Transdermal Blood Sampling for C-peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes

OBJECTIVE:C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative.RESEARCH DESIGN AND METHODS:Ninety-one individuals (71 with type 1 diabetes, 20 controls; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1–17.1], diabetes duration 4.0 years [1.5–7.7]; controls: 42.2 years [38.0–52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire.RESULTS:Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40–50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) <35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] – TCB ln[C-peptide] = 0.008, 95% CI [−0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided).CONCLUSIONS:Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment

Geochemical approaches to the quantification of dispersed volcanic ash in marine sediment

Volcanic ash has long been recognized in marine sediment, and given the prevalence of oceanic and continental arc volcanism around the globe in regard to widespread transport of ash, its presence is nearly ubiquitous. However, the presence/absence of very fine-grained ash material, and identification of its composition in particular, is challenging given its broad classification as an “aluminosilicate” component in sediment. Given this challenge, many studies of ash have focused on discrete layers (that is, layers of ash that are of millimeter-to-centimeter or greater thickness, and their respective glass shards) found in sequences at a variety of locations and timescales and how to link their presence with a number of Earth processes. The ash that has been mixed into the bulk sediment, known as dispersed ash, has been relatively unstudied, yet represents a large fraction of the total ash in a given sequence. The application of a combined geochemical and statistical technique has allowed identification of this dispersed ash as part of the original ash contribution to the sediment. In this paper, we summarize the development of these geochemical/statistical techniques and provide case studies from the quantification of dispersed ash in the Caribbean Sea, equatorial Pacific Ocean, and northwest Pacific Ocean. These geochemical studies (and their sedimentological precursors of smear slides) collectively demonstrate that local and regional arc-related ash can be an important component of sedimentary sequences throughout large regions of the ocean

Regional-scale input of dispersed and discrete volcanic ash to the Izu-Bonin and Mariana subduction zones

We have geochemically and statistically characterized bulk marine sediment and ash layers at Ocean Drilling Program Site 1149 (Izu-Bonin Arc) and Deep Sea Drilling Project Site 52 (Mariana Arc), and have quantified that multiple dispersed ash sources collectively comprise ~30-35% of the hemipelagic sediment mass entering the Izu-Bonin-Mariana subduction system. Multivariate statistical analyses indicate that the bulk sediment at Site 1149 is a mixture of Chinese Loess, a second compositionally distinct eolian source, a dispersed mafic ash, and a dispersed felsic ash. We interpret the source of these ashes as respectively being basalt from the Izu-Bonin Front Arc (IBFA) and rhyolite from the Honshu Arc. Sr-, Nd-, and Pb isotopic analyses of the bulk sediment are consistent with the chemical/statistical-based interpretations. Comparison of the mass accumulation rate of the dispersed ash component to discrete ash layer parameters (thickness, sedimentation rate, and number of layers) suggests that eruption frequency, rather than eruption size, drives the dispersed ash record. At Site 52, the geochemistry and statistical modeling indicates that Chinese Loess, IBFA, dispersed BNN (boninite from Izu-Bonin), and a dispersed felsic ash of unknown origin are the sources. At Site 1149 the ash layers and the dispersed ash are compositionally coupled, whereas at Site 52 they are decoupled in that there are no boninite layers, yet boninite is dispersed within the sediment. Changes in the volcanic and eolian inputs through time indicate strong arc- and climate-related controls

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit: a proof-of-concept study (the T1Early study)

Objective: Type 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3–5 years has been proposed as an optimal age for a single screen approach. Design: Capillary samples were collected from children attending their preschool vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 using radiobinding/luciferase immunoprecipitation system assays. Acceptability was assessed using semistructured interviews and open-ended postcard questionnaires with parents. Setting: Two primary care practices in Oxfordshire, UK. Main outcome measures: The ability to collect capillary blood to test IAbs in children at the routine preschool vaccination (3.5–4 years). Results: Of 134 parents invited, 66 (49%) were recruited (median age 3.5 years (IQR 3.4–3.6), 26 (39.4%) male); 63 provided a sample (97% successfully), and one participant was identified with a single positive IAb. Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising. Conclusions: Capillary IAb testing is a possible method to screen children for T1D. Aligning collection to the preschool vaccination visit can be convenient for families without the need for an additional visit

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit:a proof-of-concept study (the T1Early study)

Objective: Type 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3–5 years has been proposed as an optimal age for a single screen approach. Design: Capillary samples were collected from children attending their preschool vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 using radiobinding/luciferase immunoprecipitation system assays. Acceptability was assessed using semistructured interviews and open-ended postcard questionnaires with parents. Setting: Two primary care practices in Oxfordshire, UK. Main outcome measures: The ability to collect capillary blood to test IAbs in children at the routine preschool vaccination (3.5–4 years). Results: Of 134 parents invited, 66 (49%) were recruited (median age 3.5 years (IQR 3.4–3.6), 26 (39.4%) male); 63 provided a sample (97% successfully), and one participant was identified with a single positive IAb. Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising. Conclusions: Capillary IAb testing is a possible method to screen children for T1D. Aligning collection to the preschool vaccination visit can be convenient for families without the need for an additional visit

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit:a proof-of-concept study (the T1Early study)

Objective: Type 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3–5 years has been proposed as an optimal age for a single screen approach. Design: Capillary samples were collected from children attending their preschool vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 using radiobinding/luciferase immunoprecipitation system assays. Acceptability was assessed using semistructured interviews and open-ended postcard questionnaires with parents. Setting: Two primary care practices in Oxfordshire, UK. Main outcome measures: The ability to collect capillary blood to test IAbs in children at the routine preschool vaccination (3.5–4 years). Results: Of 134 parents invited, 66 (49%) were recruited (median age 3.5 years (IQR 3.4–3.6), 26 (39.4%) male); 63 provided a sample (97% successfully), and one participant was identified with a single positive IAb. Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising. Conclusions: Capillary IAb testing is a possible method to screen children for T1D. Aligning collection to the preschool vaccination visit can be convenient for families without the need for an additional visit

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit: a proof-of-concept study (the T1Early study)

Objective: Type 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3–5 years has been proposed as an optimal age for a single screen approach. Design: Capillary samples were collected from children attending their preschool vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 using radiobinding/luciferase immunoprecipitation system assays. Acceptability was assessed using semistructured interviews and open-ended postcard questionnaires with parents. Setting: Two primary care practices in Oxfordshire, UK. Main outcome measures: The ability to collect capillary blood to test IAbs in children at the routine preschool vaccination (3.5–4 years). Results: Of 134 parents invited, 66 (49%) were recruited (median age 3.5 years (IQR 3.4–3.6), 26 (39.4%) male); 63 provided a sample (97% successfully), and one participant was identified with a single positive IAb. Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising. Conclusions: Capillary IAb testing is a possible method to screen children for T1D. Aligning collection to the preschool vaccination visit can be convenient for families without the need for an additional visit

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

BACKGROUND: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. METHODS: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. FINDINGS: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). INTERPRETATION: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. FUNDING: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK

Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain

Tephrochronology and its application: A review

Tephrochronology (from tephra, Gk ‘ashes’) is a unique stratigraphic method for linking, dating, and synchronizing geological, palaeoenvironmental, or archaeological sequences or events. As well as utilising the Law of Superposition, tephrochronology in practise requires tephra deposits to be characterized (or ‘fingerprinted’) using physical properties evident in the field together with those obtained from laboratory analyses. Such analyses include mineralogical examination (petrography) or geochemical analysis of glass shards or crystals using an electron microprobe or other analytical tools including laser-ablation-based mass spectrometry or the ion microprobe. The palaeoenvironmental or archaeological context in which a tephra occurs may also be useful for correlational purposes. Tephrochronology provides greatest utility when a numerical age obtained for a tephra or cryptotephra is transferrable from one site to another using stratigraphy and by comparing and matching inherent compositional features of the deposits with a high degree of likelihood. Used this way, tephrochronology is an age-equivalent dating method that provides an exceptionally precise volcanic-event stratigraphy. Such age transfers are valid because the primary tephra deposits from an eruption essentially have the same short-lived age everywhere they occur, forming isochrons very soon after the eruption (normally within a year). As well as providing isochrons for palaeoenvironmental and archaeological reconstructions, tephras through their geochemical analysis allow insight into volcanic and magmatic processes, and provide a comprehensive record of explosive volcanism and recurrence rates in the Quaternary (or earlier) that can be used to establish time-space relationships of relevance to volcanic hazard analysis. The basis and application of tephrochronology as a central stratigraphic and geochronological tool for Quaternary studies are presented and discussed in this review. Topics covered include principles of tephrochronology, defining isochrons, tephra nomenclature, mapping and correlating tephras from proximal to distal locations at metre- through to sub-millimetre-scale, cryptotephras, mineralogical and geochemical fingerprinting methods, numerical and statistical correlation techniques, and developments and applications in dating including the use of flexible depositional age-modelling techniques based on Bayesian statistics. Along with reference to wide-ranging examples and the identification of important recent advances in tephrochronology, such as the development of new geoanalytical approaches that enable individual small glass shards to be analysed near-routinely for major, trace, and rare-earth elements, potential problems such as miscorrelation, erroneous-age transfer, and tephra reworking and taphonomy (especially relating to cryptotephras) are also examined. Some of the challenges for future tephrochronological studies include refining geochemical analytical methods further, improving understanding of cryptotephra distribution and preservation patterns, improving age modelling including via new or enhanced radiometric or incremental techniques and Bayesian-derived models, evaluating and quantifying uncertainty in tephrochronology to a greater degree than at present, constructing comprehensive regional databases, and integrating tephrochronology with spatially referenced environmental and archaeometric data into 3-D reconstructions using GIS and geostatistics