Rationale and protocol for the After Diabetes Diagnosis REsearch Support System (ADDRESS): an incident and high risk type 1 diabetes UK cohort study

INTRODUCTION: Type 1 diabetes is heterogeneous in its presentation and progression. Variations in clinical presentation between children and adults, and with ethnic group warrant further study in the UK to improve understanding of this heterogeneity. Early interventions to limit beta cell damage in type 1 diabetes are undergoing evaluation, but recruitment is challenging. The protocol presented describes recruitment of people with clinician-assigned, new-onset type 1 diabetes to understand the variation in their manner of clinical presentation, to facilitate recruitment into intervention studies and to create an open-access resource of data and biological samples for future type 1 diabetes research. METHODS AND ANALYSIS: Using the National Institute for Health Research Clinical Research Network, patients >5 years of age diagnosed clinically with type 1 diabetes (and their siblings) are recruited within 6 months of diagnosis. Participants agree to have their clinical, laboratory and demographic data stored on a secure database, for their clinical progress to be monitored using information held by NHS Digital, and to be contacted about additional research, in particular immunotherapy and other interventions. An optional blood sample is taken for islet autoantibody measurement and storage of blood and DNA for future analyses. Data will be analysed statistically to describe the presentation of incident type 1 diabetes in a contemporary UK population. ETHICS AND DISSEMINATION: Ethical approval was obtained from the independent NHS Research Ethics Service. Results will be presented at national and international meetings and submitted for publication to peer-reviewed journals.This work was supported by Diabetes UK grant number 09/0003919 and the Juvenile Diabetes Research Foundation grant number 9-2010-407. Recruitment is supported by staff at the National Institute for Health Research Clinical Research Network

Comparison of GPS analysis strategies for high-accuracy vertical land motion

Tide gauges measure sea level changes relative to land. To separate absolute changes in sea level from vertical land movements tide gauges are often co-located with Continuous GPS (CGPS). In order to achieve an accuracy of better than 1 mm/yr, as required for sea level studies in the global change context, vertical land motion needs to be determined with the same accuracy. This is an ambitious goal for CGPS and needs a carefully designed analysis strategy. We have compared the independent results from six different analysis centres, using three different GPS processing softwares and a number of different analysis strategies. Based on the comparison, we discuss the achieved accuracy and the quality of the different strategies. The data analysed are from the CGPS network of the European Sea Level Service and cover the time window from the beginning of 2000 until the end of 2003. The comparison reveals large differences in the day-to-day variations of the coordinate time series and also in the seasonal cycle contained in these. The trends show systematic differences, depending on software and strategy used. To a large extent, the latter deviations can be explained by differences in the realisation of the reference frame, while some parts may be due to other, as yet, unidentified contributions. The results suggest that the reference frame and its relation to the center of mass of the Earth system may be the main limitation in achieving the accuracy goal for the secular velocity of vertical land motion.Peer ReviewedPostprint (published version

Investigating the Role of T-Cell Avidity and Killing Efficacy in Relation to Type 1 Diabetes Prediction

During the progression of the clinical onset of Type 1 Diabetes (T1D), high-risk individuals exhibit multiple islet autoantibodies and high-avidity T cells which progressively destroy beta cells causing overt T1D. In particular, novel autoantibodies, such as those against IA-2 epitopes (aa1-577), had a predictive rate of 100% in a 10-year follow up (rapid progressors), unlike conventional autoantibodies that required 15 years of follow up for a 74% predictive rate (slow progressors). The discrepancy between these two groups is thought to be associated with T-cell avidity, including CD8 and/or CD4 T cells. For this purpose, we build a series of mathematical models incorporating first one clone then multiple clones of islet-specific and pathogenic CD8 and/or CD4 T cells, together with B lymphocytes, to investigate the interaction of T-cell avidity with autoantibodies in predicting disease onset. These models are instrumental in examining several experimental observations associated with T-cell avidity, including the phenomenon of avidity maturation (increased average T-cell avidity over time), based on intra- and cross-clonal competition between T cells in high-risk human subjects. The model shows that the level and persistence of autoantibodies depends not only on the avidity of T cells, but also on the killing efficacy of these cells. Quantification and modeling of autoreactive T-cell avidities can thus determine the level of risk associated with each type of autoantibodies and the timing of T1D disease onset in individuals that have been tested positive for these autoantibodies. Such studies may lead to early diagnosis of the disease in high-risk individuals and thus potentially serve as a means of staging patients for clinical trials of preventive or interventional therapies far before disease onset

A century of sea level measurements at Newlyn, SW England

The Newlyn Tidal Observatory is the most important sea level station in the UK. It commenced operations in 1915 as part of the Second Geodetic Levelling of England and Wales, and the mean sea level determined from the tide gauge during the first six years (May 1915-April 1921) defined Ordnance Datum Newlyn (ODN) which became the national height datum for the whole of Great Britain. The 100 years of sea level data now available have contributed significantly to many studies in oceanography, geology and climate change. This paper marks the centenary of this important station by reviewing the sea level (and, more recently, detailed land level) measurements and Newlyn’s contributions to UK cartography, geodesy and sea-level science in general. Recommendations are made on how sea and land level measurements at Newlyn might be enhanced in the future

The apparent British sea slope is caused by systematic errors in the levelling-based vertical datum

The spirit-levelling–based British vertical datum (Ordnance Datum Newlyn) implies a south–north apparent slope in mean sea level of up to 53 mm deg–1 latitude, due to the datum falling on heading northwards. Although this apparent slope has been investigated since the 1960s, explanations of its origin have remained inconclusive. It has also been suggested that, rather than a slope, the British vertical datum includes a step of about 240 mm affecting all sites north of about 53°N. In either case, the British vertical datum may be of limited use for any study requiring accurate heights or changes in heights, such as testing geoid models, groundwater and hydrocarbon extraction, the calibration and validation of satellite-based digital terrain models, and the unification of vertical datums internationally. Within the last decade, however, based on an apparent reduction in the slope to only −12 mm deg–1 latitude with respect to recent geoid models, it has been claimed that the British vertical datum does provide a physically meaningful surface for use in scientific applications.In this paper, we reinvestigate the presence of apparent south–north sea slopes around Britain and reported slopes in the vertical datum, using the EGM2008 global gravitational model, together with mean sea level and GPS data from British tide gauges, GPS ellipsoidal heights of 178 fundamental benchmarks across mainland Britain, and vertical deflection observations at 192 stations. We demonstrate a south–north slope in the British vertical datum of −(20–25) mm deg–1 latitude with respect to both mean sea level (corrected for the ocean's mean dynamic topography and the inverse barometer response to atmospheric pressure loading) and the EGM2008 quasigeoid model, while EGM2008 is shown to exhibit a negligible slope of (2 ± 4) mm deg–1 with respect to mean sea level. It is clear, therefore, that the slope can only arise from systematic errors in the levelling, although we are unable to isolate their exact origin. Using an offset detection method based on a penalized likelihood maximization using the Schwarz Information Criterion, we do not detect a step in the vertical datum affecting all sites north of 53°N, but do identify regional distortions that we attribute to the inhomogeneity in both the levelling data used and the least squares adjustment procedures used to realize the datum. We conclude that the British vertical datum remains unsuitable for scientific purposes

Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

ObjectiveTo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.Research design and methodsWe monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.ResultsAutoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.ConclusionsWe demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used