Early increase in HbA1c trajectory predicts development of severe microangiopathy in patients with type 1 diabetes: the VISS study.

INTRODUCTION: To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. RESEARCH DESIGN AND METHODS: In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). RESULTS: After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. CONCLUSIONS: The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR.

Impact of HbA1c Followed 32 Years From Diagnosis of Type 1 Diabetes on Development of Severe Retinopathy and Nephropathy: The VISS Study.

OBJECTIVE: To evaluate HbA1c followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS: In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA1c (wHbA1c) was calculated by integrating the area under all HbA1c values. Complications were analyzed in relation to wHbA1c categorized into five levels. RESULTS: After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA1c did not develop PDR or macroalbuminuria. The lowest wHbA1c values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA1c, being 74% and 44% in the highest category, wHbA1c >9.5% (>80 mmol/mol). In comparison with the follow-up done after 20-24 years' duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA1c values. CONCLUSIONS: wHbA1c followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA1c <7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.

Impact of Age of Onset, Puberty, and Glycemic Control Followed From Diagnosis on Incidence of Retinopathy in Type 1 Diabetes: The VISS Study.

OBJECTIVE: To evaluate sex, age at diabetes onset, puberty, and HbA1c, with subjects followed from diabetes diagnosis and during different time periods, as risk factors for developing diabetic simplex and proliferative retinopathy. RESEARCH DESIGN AND METHODS: In a population-based observational study, HbA1c for 451 patients diagnosed with diabetes before 35 years of age during 1983-1987 in southeast Sweden was followed for up to 18-24 years from diagnosis. Long-term mean weighted HbA1c (wHbA1c) was calculated. Retinopathy was evaluated by fundus photography and analyzed in relation to wHbA1c levels. RESULTS: Lower wHbA1c, diabetes onset ≤5 years of age, and diabetes onset before puberty, but not sex, were associated with longer time to appearance of simplex retinopathy. Proliferative retinopathy was associated only with wHbA1c. The time to first appearance of any retinopathy decreased with increasing wHbA1c. Lower wHbA1c after ≤5 years' diabetes duration was associated with later onset of simplex retinopathy but not proliferative retinopathy. With time, most patients developed simplex retinopathy, except for those of the category wHbA1c ≤50 mmol/mol (6.7%), for which 20 of 36 patients were without any retinopathy at the end of the follow-up in contrast to none of 49 with wHbA1c >80 mmol/mol (9.5%). CONCLUSIONS: Onset at ≤5 years of age and lower wHbA1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy. There is a strong positive association between long-term mean HbA1c measured from diagnosis and up to 20 years and appearance of both simplex and proliferative retinopathy.

Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden).

OBJECTIVE: HbA1c is strongly related to the development of diabetes complications, but it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of the current study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. RESEARCH DESIGN AND METHODS: A longitudinal observation study followed an unselected population of 451 patients diagnosed with type 1 diabetes during 1983-1987 before the age of 35 years in a region of Southeast Sweden. Retinopathy was evaluated by fundus photography and nephropathy data collected from medical records. HbA1c was measured starting from diagnosis and during the whole follow-up period of 20-24 years. Long-term weighted mean HbA1c was then calculated. Complications were analyzed in relation to HbA1c levels. RESULTS: The incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. CONCLUSIONS: Long-term weighted mean HbA1c, measured from diagnosis, is closely associated with the development of severe complications in type 1 diabetes. Keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years.

Family-based behavioural intervention program for obese children: an observational study of child and parent lifestyle interpretations.

BACKGROUND: Family-based behavioural intervention programs (FBIPs) against childhood obesity have shown promising results, but the mediating mechanisms have not been identified. The aim of this study was to examine changes in obese childrens lifestyle habits during a 2-year FBIP according to their own and parents' reports, the concordance between these reports and the correlations to change in post-intervention z-BMI. METHODS: An observational study of 26 children (8.3-12.0 years) and their parents participating in a 2-year FBIP was performed. Weight and height were measured from baseline to 12 months after the end of the program. Eating habits and physical- and sedentary activity were reported separately by children and parents. Data were analysed with regard to concordance between parents' and children's reports and association between the lifestyle reports and change in z-BMI at the study endpoint using descriptive statistics and parametric and non-parametric tests. RESULTS: According to both children's and parents' reports, the level of physical activity among the children had increased after the intervention as well as the agreement between the informants' reports. According to the children, eating habits had improved, while the parents' reports showed an improvement only with regard to binge eating. The concordance between children and parents regarding eating habits was slight to fair also after the intervention. No statistically significant associations between changes in lifestyle reports and changes in z-BMI were observed. CONCLUSIONS: Child and parent reports of physical activity were found to converge and display an improvement in a 2-year FBIP, while the reports on eating habits showed a more refractory pattern. Changes in concordance and agreement between children and parents reports did not correlate with weight reduction. Further methods development and studies of the processes during family-based interventions against childhood obesity are warranted.

As Facts and Chats Go Online, What Is Important for Adolescents with Type 1 Diabetes?

BACKGROUND: Continued refinement of resources for patient information, education and support is needed. Considering the rapid development of new communication practices, the perspectives of young people themselves warrant more attention using a wide research focus. The purpose of this study was to understand information-seeking behaviours, Internet use and social networking online in adolescents with type 1 diabetes (T1DM). This applied to their everyday life, including the context of diabetes and their experiences and need of contact with T1DM peers. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-four adolescents aged 10-17 years with T1DM were recruited from a county hospital in the south-east of Sweden. Qualitative data were obtained using eight focus groups, wherein each participant engaged in a 60-90 minute video/audio-recorded session. The focus group data were transcribed and analysed using qualitative content analysis. Some demographic and medical information was also collected. The three main categories that were identified; Aspects of Security, Updating, and Plainness and their sub-categories gave significant information about how to enhance information retrieval and peer contacts related to T1DM. Regarding the persons' information-seeking behaviour, Internet use, and use of social media some differences could be identified depending on gender and age. CONCLUSIONS/SIGNIFICANCE: Sensitivity and adaptation to users' needs and expectations seem crucial in the development of future online resources for adolescents with T1DM. To start with, this could mean applying a wider range of already existing information and communication technologies. Health practitioners need to focus on the areas of security of information and communication, frequency of updating, and simplicity of design-less is more.

Parents of adolescents with type 1 diabetes--their views on information and communication needs and internet use. A qualitative study.

BACKGROUND: Little is known about parents' views on the use of online resources for information, education and support regarding childhood type 1 diabetes (T1DM). Considering the rapidly evolving new communication practices, parents' perspectives need to be explored. The main purpose of this paper was to explore parents' perceptions of their information-seeking, Internet use, and social networking online. This applied to their everyday life, including the contexts of T1DM and contact with peers. A second aim was to identify implications for future development of Internet use in this respect. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-seven parents of 24 young persons aged 10-17 with T1DM participated in eight focus group interviews during their regular visits to a county hospital. Focus group discussions were video/audio-taped, transcribed and analysed using inductive qualitative content analysis. Self-reported demographic and medical information was also collected. A main theme was Finding things out, including two sub-themes, Trust and Suitability. The latter were key factors affecting parents' perceptions of online resources. Parents' choice of information source was related to the situation, previous experiences and knowledge about sources and, most importantly, the level of trust in the source. A constantly present background theme was Life situation, including two sub-themes, Roles and functions and Emotions and needs. Parents' information-seeking regarding T1DM varied greatly, and was closely associated with their life situation, the adolescents development phases and the disease trajectory. CONCLUSIONS/SIGNIFICANCE: Health practitioners and system developers need to focus on creating trust and suitability for users' needs. They should understand the children's diverse needs, which depend on their life situation, on the children's development, and on the disease trajectory. To enhance trust in online health information and support services, the participation of local practitioners is crucial.

Long-term clinical outcome after Lyme neuroborreliosis in childhood.

OBJECTIVES: To determine long-term clinical outcome in children with confirmed Lyme neuroborreliosis (LNB) and to evaluate persistent subjective symptoms compared with a control group. METHODS: After a median of 5 years, 84 children with confirmed LNB underwent a neurologic re-examination, including a questionnaire. Medical records were analyzed, and a control group (n = 84) was included. RESULTS: The total recovery rate was 73% (n = 61). Objective neurologic findings, defined as "definite sequelae," were found in 16 patients (19%). The majority of these children had persistent facial nerve palsy (n = 11), but other motor or sensory deficits occurred (n = 5). Neurologic signs and/or symptoms defined as "possible sequelae" were found in another 7 patients (8%), mainly of sensory character. Nonspecific subjective symptoms were reported by 35 patients (42%) and 32 controls (38%) (nonsignificant). Affected daily activities or school performance were reported to the same extent in both groups (23% vs 20%, nonsignificant). CONCLUSIONS: The long-term clinical recovery rate was 73% in children with confirmed LNB. Persistent facial nerve palsy occurred in 13%, whereas other motor or sensory deficits were found in another 14%. Neurologic deficits did not affect daily activities or school performance more often among patients than controls and should be considered as mild. Furthermore, nonspecific subjective symptoms such as headache, fatigue, or memory or concentration problems were reported as often among patients as controls and should not be considered as sequelae after LNB.

Family-based behavioural intervention programme for obese children: a feasibility study.

OBJECTIVES: To assess a 2-year family-based behavioural intervention programme against child obesity. DESIGN: Single-group pre- and post-intervention feasibility study. SETTING: Swedish paediatric outpatient care. PARTICIPANTS: 26 obese children aged 8.3-12.0 years and their parents who had consented to actively participate in a 2-year intervention. INTERVENTIONS: 25 paediatric outpatient group sessions over a 2-year period with parallel groups for children and parents. The basis for the programme was a manual containing instructions for tutor-supervised group sessions with obese children and their parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was change in standardised body mass index between baseline and after 36 months. The secondary outcome measures were change in the waist:height ratio, metabolic parameters and programme adherence. The participants were examined at baseline and after 3, 12 and 24 months of therapy and at follow-up 12 months after completion of the programme. RESULTS: The primary outcome measure, standardised body mass index, declined from a mean of 3.3 (0.7 SD) at baseline to 2.9 (0.7 SD) (p<0.001) at follow-up 12 months after completion of the programme. There was no change in the waist:height ratio. Biomedical markers of blood glucose metabolism and lipid status remained in the normal range. 96% of the families completed the programme. CONCLUSIONS: This feasibility study of a 2-year family-based behavioural intervention programme in paediatric outpatient care showed promising results with regard to further weight gain and programme adherence. These findings must be confirmed in a randomised controlled trial with longer follow-up before the intervention programme can be implemented on a larger scale.

Transcobalamin deficiency caused by compound heterozygosity for two novel mutations in the TCN2 gene: a study of two affected siblings, their brother, and their parents.

Transcobalamin (TC) deficiency (OMIM# 275350) is a rare, autosomal recessive disorder that presents in early infancy with a broad spectrum of symptoms, including failure to thrive, megaloblastic anemia, immunological deficiency, and neurological symptoms. Here we report a study of a family (parents and three children) with two children suffering from TC deficiency caused by two different mutations in the TCN2 gene. Initially, molecular genetic analysis of genomic DNA revealed a heterozygous mutation in the +1 position of exon 7 (c.1106+1 G > A) in the father and all three children. Bioinformatic analysis indicates that this mutation causes exon skipping, and further experiments supported this hypothesis and suggested that the mutant allele undergoes nonsense-mediated messenger RNA (mRNA) decay. We did not identify further mutations in genomic DNA that could explain TC deficiency in the two children. However, further efforts using complementary DNA (cDNA) derived from RNA from blood leukocytes identified a large deletion removing the entire exon 8, resulting in a frameshift and a premature stop codon (p.E371fsX372) in the mother and the two affected children. Our data indicate that if exon-by-exon DNA sequencing of genomic DNA does not uncover mutations corresponding to the phenotype, a systematic search for other mutations should be initiated by sequencing cDNA or using semiquantitative methods to detect large deletions in TCN2.

Good glycemic control remains crucial in prevention of late diabetic complications--the Linköping Diabetes Complications Study.

BACKGROUND: Several intervention studies have convincingly demonstrated the importance of good glycemic control to avoid long-term diabetic complications, but the importance of other risk factors remains controversial. We previously reported a markedly reduced incidence of severe retinopathy and nephropathy during the past decades in an unselected population of type 1 diabetes mellitus diagnosed in childhood. The aim of the present study was to analyze possible risk factors, which could explain the improved prognosis. METHODS: In this longitudinal population-based cohort study, we followed all 269 patients in whom type 1 diabetes mellitus was diagnosed in childhood 1961-1985 in a well-defined geographical area in Sweden. The patients were followed until the end of 1990 s. Multivariable regression models were used to analyze the importance of hemoglobin A1c (HbA(1c)), diabetes duration, blood pressure, cardiovascular risk factors and persisting C-peptide secretion for the development of diabetic retinopathy and nephropathy. RESULTS: Beside longer duration and higher HbA(1c), blood pressure and lipid values were higher and cardiovascular disease and smoking were more common in patients with severe complications. However, multivariable analysis abolished these associations. Diabetes duration and long-term HbA(1c) were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA(1c) was above 9.6% [Diabetes Control and Complications Trial (DCCT) corrected value], while the risk of severe retinopathy increased already when HbA(1c) exceeded 8.6%. CONCLUSION: In this unselected population, glycemic control was the only significant risk factor for the development of long-term complications.

Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome.

BACKGROUND: Evaluation of children with clinically suspected neuroborreliosis (NB) is difficult. With a prospective study design we wanted to characterize children with signs and symptoms indicative for NB, investigate clinical outcome and, if possible, identify factors of importance for recovery. MATERIAL/METHODS: Children being evaluated for NB (n = 177) in southeast Sweden were categorized into 3 groups: "confirmed neuroborreliosis" (41%) with Borrelia antibodies in the cerebrospinal fluid, "possible neuroborreliosis" (26%) with pleocytosis but no Borrelia antibodies in the cerebrospinal fluid, and "not determined" (33%) with no pleocytosis and no Borrelia antibodies in the cerebrospinal fluid. Antibiotic treatment was given to 69% of children. Patients were followed during 6 months and compared with a matched control group (n = 174). RESULTS: Clinical recovery at the 6-month follow-up (n = 177) was generally good and no patient was found to have recurrent or progressive neurologic symptoms. However, persistent facial nerve palsy caused dysfunctional and cosmetic problems in 11% of patients. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. Influence on daily life was reported to the same extent in patients and controls. Consequently, persistent headache and fatigue at follow-up should not be considered as attributable to NB. No prognostic factors could be identified. CONCLUSIONS: Clinical recovery was satisfactory in children being evaluated for NB although persistent symptoms from facial nerve palsy occurred. Persistent nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls.

Clinical manifestations and beta cell function in Swedish diabetic children have remained unchanged during the last 25 years.

BACKGROUND: The incidence of type 1 diabetes in childhood has doubled in Sweden during the last decades. Environmental factors may cause a different disease process, residual beta cell function and clinical manifestation. Insulin therapy has become more intensive. The aim of this study was to examine the clinical characteristics at onset, C-peptide secretion during the first years after diagnosis and if there was any secular trends during the last 25 years. METHODS: All 316 children diagnosed with type 1 diabetes during 1976--2000 and living in the Linköping area were included. Information about clinical characteristics at diagnosis, duration of partial remission, insulin therapy at diagnosis and during the first years was collected from medical records. C-peptide secretion (fasting and stimulated) was measured regularly during the first 5 years. For analysis, the population was divided in five cohorts according to the year of diagnosis. RESULTS: The clinical characteristics at onset were unchanged as well as duration of partial remission. C-peptide secretion was highest after 3 months and then declined gradually. After 5 years 32.7% of the patients had measurable fasting C-peptide, but only 6.5% > 0.1 nmol/L. HbA1c and insulin doses were lower in patients with persistent fasting C-peptide secretion > 0.1 nmol/L. The cohort 1996--2000 had higher stimulated C-peptide secretion at diagnosis and at 3 months, after longer follow-up there was no difference. CONCLUSION: The clinical characteristics at diagnosis, partial remission and duration of C-peptide secretion have remained largely unchanged for the last 25 years.

Early diabetic complications in a population of young patients with type 1 diabetes mellitus despite intensive treatment.

AIM: To describe the prevalence of early complications in an unselected population of patients with type 1 diabetes mellitus (DM1) diagnosed in childhood with intensive insulin treatment from diagnosis. METHODS: Eighty children and adolescents with DM1, age 7-22 years and DM1 duration >3 years, were studied. Neuropathy was defined as abnormal nerve conduction finding in > or = 2 of 4 nerves (sural and peroneal nerves), nephropathy as albumin excretion rate > or = 20 microg/min and retinopathy as all grades of retinal changes in fundus photographs. RESULTS: The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% after 13 years DM1 duration. Mean (SD) long-term HbA1c was 8.4 (0.9)% (DCCT-corrected value). CONCLUSION: Even in a population with intensive insulin treatment from the beginning and fairly good metabolic control, the prevalence of subclinical neuropathy was high, while other diabetic complications were lower than usually reported.

Up-regulation of Borrelia-specific IL-4- and IFN-gamma-secreting cells in cerebrospinal fluid from children with Lyme neuroborreliosis.

The clinical course and outcome of several infectious diseases are dependent on the type of immune response elicited against the pathogen. In adults with neuroborreliosis (NB), a type 1 response with high production of Borrelia-specific IFN-gamma, but no IL-4, has been reported. Since children have a more benign course of NB than adults, we wanted to investigate type 1 and type 2 responses in children with NB. Cerebrospinal fluid (CSF) and blood were collected from children during the acute stage of 'confirmed NB' (n = 34), 'possible NB' (n = 30) and 'non-NB' (n = 10). The number of Borrelia-specific IL-4- and IFN-gamma-secreting cells was measured by enzyme-linked immunospot assay. Borrelia-specific secretion of both IL-4 and IFN-gamma was increased in CSF in confirmed (P < 0.05) and possible (P < 0.01) NB, when compared with non-NB controls. Furthermore, children with NB had significantly higher Borrelia-specific IL-4 secretion in CSF than an adult reference material with NB (P < 0.05). There were no differences in cytokine secretion in relation to onset or recovery of neurological symptoms. Since IL-4 is known to down-regulate the pro-inflammatory and possibly harmful effects of prolonged IFN-gamma responses, the prominent IL-4 response observed in the central nervous system compartment might contribute to the more benign disease course seen in children with Lyme NB.

Moderate Dose Inhaled Budesonide Disguising Symptoms of Addison's Disease in An Asthmatic Boy with Silent Celiac Disease.

Inhaled corticosteroids are first-line treatment for asthma. Moderate doses of budesonide have been supposed not to affect hypothalamic-pituitary-adrenal axis function. We report the case of a boy with asthmatic symptoms and a late diagnosis of celiac disease, in whom inhaled budesonide in a dose used in conventional asthma therapy seems to have been systemically absorbed in amounts large enough to temporarily disguise the symptoms of a developing adrenal insufficiency. Inhaled corticosteroids in a dose used in standard asthma therapy seem to have the potential of disguising a developing Addison's disease. Furthermore, celiac disease, especially if diagnosed in late childhood, may be associated with Addison's disease causing a complex symptom pattern.