Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.

The Promise of Proton Beam Therapy for Oesophageal Cancer: A Systematic Review of Dosimetric and Clinical Outcomes.

AIMS: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable. MATERIALS AND METHODS: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised. RESULTS: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy. CONCLUSION: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies.

'25-Hydroxyvitamin D, Autoantigenic and Total Antibody Concentrations: Results from a Danish Case-control Study of Newly Diagnosed Patients with Childhood Type 1 Diabetes and their Healthy Siblings'.

B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been conducted within this field. Our objective was to investigate whether higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with ß-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma-associated antigen-2A (IA-2A). Further, we also wanted to examine the relationship between 25(OH)D and total antibody concentrations. We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean concentration of GADA, IA-2A and antibody isotypes by a 10 nmol/l increase in 25(OH)D concentration was modelled by a robust log-normal regression model. We found no association between 25(OH)D and GADA [adjusted RC per 10 nmol/l increase: 1.00; 95% confidence interval (CI): 0.98-1.02] and IA-2A [adjusted RC per 10 nmol/l increase: 0.92; CI: 0.76-1.12]. Further, 25(OH)D was not associated with the total concentration of antibody isotypes [immunoglobulin (Ig)A, IgE, IgG and IgM]. All null findings were unaltered after adjustment for genetic variation in the vitamin D pathway. Physiological concentrations of 25(OH)D are unlikely to have a clinically important effect on antibody concentrations in a paediatric population of newly diagnosed patients with T1D and their healthy siblings.

Increased mortality in a Danish cohort of young people with Type 1 diabetes mellitus followed for 24 years.

AIM: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. METHODS: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. RESULTS: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). CONCLUSION: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.

Retinal vascular geometry and its association to microvascular complications in patients with type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

PURPOSE: To examine associations between retinal vascular geometry (tortuosity, branching coefficient [BC] and length-diameter ratio [LDR]) and diabetic proliferative retinopathy (PDR), nephropathy, and peripheral neuropathy in patients with type 1 diabetes mellitus (T1DM). METHODS: A cohort of patients with T1DM participated in a clinical examination in 2011. Blood and urine analyses were done and retinal images taken. PDR was defined as Early Treatment Diabetic Retinopathy Study level 61 or above, nephropathy as albumin-creatinin ratio ≥300 mg/g, and neuropathy as vibration perception threshold >25 Volt. Retinal vessel parameters were measured using semi-automated software. Multiple logistic regressions were performed to investigate correlations between retinal vascular parameters and outcomes. Models were adjusted for other variables (sex, age, duration of diabetes, systolic and diastolic blood pressure, HbA1c, and presence of microvascular complications). Odds ratios were given per standard deviation in retinal vascular parameter. RESULTS: Retinal vascular analyses were performed in 181 patients. Mean age and duration of diabetes were 37.0 years and 29.4 years respectively, and 50.8% were male. Prevalence of PDR, nephropathy, and neuropathy were 26.5%, 6.8%, and 10.1% , respectively. Patients with increased arteriolar BC had a higher risk of nephropathy (OR: 3.10, 95% CI: [1.01-9.54]). Patients with increased venular BC had a higher risk of neuropathy (OR: 2.11, 95% CI: [1.11-4.03]). No associations were found in patients with PDR. CONCLUSIONS: By analyzing the retinal vascular tree in patients with T1DM, we found a higher risk of complications in kidneys and nerves when BC was increased. This might indicate a suboptimal construction of the vascular tree in these patients.

Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen.

Prophylactic Swallowing Exercises in Head and Neck Cancer Radiotherapy.

Many head and neck cancer (HNC) survivors experience reduced quality of life due to radiotherapy (RT)-related dysphagia. The aim of this prospective randomized trial was to evaluate the impact of prophylactic swallowing exercises on swallowing-related outcomes in HNC patients treated with curative RT. Patients treated with primary RT for HNC were candidates for this randomized protocol. Participants in the exercise group were instructed to perform swallowing exercises at home. Participants in the control group were given standard care. Patients were evaluated with modified barium swallow and several other secondary outcome measures at four and nine different time points, respectively. Data were analyzed according to intention-to-treat analyses. A total of 44 consecutive patients were included; 22 in each group. In general, there was no difference between the two groups regarding any of the dysphagia outcomes during and after treatment. Adherence to exercises was poor and dropouts due to especially fatigue were very frequent in both groups. Systematic swallowing exercises had no impact on swallowing outcomes within the first year after RT. Despite repeated supervised sessions, adherence to exercises was a major issue and dropouts were frequent in both the intervention and control group.

Prevalence and predictors of severe hypoglycemia in Danish children and adolescents with diabetes.

OBJECTIVE: To investigate the prevalence of severe hypoglycemia in Danish children and adolescents with type 1 diabetes and to pinpoint predictors of this acute complication in children on modern treatment modalities. RESEARCH DESIGN AND METHODS: The study is based on data from DanDiabKids, a national diabetes register for children and adolescents. The register contains data on patients with type 1 diabetes with an ascertainment rate of 99%. Data from 3320 patients aged 0-18 yr was included in the study period from 1998 to 2009 and analyzed using a negative binomial model. RESULTS: One thousand nine hundred and ninety-nine episodes of severe hypoglycemia in 867 patients were registered conferring an overall incidence of severe hypoglycemia of 15.1 [95% confident interval (CI): 13.8; 16.4] per 100 patient years. This remained unchanged during the study period. Duration of diabetes, age and treatment in centers managing less than 100 patients significantly increased the risk of severe hypoglycemia (p < 0.001). Patients on insulin pump therapy had a 42% reduced risk of severe hypoglycemia compared with pen treated patients (p = 0.01). Patients treated with five or more daily insulin injections had a 31% (95% CI: 17; 49) reduced risk of severe hypoglycemia compared to patients on fewer daily injections (p = 0.015). CONCLUSIONS: Despite improvements in metabolic control over a decade the prevalence of severe hypoglycemic events remained unchanged. More intensive treatments such as insulin pump therapy and multiple daily injections on a national level seems to be a protective factor for developing severe hypoglycemia up to 2009.

Long-term incidence of vitrectomy and associated risk factors in young Danish patients with Type 1 diabetes: the Danish Cohort of Paediatric Diabetes 1987.

AIMS: To examine the long-term incidence of vitrectomy in young people with Type 1 diabetes. METHODS: We prospectively studied 324 people with Type 1 diabetes who participated in baseline examinations in 1995. Surgical history was obtained from the Danish National Patient Registry in April 2012. RESULTS: During the 17-year study period, 39 people (12.0%) underwent vitrectomy at least once. The mean age and diabetes duration at first vitrectomy were 29.8 and 22.9 years, respectively, and 64.1% of the participants were men. In multivariable Cox regression analysis, baseline age (hazard ratio 0.81 per 1 year increase), BMI (hazard ratio 1.21 per 1 kg/m(2) increase), HbA1c (hazard ratio 1.72 per 1% increase) and diabetic retinopathy (hazard ratio 2.85 and 6.07 for mild and moderate/severe diabetic retinopathy vs none, respectively) were independent predictors of vitrectomy (P < 0.05 for all variables). CONCLUSIONS: Vitrectomy is a relatively common procedure in young people with Type 1 diabetes, with poor glycaemic control being the strongest modifiable risk factor.

Nationwide reduction in the frequency of severe hypoglycemia by half.

AIMS: To examine contemporary rates of severe hypoglycemia (SH) and identify the effect of predictors of SH in a pediatric type 1 diabetes population. METHODS: The national diabetes register provided data on children residing in Denmark from 2008 to 2013 in this register-based population study. Robust Poisson regression models were applied. RESULTS: The study population [n = 2,715 (50.9 % boys), mean (SD) age at onset; 8.1 (4.0) years, diabetes duration; 5.6 (4.9) years] comprised 7,390 person-years of data and 561 events of SH. The overall incidence of SH was 7.6 per 100 person-years. The incidence rate peaked with 16.0 per 100 person-years in 2008 reaching a nadir of 4.9 in 2011. Overall, insulin pump reduced the rate of SH with 27 % compared to any pen treatment (P = 0.003). When stratifying pen treatment, premixed insulin increased the rate of SH by 1.9-fold (P = 0.0015) and NPH increased the rate by 1.6-fold (P = 0.003) versus pump treatment, whereas long-acting insulin analogues were comparable with pump treatment (P = 0.1485). We found no association of SH with glycemic control (P > 0.05). CONCLUSIONS: A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia.

Microaneurysm count as a predictor of long-term progression in diabetic retinopathy in young patients with type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

PURPOSE: To investigate microaneurysm (MA) count as a predictor of long-term progression of diabetic retinopathy (DR) in young patients with type 1 diabetes mellitus (T1DM). METHODS: We examined 185 patients with T1DM at baseline (1995) and at follow-up (2011). At baseline, mean age and duration of diabetes were 20.6 and 12.9 years, respectively. Two-field (1995) and seven-field (2011) fundus photographs were taken in accordance with the European Diabetes Study Group (EURODIAB) and the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. DR was graded in accordance to the ETDRS protocol, allowing for non-standard photography at baseline. Baseline MAs were counted; patients without DR and those with MAs only were included. Multivariable logistic regressions were performed to investigate MA-count as a predictor of two-step progression, progression to proliferative DR (PDR), and incident diabetic macula edema (DME). RESULTS: We included 138 patients (138 eyes). Of these, 58 had no retinopathy and 80 had MAs only. At follow-up, rates of two-step progression of DR, progression to PDR and incident DME were 52.9, 21.7, and 10.1 %, respectively. In logistic regression models, MA count was able to predict progression to PDR (OR: 1.51 per MA; 95 % CI: [1.04-2.20]) and DME (OR: 1.69 per MA; 95 % CI: [1.05-2.77]), but not two-step progression (OR 0.91 per MA, 95 % CI: [0.64-1.31]). CONCLUSIONS: In younger patients with T1DM, MA count predicts long-term incidence of PDR and DME. This demonstrates that early DR is a warning sign of late retinopathy complications and that the number of MAs is an important factor for long-term outcome.

Systemic levels of CCL2, CCL3, CCL4 and CXCL8 differ according to age, time period and season among children newly diagnosed with type 1 diabetes and their healthy siblings.

The mechanisms by which antigen-specific T cells migrate to the islets of Langerhans in type 1 diabetes (T1D) are largely unknown. Chemokines attract immune cells to sites of inflammation. The aim was to elucidate the role of inflammatory chemokines in T1D at time of diagnosis. From a population-based registry of children diagnosed with T1D from 1997 to 2005, we studied five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8). Four hundred and eighty-two cases and 479 sibling frequencies matched on age and sample year distribution were included. Patients showed lower levels of CCL4 compared to siblings, but this result was not significant after correction for multiple testing. CCL2, CCL3, CCL4 and CXCL8 levels were highest in the most recent cohorts (P < 0.01) in both patients and siblings. A significant seasonal variation - for most of the chemokines - was demonstrated with the highest level during the summer period in both patients and siblings. In addition, there was a significant inverse relationship between CCL4 levels and age. When comparing patients and siblings, remarkably few differences were identified, but interestingly chemokine levels varied with age, season and period for the entire study population. Such variations should be taken into account when studying chemokines in paediatric populations.

Diabetic ketoacidosis at the onset of type 1 diabetes is associated with future HbA1c levels.

AIMS/HYPOTHESIS: We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes. METHODS: The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996-2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods. RESULTS: The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA1c (%) levels (0.24; 95% CI 0.11, 0.36; p = 0.0003) and increased insulin dose-adjusted HbA1c (IDAA1c, 0.51; 95% CI 0.31, 0.70; p < 0.0001) during follow-up, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p < 0.0001); however, these children had a lower HbA1c (%) level over time (-0.35; 95% CI -0.46, -0.24; p < 0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA1c, changing the effect of DKA, after adjustment for covariates (p < 0.0001). CONCLUSIONS/INTERPRETATION: DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA1c and IDAA1c, respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population.

Association between age, IL-10, IFNγ, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes.

AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes. METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months. RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups. CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.

Association of adiponectin, interleukin (IL)-1ra, inducible protein 10, IL-6 and number of islet autoantibodies with progression patterns of type 1 diabetes the first year after diagnosis.

The progression of type 1 diabetes after diagnosis is poorly understood. Our aim was to assess the relation of disease progression of juvenile-onset type 1 diabetes, determined by preserved beta cell function the first year after diagnosis, with systemic cytokine concentrations and number of autoantibodies. Juvenile patients (n = 227) had a meal-stimulated C-peptide test 1 and 6 months after diagnosis. On the basis of the C-peptide course for the duration of 1-6 months, four progression groups were defined: patients with persistently low beta cell function ('stable-low'), rapid progressers, slow progressers and remitters. Serum concentrations of adiponectin, interleukin (IL)-1ra, inducible protein 10 (IP-10), IL-6 and glutamic acid decarboxylase (GAD), IA-2A and islet-cell antibodies (ICA) were measured at 1, 6 and 12 months. We found that adiponectin concentrations at 1 month predicted disease progression at 6 months (P = 0·04). Patients with low adiponectin had a higher probability of becoming remitters than rapid progressers, odds ratio 3·1 (1·3-7·6). At 6 and 12 months, adiponectin differed significantly between the groups, with highest concentrations among stable-low and rapid progressers patients (P = 0·03 and P = 0·006). IL-1ra, IP-10 and IL-6 did not differ between the groups at any time-point. The number of autoantibodies differed significantly between the groups at 1 month (P = 0·04), where rapid progressers had the largest number. There was no difference between the groups in human leucocyte antigen-associated risk. We define progression patterns distinguishing patients diagnosed with low beta cell function from those with rapid decline, slow decline or actual increase in beta cell function, pointing to different mechanisms of disease progression. We find that adiponectin concentration at 1 month predicts, and at 6 and 12 months associates with, distinct progression patterns.

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere childhood diabetes study group centre differences study 2005.

OBJECTIVE: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. METHODS: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. RESULTS: A total of 2062 adolescents completed questionnaires (age 14.4 +/- 2.3 yr; diabetes duration 6.1 +/- 3.5 yr). Mean HbA 1c = 8.2 +/- 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). CONCLUSIONS: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes.

Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with beta-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the beta-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased beta-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?

AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.