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This review of annually laminated speleothems firstly considers the four types of annual laminae found within speleothems: fluorescentlaminae formed by annual variations in organic matter flux; visible or petrographic laminae, formed by annual variations in calcitetexture or fabric; calcite-aragonite couplets; and finally trace element laminae. The methods available to confirm the annual nature, or otherwise, of lamina deposition are reviewed. We consider the use of annual laminae in chronology building, with particular relevanceto palaeoclimate reconstructions. Finally, the use of annual lamina width as a palaeoclimate proxy is reviewed.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.earscirev.2005.08.003 Byline: Ian J. Fairchild (a), Claire L. Smith (a), Andy Baker (a), Lisa Fuller (a), Christoph Spotl (b), Dave Mattey (c), Frank McDermott (d), E.I.M.F. (e) Keywords: Speleothems; Stable isotopes; Trace elements; Palaeoclimate; Time series analysis; Karst Abstract: Speleothems are primarily studied in order to generate archives of climatic change and results have led to significant advances in identifying and dating major shifts in the climate system. However, the climatological meaning of many speleothem records cannot be interpreted unequivocally; this is particularly so for more subtle shifts and shorter time periods, but the use of multiple proxies and improving understanding of formation mechanisms offers a clear way forward. An explicit description of speleothem records as time series draws attention to the nature and importance of the signal filtering processes by which the weather, the seasons, and longer-term climatic and other environmental fluctuations become encoded in speleothems. We distinguish five sources of variation that influence speleothem geochemistry, i.e. atmospheric, vegetation/soil, karstic aquifer, primary speleothem crystal growth and secondary alteration, and give specific examples of their influence. The direct role of climate diminishes progressively through these five factors. We identify and review a number of processes identified in recent and current work that bear significantly on the conventional interpretation of speleothem records, for example: (1) speleothem geochemistry can vary seasonally and hence a research need is to establish the proportion of growth attributable to different seasons and whether this varies over time; (2) whereas there has traditionally been a focus on monthly mean [delta].sup.18O data of atmospheric moisture, current work emphasizes the importance of understanding the synoptic processes that lead to characteristic isotope signals, since changing relative abundance of different weather types might control their variation on the longer-term; (3) the ecosystem and soil zone overlying the cave fundamentally imprint the carbon and trace element signals and can show characteristic variations with time; (4) new modelling on aquifer plumbing allows quantification of the effects of aquifer mixing; (5) recent work has emphasized the importance and seasonal variability of CO.sub.2-degassing leading to calcite precipitation upflow of a depositional site on carbon isotope and trace element composition of speleothems; (6) although much is known about the chemical partitioning between water and stalagmites, variability in relation to crystal growth mechanisms and kinetics is a research frontier; (7) aragonite is susceptible to conversion to calcite with major loss of chemical information, but the controls on the rate of this process are obscure. Analytical factors are critical in generating high-resolution speleothem records. A variety of methods of trace element analysis is available, but standardization is a common problem with the most rapid methods. New stable isotope data on Irish stalagmite CC3 compares rapid laser-ablation techniques with the conventional analysis of micromilled powders and ion microprobe methods. A high degree of comparability between techniques for [delta].sup.18O is found on the millimeter to centimeter scale, but a previously described high-amplitude oxygen isotope excursion around 8.3 ka is identified as an analytical artefact related to fractionation of the laser-analysis associated with sample cracking. High-frequency variability of not less than 0.5a[degrees] may be an inherent feature of speleothem [delta].sup.18O records. Author Affiliation: (a) School of Geography, Earth and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK (b) Institut fur Geologie und Palaontologie, Leopold-Franzens-Universitat Innsbruck, Innrain 52, 6020 Innsbruck, Austria (c) Department of Geology, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK (d) UCD School of Geological Sciences, University College Dublin, Belfield, Dublin 4, Ireland (e) Edinburgh Ion Microprobe Facility, Institute of Earth Science, School of Geosciences, University of Edinburgh EH9 3JW, UK Article History: Received 20 May 2005; Accepted 5 August 2005

Background: Deregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL. Methods: JJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level. Results: In total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels. Conclusions: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL. This report describes the clinical activity of a highly potent and selective Notch inhibitor, Crenigacestat, in combination with dexamethasone in adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (‐LBL). In this study, the recommended phase 2 dose of 75 mg of Crenigacestat 3 times per week is established for patients with T‐ALL/T‐LBL in combination with dexamethasone. [ABSTRACT FROM AUTHOR]

Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14‐mm improvement and ≤1% risk for a placebo‐like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment. [ABSTRACT FROM AUTHOR]

In State v. Hayes, the North Dakota Supreme Court held a district court abuses its discretion when it imposes a pretrial release condition on a defendant requiring her to submit to warrantless searches and seizures of her person, vehicle, and home under North Dakota Rule of Criminal Procedure 46(a)(2)(M), without first finding those conditions were necessary. In addition, the court held when a person is left between the choice of violating his or her bail conditions or consenting to a search, the person is unable to consent without coercion. Finally, the court held the good faith exception to the warrant requirement did not apply to the officer's enforcement of the bond order signed by the district court. The decision in Hayes will significantly affect pretrial release in North Dakota, because district courts will no longer be able to impose any pretrial release conditions under Rule 46(a)(2)(M) without an explicit finding of their appropriateness in a neutral and detached manner. [ABSTRACT FROM AUTHOR]

Determines the relationship between defoliation levels and reproductive fitness through fruit and seed of Vicia sativa. Reduction in seeds in artificially-defoliated plants; Germination rates of seeds from artificially-defoliated Vicia; Implication on the plant's survival.

Domestic gardens are an important component of cities, contributing significantly to urban green infrastructure (GI) and its associated ecosystem services. However, domestic gardens are incredibly heterogeneous which presents challenges for quantifying their GI contribution and associated benefits for sustainable urban development. This study applies an innovative methodology that combines citizen science data with high resolution image analysis to create a garden dataset in the case study city of Manchester, UK. An online Citizen Science Survey (CSS) collected estimates of proportional coverage for 10 garden land surface types from 1031 city residents. High resolution image analysis was conducted to validate the CSS estimates, and to classify 7 land surface cover categories for all garden parcels in the city. Validation of the CSS land surface estimations revealed a mean accuracy of 76.63% (s = 15.24%), demonstrating that citizens are able to provide valid estimates of garden surface coverage proportions. An Object Based Image Analysis (OBIA) classification achieved an estimated overall accuracy of 82%, with further processing required to classify shadow objects. CSS land surface estimations were then extrapolated across the entire classification through calculation of within image class proportions, to provide the proportional coverage of 10 garden land surface types (buildings, hard impervious surfaces, hard pervious surfaces, bare soil, trees, shrubs, mown grass, rough grass, cultivated land, water) within every garden parcel in the city. The final dataset provides a better understanding of the composition of GI in domestic gardens and how this varies across the city. An average garden in Manchester has 50.23% GI, including trees (16.54%), mown grass (14.46%), shrubs (9.19%), cultivated land (7.62%), rough grass (1.97%) and water (0.45%). At the city scale, Manchester has 49.0% GI, and around one fifth (20.94%) of this GI is contained within domestic gardens. This is useful evidence to inform local urban development policies. [ABSTRACT FROM AUTHOR]

Neonatal infection remains a primary cause of infant morbidity and mortality worldwide and yet our understanding of how human neonates respond to infection remains incomplete. Changes in host gene expression in response to infection may occur in any part of the body, with the continuous interaction between blood and tissues allowing blood cells to act as biosensors for the changes. In this study we have used whole blood transcriptome profiling to systematically identify signatures and the pathway biology underlying the pathogenesis of neonatal infection. Blood samples were collected from neonates at the first clinical signs of suspected sepsis alongside age matched healthy control subjects. Here we report a detailed description of the study design, including clinical data collected, experimental methods used and data analysis workflows and which correspond with data in Gene Expression Omnibus (GEO) data sets (GSE25504). Our data set has allowed identification of a patient invariant 52-gene classifier that predicts bacterial infection with high accuracy and lays the foundation for advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis.