldorf University study ID: 2017114504.