Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort.

OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results

Association Between Maternal Diabetes in Utero and Age at Offspring's Diagnosis of Type 2 Diabetes

OBJECTIVE—The purpose of this study was to examine age of diabetes diagnosis in youth who have a parent with diabetes by diabetes type and whether the parent's diabetes was diagnosed before or after the youth's birth

Crustal strain in central Greece from repeated GPS measurements in the interval 1989-1997

A 66-station GPS network spanning central Greece, first observed in 1989, has been occupied fully on three occasions: June 1989, October 1991 and May 1993. Subsets of this network bounding the Gulf of Korinthos have also been occupied in June 1995, October 1995, May 1996 and September/October 1997. The first three occupations were processed using a fiducial GPS methodology, whereas later surveys were processed using CODE precise orbits. Combination of data from different surveys to yield smooth site velocities requires global network translations at each epoch to compensate for errors in the realization of the reference frame. This method provides a posteriori estimates of the relative coordinate errors and reference frame noise. Only one earthquake, the 1995 June 15 Egion event, has caused significant local coseismic displacement, and its effects on the interseismic velocity field are removed using an elastic dislocation model. We constrain the orientation of the 100 yr triangulation—GPS velocity estimates of Davies et al. (1997) using 14 sites common to the two networks. The goodness of fit of this transformation indicates that the short-term and 100 yr geodetic estimates of deformation are highly compatible. We infer that short-term geodetic studies are capable of determining longer-term deformation rates provided that transient, local effects can be modelled. From the combined velocity field, we estimate principal strains and rigid-body rotation rates at points on a regular grid using data from neighbouring sites. Strain rates are high within the Gulf of Korinthos and much lower elsewhere. The extension rate across the Gulf of Korinthos increases from east to west. Comparison of the extension rate with historical and recent rates of seismic release of strain reveals significant medium-term seismic hazard in the western Gulf of Korinthos, and may also indicate long-term aseismic strai

Evaluation of Serum 1,5 Anhydroglucitol Levels as a Clinical Test to Differentiate Subtypes of Diabetes

OBJECTIVE: Assignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology. RESEARCH DESIGN AND METHODS: 1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology. RESULTS: Mean (SD range) 1,5AG levels were: GCK-MODY 13.06 microg/ml (5.74-29.74), HNF1A-MODY 4.23 microg/ml (2.12-8.44), type 1 diabetes 3.09 microg/ml (1.45-6.57), LADA 3.46 microg/ml (1.42-8.45), and type 2 diabetes 5.43 (2.12-13.23). Levels in GCK-MODY were higher than in other groups (P < 10(-4) vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes. CONCLUSIONS: In our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing

Regional integration of long-term national dense GNSS network solutions

The EUREF Permanent Network Densification is a collaborative effort of 26 European GNSS analysis centers providing series of daily or weekly station position estimates of dense national and regional GNSS networks, in order to combine them into one homogenized set of station positions and velocities. During the combination, the station meta-data, including station names, DOMES numbers, and position offset definitions were carefully homogenized, position outliers were efficiently eliminated, and the results were cross-checked for any remaining inconsistencies. The results cover the period from March 1999 to January 2017 (GPS week 1000-1933) and include 31 networks with positions and velocities for 3192 stations, well covering Europe. The positions and velocities are expressed in ITRF2014 and ETRF2014 reference frames based on the Minimum Constraint approach using a selected set of ITRF2014 reference stations. The position alignment with the ITRF2014 is at the level of 1.5, 1.2, and 3.2 mm RMS for the East, North, Up components, respectively, while the velocity RMS values are 0.17, 0.14, and 0.38 mm/year for the East, North, and Up components, respectively. The high quality of the combined solution is also reflected by the 1.1, 1.1, and 3.5 mm weighted RMS values for the East, North, and Up components, respectively

Regional integration of long-term national dense GNSS network solutions

The EUREF Permanent Network Densification is a collaborative effort of 26 European GNSS analysis centers providing series of daily or weekly station position estimates of dense national and regional GNSS networks, in order to combine them into one homogenized set of station positions and velocities. During the combination, the station meta-data, including station names, DOMES numbers, and position offset definitions were carefully homogenized, position outliers were efficiently eliminated, and the results were cross-checked for any remaining inconsistencies. The results cover the period from March 1999 to January 2017 (GPS week 1000-1933) and include 31 networks with positions and velocities for 3192 stations, well covering Europe. The positions and velocities are expressed in ITRF2014 and ETRF2014 reference frames based on the Minimum Constraint approach using a selected set of ITRF2014 reference stations. The position alignment with the ITRF2014 is at the level of 1.5, 1.2, and 3.2\ua0mm RMS for the East, North, Up components, respectively, while the velocity RMS values are 0.17, 0.14, and 0.38\ua0mm/year for the East, North, and Up components, respectively. The high quality of the combined solution is also reflected by the 1.1, 1.1, and 3.5\ua0mm weighted RMS values for the East, North, and Up components, respectively

"I feel so stupid because I can't give a proper answer ..." How older adults describe chronic pain: a qualitative study

Background - Over 50% of older adults experience chronic pain. Poorly managed pain threatens independent functioning, limits social activities and detrimentally affects emotional wellbeing. Yet, chronic pain is not fully understood from older adults’ perspectives; subsequently, pain management in later life is not necessarily based on their priorities or needs. This paper reports a qualitative exploration of older adults’ accounts of living with chronic pain, focusing on how they describe pain, with a view to informing approaches to its assessment. Methods - Cognitively intact men and women aged over sixty-five who lived in the community opted into the study through responding to advertisements in the media and via contacts with groups and organisations in North-East Scotland. Interviews were transcribed and thematically analysed using a framework approach. Results - Qualitative individual interviews and one group interview were undertaken with 23 older adults. Following analysis, the following main themes emerged: diversity in conceptualising pain using a simple numerical score; personalising the meaning of pain by way of stories, similes and metaphors; and, contextualising pain in relation to its impact on activities. Conclusions - The importance of attending to individuals’ stories as a meaningful way of describing pain for older adults is highlighted, suggesting that a narrative approach, as recommended and researched in other areas of medicine, may usefully be applied in pain assessment for older adults. Along with the judicious use of numerical tools, this requires innovative methods to elicit verbal accounts, such as using similes and metaphors to help older adults describe and discuss their experience, and contextualising the effects of pain on activities that are important to them

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes

This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version is available in Diabetes in print and online at http://diabetes.diabetesjournals.orgThe erratum to this article is available in ORE at http://hdl.handle.net/10871/40335Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.JDRFNational Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College LondonEuropean Union (EU FP7) award - Persistent Virus Infection in Diabetes Network Study Group (PEVNET)EU FP7 Large-Scale Focused Collaborative Research Project on Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes (NAIMIT)EU FP7 Large-Scale Focused Collaborative Research Project on β-cell preservation through antigen-specific immunotherapy in Type 1 Diabetes: Enhanced Epidermal Antigen Delivery Systems (EE-ASI)National Institutes of Health (NIH)National Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Allergy and Infectious DiseasesEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Center for Research ResourcesGeneral Clinical Research CenterAmerican Diabetes Association (ADA

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