The New Zealand Kauri (Agathis Australis) Research Project: A Radiocarbon Dating Intercomparison of Younger Dryas Wood and Implications for IntCal13

We describe here the New Zealand kauri (Agathis australis) Younger Dryas (YD) research project, which aims to undertake Δ14C analysis of ~140 decadal floating wood samples spanning the time interval ~13.1–11.7 kyr cal BP. We report 14C intercomparison measurements being undertaken by the carbon dating laboratories at University of Waikato (Wk), University of California at Irvine (UCI), and University of Oxford (OxA). The Wk, UCI, and OxA laboratories show very good agreement with an interlaboratory comparison of 12 successive decadal kauri samples (average offsets from consensus values of –7 to +4 14C yr). A University of Waikato/University of Heidelberg (HD) intercomparison involving measurement of the YD-age Swiss larch tree Ollon505, shows a HD/Wk offset of ~10–20 14C yr (HD younger), and strong evidence that the positioning of the Ollon505 series is incorrect, with a recommendation that the 14C analyses be removed from the IntCal calibration database

Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P<0.001). A higher proportion of patients in each ERTU group achieved HbA1c <7% relative to placebo (P<0.001). ERTU significantly reduced FPG and body weight (P<0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class

The Ess/Type VII secretion system of Staphylococcus aureus shows unexpected genetic diversity

We thank the core sequencing and informatics teams at the Sanger Institute for their assistance and The Wellcome Trust for its support of the Sanger Institute Pathogen Genomics and Biology groups. SRH, JP and MTGH were supported by Wellcome Trust grant 098051. Bioinformatics and Computational Biology analyses were supported by the University of St Andrews Bioinformatics Unit that is funded by a Wellcome Trust ISSF award (grant 105621/Z/14/Z). SP is funded by the UKCRC Translational Infection Research Initiative, and the NIHR Cambridge Biomedical Research Centre. CPH is supported by the Wellcome Trust (grant number 104241/z/14/z) TP is a Royal Society/Wolfson Merit Award Holder.BACKGROUND: Type VII protein secretion (T7SS) is a specialised system for excreting extracellular proteins across bacterial cell membranes and has been associated with virulence in Staphylococcus aureus. The genetic diversity of the ess locus, which encodes the T7SS, and the functions of proteins encoded within it are poorly understood. RESULTS: We used whole genome sequence data from 153 isolates representative of the diversity of the species to investigate the genetic variability of T7SS across S. aureus. The ess loci were found to comprise of four distinct modules based on gene content and relative conservation. Modules 1 and 4, comprising of the 5' and 3' modules of the ess locus, contained the most conserved clusters of genes across the species. Module 1 contained genes encoding the secreted protein EsxA, and the EsaAB and EssAB components of the T7SS machinery, and Module 4 contained two functionally uncharacterized conserved membrane proteins. Across the species four variants of Module 2 were identified containing the essC gene, each of which was associated with a specific group of downstream genes. The most diverse module of the ess locus was Module 3 comprising a highly variable arrangement of hypothetical proteins. RNA-Seq was performed on representatives of the four Module 2 variants and demonstrated strain-specific differences in the levels of transcription in the conserved Module 1 components and transcriptional linkage Module 2, and provided evidence of the expression of genes the variable regions of the ess loci. CONCLUSIONS: The ess locus of S. aureus exhibits modularity and organisational variation across the species and transcriptional variation. In silico analysis of ess loci encoded hypothetical proteins identified potential novel secreted substrates for the T7SS. The considerable variety in operon arrangement between otherwise closely related isolates provides strong evidence for recombination at this locus. Comparison of these recombination regions with each other, and with the genomes of other Staphylococcal species, failed to identify evidence of intra- and inter-species recombination, however the analysis identified a novel T7SS in another pathogenic staphylococci, Staphylococcus lugdunensis.Publisher PDFPeer reviewe

Decadally resolved lateglacial radiocarbon evidence from New Zealand kauri

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of Arizona Board of Regents on behalf of the University of Arizona for personal use, not for redistribution. The definitive version was published in Radiocarbon 58 (2016): 709-733, doi: 10.1017/RDC.2016.86.The Last Glacial-Interglacial Transition (LGIT; 15,000-11,000 cal BP) was characterized by complex spatiotemporal patterns of climate change, with numerous studies requiring accurate chronological control to decipher leads from lags in global paleoclimatic, -environmental and archaeological records. However, close scrutiny of the few available tree-ring chronologies and 14C-dated sequences composing the IntCal13 radiocarbon calibration curve, indicates significant weakness in 14C calibration across key periods of the LGIT. Here, we present a decadally-resolved atmospheric 14C record derived from New Zealand kauri spanning the Lateglacial from ~13,100 - 11,365 cal BP. Two floating kauri 14C time series, curve-matched to IntCal13, serve as a radiocarbon backbone through the Younger Dryas. The floating Northern Hemisphere (NH) 14C datasets derived from the YD-B and Central European Lateglacial Master tree-ring series are matched against the new kauri data, forming a robust NH 14C time series to ~14,200 cal BP. Our results show that IntCal13 is questionable from ~12,200 - 11,900 cal BP and the ~10,400 BP 14C plateau is approximately five decades too short. The new kauri record and re-positioned NH pine 14C series offer a refinement of the international 14C calibration curves IntCal13 and SHCal13, providing increased confidence in the correlation of global paleorecords.This work was part funded by the Foundation for Research, Science and Technology (FRST)—now Ministry for Business, Innovation & Employment (MBIE)-PROP-20224-SFK-UOA), a Royal Society of New Zealand grant, the Australian Research Council (FL100100195 and DP0664898) and the Natural Environment Research Council (NE/H009922/1, NE/I007660/1, NER/A/S/2001/01037 and NE/H007865/1)

Interrogation of IDH1 Status in Gliomas by Fourier Transform Infrared Spectroscopy

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are found in a high proportion of diffuse gliomas. The presence of the IDH1 mutation is a valuable diagnostic, prognostic and predictive biomarker for the management of patients with glial tumours. Techniques involving vibrational spectroscopy, e.g., Fourier transform infrared (FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer detection, and have the potential to contribute to diagnostics. The implementation of FTIR microspectroscopy during surgical biopsy could present a fast, label-free method for molecular genetic classification. For example, the rapid determination of IDH1 status in a patient with a glioma diagnosis could inform intra-operative decision-making between alternative surgical strategies. In this study, we utilized synchrotron-based FTIR microanalysis to probe tissue microarray sections from 79 glioma patients, and distinguished the positive class (IDH1-mutated) from the IDH1-wildtype glioma, with a sensitivity and specificity of 82.4% and 83.4%, respectively. We also examined the ability of attenuated total reflection (ATR)-FTIR spectroscopy in detecting the biomolecular events and global epigenetic and metabolic changes associated with mutations in the IDH1 enzyme, in blood serum samples collected from an additional 72 brain tumour patients. Centrifugal filtration enhanced the diagnostic ability of the classification models, with balanced accuracies up to ~69%. Identification of the molecular status from blood serum prior to biopsy could further direct some patients to alternative treatment strategies

The Study on Stress, Spirituality, and Health (SSSH): Psychometric Evaluation and Initial Validation of the SSSH Baseline Spirituality Survey

This paper describes the development and initial psychometric testing of the baseline Spirituality Survey (SS-1) from the Study on Stress, Spirituality, and Health (SSSH) which contained a mixture of items selected from validated existing scales and new items generated to measure important constructs not captured by existing instruments. The purpose was to establish the validity of new and existing measures in our racially/ethnically diverse sample. Psychometric properties of the SS-1 were evaluated using standard psychometric analyses in 4,634 SSSH participants. Predictive validity of SS-1 scales was assessed in relation to the physical and mental health component scores from the Short-Form 12 Health Survey (SF-12). Scales exhibited adequate to strong psychometric properties and demonstrated construct and predictive validity. Overall, the correlational findings provide solid evidence that the SS-1 scales are associated with a wide range of relevant R/S attitudes, mental health, and to a lesser degree physical health

Clinical validation of a spectroscopic liquid biopsy for earlier detection of brain cancer

BackgroundDiagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most.MethodsBlood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease.ResultsOur liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%).ConclusionsThis simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care

Dynamical Mass Measurement of the Young Spectroscopic Binary V343 Normae AaAb Resolved With the Gemini Planet Imager

We present new spatially resolved astrometry and photometry from the Gemini Planet Imager of the inner binary of the young multiple star system V343 Normae, which is a member of the beta Pictoris moving group. V343 Normae comprises a K0 and mid-M star in a ~4.5 year orbit (AaAb) and a wide 10" M5 companion (B). By combining these data with archival astrometry and radial velocities we fit the orbit and measure individual masses for both components of M_Aa = 1.10 +/- 0.10 M_sun and M_Ab = 0.290 +/- 0.018 M_sun. Comparing to theoretical isochrones, we find good agreement for the measured masses and JHK band magnitudes of the two components consistent with the age of the beta Pic moving group. We derive a model-dependent age for the beta Pic moving group of 26 +/- 3 Myr by combining our results for V343 Normae with literature measurements for GJ 3305, which is another group member with resolved binary components and dynamical masses.Comment: 12 pages, 7 figures. Accepted to A

Punctuated shutdown of Atlantic Meridional Overturning circulation during Greenland Stadial 1

The Greenland Stadial 1 (GS-1; ~12.9 to 11.65 kyr cal BP) was a period of North Atlantic cooling, thought to have been initiated by North America fresh water runof that caused a sustained reduction of North Atlantic Meridional Overturning Circulation (AMOC), resulting in an antiphase temperature response between the hemispheres (the ‘bipolar seesaw’). Here we exploit sub-fossil New Zealand kauri trees to report the frst securely dated, decadally-resolved atmospheric radiocarbon (¹⁴C) record spanning GS-1. By precisely aligning Southern and Northern Hemisphere tree-ring ¹⁴C records with marine ¹⁴C sequences we document two relatively short periods of AMOC collapse during the stadial, at ~12,920-12,640 cal BP and 12,050-11,900 cal BP. In addition, our data show that the interhemispheric atmospheric ¹⁴C ofset was close to zero prior to GS-1, before reaching ‘near-modern’ values at ~12,660 cal BP, consistent with synchronous recovery of overturning in both hemispheres and increased Southern Ocean ventilation. Hence, sustained North Atlantic cooling across GS-1 was not driven by a prolonged AMOC reduction but probably due to an equatorward migration of the Polar Front, reducing the advection of southwesterly air masses to high latitudes. Our fndings suggest opposing hemispheric temperature trends were driven by atmospheric teleconnections, rather than AMOC changes

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy