The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance:development of other autoantibodies and progression to type 1 diabetes

AIMS/HYPOTHESIS: Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention. METHODS: The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies. RESULTS: Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry. CONCLUSIONS/INTERPRETATION: Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3830-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Interventions in entrepreneurial learning: Blended learning and ICT capacity

The effective use of information and communications technologies (ICT) can benefit most small businesses. This article examines the design, development and delivery of a pilot blended learning program for entrepreneurial learning that targets the use of ICT by tradespeople. The study involves a case study of tradespeople in Australia who participated in a program designed to build their capacity to identify, use and evaluate ICT to enhance their business practices. The program combined traditional instructional approaches (through face-to-face and online sessions for delivering basic ICT concepts to participants) with learner-centred approaches (through a combination of student mentor visits and practical exercises to identify applications that were context-specific for each participant's business). A blended learning assessment framework is employed throughout the article to inform and evaluate various aspects of the program. Project participants rated the face-to-face sessions, student mentor visits and practical exercises as very effective. However, some participants could not free up the time from their employment to participate in all of the face-to-face classes. From a theoretical perspective, an amended blended learning assessment framework for the delivery of ICT programs to entrepreneurs is presented and potential lessons for the delivery of ICT concepts to entrepreneurs in the trades and similar vocations are proposed

Conformation-dependent GAD65 autoantibodies in diabetes

Aims/hypothesis. Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. Methods. We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. Results. The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients (n=85) by a mean of 72% (p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults (n=24) showed a similar reduction in binding (79% reduction, p<0.0001). First-degree relatives who subsequently progressed to Type 1 diabetes (n=12) showed a reduction in binding of 80% compared with a reduction of only 65% among relatives who had not progressed to disease (n=38; p=0.025). In healthy GAD65Ab-positive individuals who did not progress to diabetes during a 9-year follow-up period (n=51), binding to GAD65-E517P was reduced by only 28% compared with binding to wild-type GAD65. Conclusions/interpretation. Differences in autoantibody binding to wild-type GAD65 versus GAD65-E517P may provide predictive information about Type 1 diabetes risk beyond that provided by the presence or absence of GAD65 autoantibodies. Lack of binding to mutant GAD65-E517P defines GAD65-positive individuals who are at higher risk of developing diabetes

Use of Dried Capillary Blood Sampling for Islet Autoantibody Screening in Relatives:A Feasibility Study

Background: Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot–based screening to identify islet autoantibody–positive relatives potentially eligible for inclusion in prevention trials. Materials and Methods: Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. Results: Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. Conclusions: Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies.</p

An assessment of static Precise Point Positioning using GPS only, GLONASS only, and GPS plus GLONASS

The aim of this paper is to look into the achievable repeatability and accuracy from Precise Point Positioning (PPP) daily solutions when using GPS only (PPP GPS), GLONASS only (PPP GLO), and GPS plus GLONASS (PPP GPS+GLO) for static positioning. As part of the assessment, a comparison with global double difference (DD) GPS daily solutions is presented. It is shown, therefore, that all of the PPP daily solutions can achieve millimetric level repeatability, similar to the global DD GPS solutions. Furthermore, the mean of the biases between the PPP daily solutions and the global DD GPS daily solutions are constellation type dependent, while an improvement is found in the vertical component for PPP GPS+GLO over PPP GLO, as the latter may be more affected by any imperfections in the models for GLONASS antenna phase centre variations. It is concluded that PPP GLO daily solutions have the ability to be used as independent solutions to PPP GPS daily solutions for static positioning, and as an alternative to PPP GPS+GLO or global DD GPS daily solutions

Evaluation of the image quality and validity of handheld echocardiography for stroke volume and left ventricular ejection fraction quantification:a method comparison study

Bedside quantification of stroke volume (SV) and left ventricular ejection fraction (LVEF) is valuable in hemodynamically compromised patients. Miniaturized handheld ultrasound (HAND) devices are now available for clinical use. However, the performance level of HAND devices for quantified cardiac assessment is yet unknown. The aim of this study was to compare the validity of HAND measurements with standard echocardiography (SE) and three-dimensional echocardiography (3DE). Thirty-six patients were scanned with HAND, SE and 3DE. LVEF and SV quantification was done with automated software for the HAND, SE and 3DE dataset. The image quality of HAND and SE was evaluated by scoring segmental endocardial border delineation (2 = good, 1 = poor, 0 = invisible). LVEF and SV of HAND was evaluated against SE and 3DE using correlation and Bland-Altman analysis. The correlation, bias, and limits of agreement (LOA) between HAND and SE were 0.68 [0.46:0.83], 1.60% [- 2.18:5.38], and 8.84% [- 9.79:12.99] for LVEF, and 0.91 [0.84:0.96], 1.32 ml [- 0.36:4.01], 15.54 ml [- 18.70:21.35] for SV, respectively. Correlation, bias, and LOA between HAND and 3DE were 0.55 [0.6:0.74], - 0.56% [- 2.27:1.1], and 9.88% [- 13.29:12.17] for LVEF, and 0.79 [0.62:0.89], 6.78 ml [2.34:11.21], 12.14 ml [- 26.32:39.87] for SV, respectively. The image quality scores were 9.42 ± 2.0 for the apical four chamber views of the HAND dataset and 10.49 ± 1.7 for the SE dataset and (P &lt; 0.001). Clinically acceptable accuracy, precision, and image quality was demonstrated for HAND measurements compared to SE. In comparison to 3DE, HAND showed a clinically acceptable accuracy and precision for LVEF quantification.</p

Evaluation of the image quality and validity of handheld echocardiography for stroke volume and left ventricular ejection fraction quantification:a method comparison study

Bedside quantification of stroke volume (SV) and left ventricular ejection fraction (LVEF) is valuable in hemodynamically compromised patients. Miniaturized handheld ultrasound (HAND) devices are now available for clinical use. However, the performance level of HAND devices for quantified cardiac assessment is yet unknown. The aim of this study was to compare the validity of HAND measurements with standard echocardiography (SE) and three-dimensional echocardiography (3DE). Thirty-six patients were scanned with HAND, SE and 3DE. LVEF and SV quantification was done with automated software for the HAND, SE and 3DE dataset. The image quality of HAND and SE was evaluated by scoring segmental endocardial border delineation (2 = good, 1 = poor, 0 = invisible). LVEF and SV of HAND was evaluated against SE and 3DE using correlation and Bland-Altman analysis. The correlation, bias, and limits of agreement (LOA) between HAND and SE were 0.68 [0.46:0.83], 1.60% [- 2.18:5.38], and 8.84% [- 9.79:12.99] for LVEF, and 0.91 [0.84:0.96], 1.32 ml [- 0.36:4.01], 15.54 ml [- 18.70:21.35] for SV, respectively. Correlation, bias, and LOA between HAND and 3DE were 0.55 [0.6:0.74], - 0.56% [- 2.27:1.1], and 9.88% [- 13.29:12.17] for LVEF, and 0.79 [0.62:0.89], 6.78 ml [2.34:11.21], 12.14 ml [- 26.32:39.87] for SV, respectively. The image quality scores were 9.42 ± 2.0 for the apical four chamber views of the HAND dataset and 10.49 ± 1.7 for the SE dataset and (P &lt; 0.001). Clinically acceptable accuracy, precision, and image quality was demonstrated for HAND measurements compared to SE. In comparison to 3DE, HAND showed a clinically acceptable accuracy and precision for LVEF quantification.</p

GAD65 Autoantibody Responses in Japanese Latent Autoimmune Diabetes in Adult Patients

OBJECTIVE—To determine whether development of insulin requirement in patients with latent autoimmune diabetes in adults (LADA) is accompanied with the emergence of a type 1 diabetes–like autoimmune response