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In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD.
Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores.
Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores.
Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
Herbicide-resistant Amaranthus spp. continue to cause management difficulties in soybean. New soybean technologies under development, including resistance to various combinations of glyphosate, glufosinate, dicamba, 2,4-D, isoxaflutole, and mesotrione, will make possible the use of additional herbicide sites of action in soybean than is currently available. When this research was conducted, these soybean traits were still regulated and testing herbicide programs with the appropriate soybean genetics in a single experiment was not feasible. Therefore, the effectiveness of various herbicide programs (PRE herbicides followed by POST herbicides) was evaluated in bare-ground experiments on glyphosate-resistant Palmer amaranth and glyphosate-resistant waterhemp (both tall and common) at locations in Arkansas, Illinois, Indiana, Missouri, Nebraska, and Tennessee. Twenty-five herbicide programs were evaluated; 5 of which were PRE herbicides only, 10 were PRE herbicides followed by POST herbicides 3 to 4 wks after (WA) the PRE application (EPOST), and 10 were PRE herbicides followed by POST herbicides 6 to 7 WA the PRE application (LPOST). Programs with EPOST herbicides provided 94% or greater control of Palmer amaranth and waterhemp at 3 to 4 WA the EPOST. Overall, programs with LPOST herbicides resulted in a period of weed emergence in which weeds would typically compete with a crop. Weeds were not completely controlled with the LPOST herbicides because weed sizes were larger (≥ 15 cm) compared with their sizes at the EPOST application (≤ 7 cm). Most programs with LPOST herbicides provided 80 to 95% control at 3 to 4 WA applied LPOST. Based on an orthogonal contrast, using a synthetic-auxin herbicide LPOST improves control of Palmer amaranth and waterhemp over programs not containing a synthetic-auxin LPOST. These results show herbicides that can be used in soybean and that contain auxinic- or HPPD-resistant traits will provide growers with an opportunity for better control of glyphosate-resistant Palmer amaranth and waterhemp over a wide range of geographies and environments.
Field studies were conducted at 35 sites throughout the north-central United States in 1998 and 1999 to determine the effect of postemergence glyphosate application timing on weed control and grain yield in glyphosate-resistant corn. Glyphosate was applied at various timings based on the height of the most dominant weed species. Weed control and corn grain yields were considerably more variable when glyphosate was applied only once. The most effective and consistent season-long annual grass and broadleaf weed control occurred when a single glyphosate application was delayed until weeds were 15 cm or taller. Two glyphosate applications provided more consistent weed control when weeds were 10 cm tall or less and higher corn grain yields when weeds were 5 cm tall or less, compared with a single application. Weed control averaged at least 94 and 97% across all sites in 1998 and 1999, respectively, with two glyphosate applications but was occasionally less than 70% because of late emergence of annual grass and Amaranthus spp. or reduced control of Ipomoea spp. With a single application of glyphosate, corn grain yield was most often reduced when the application was delayed until weeds were 23 cm or taller. Averaged across all sites in 1998 and 1999, corn grain yields from a single glyphosate application at the 5-, 10-, 15-, 23-, and 30-cm timings were 93, 94, 93, 91, and 79% of the weed-free control, respectively. There was a significant effect of herbicide treatment on corn grain yield in 23 of the 35 sites when weed reinfestation was prevented with a second glyphosate application. When weed reinfestation was prevented, corn grain yield at the 5-, 10-, and 15-cm application timings was 101, 97, and 93% of the weed-free control, respectively, averaged across all sites. Results of this study suggested that the optimum timing for initial glyphosate application to avoid corn grain yield loss was when weeds were less than 10 cm in height, no more than 23 d after corn planting, and when corn growth was not more advanced than the V4 stage.
Palmer amaranth and waterhemp have become increasingly troublesome weeds throughout the United States. Both species are highly adaptable and emerge continuously throughout the summer months, presenting the need for a residual PRE application in soybean. To improve season-long control of Amaranthus spp., 19 PRE treatments were evaluated on glyphosate-resistant Palmer amaranth in 2013 and 2014 at locations in Arkansas, Indiana, Nebraska, Illinois, and Tennessee; and on glyphosate-resistant waterhemp at locations in Illinois, Missouri, and Nebraska. The two Amaranthus species were analyzed separately; data for each species were pooled across site-years, and site-year was included as a random variable in the analyses. The dissipation of weed control throughout the course of the experiments was compared among treatments with the use of regression analysis where percent weed control was described as a function of time (the number of weeks after treatment [WAT]). At the mean (i.e., average) WAT (4.3 and 3.2 WAT for Palmer amaranth and waterhemp, respectively) isoxaflutole + S-metolachlor + metribuzin had the highest predicted control of Palmer amaranth (98%) and waterhemp (99%). Isoxaflutole + S-metolachlor + metribuzin, S-metolachlor + mesotrione, and flumioxazin + pyroxasulfone had a predicted control ≥ 97% and similar model parameter estimates, indicating control declined at similar rates for these treatments. Dicamba and 2,4-D provided some, short-lived residual control of Amaranthus spp. When dicamba was added to metribuzin or S-metolachlor, control increased compared to dicamba alone. Flumioxazin + pyroxasulfone, a currently labeled PRE, performed similarly to treatments containing isoxaflutole or mesotrione. Additional sites of action will provide soybean growers more opportunities to control these weeds and reduce the potential for herbicide resistance.
Field experiments were conducted across the north-central United States to determine the benefits of various weed control strategies in corn. Weed control, corn yield, and economic return increased when a preemergence (PRE) broad-spectrum herbicide was followed by (fb) postemergence (POST) herbicides. Weed control decisions based on field scouting after a PRE broad-spectrum herbicide application increased weed control and economic return. Application of a PRE grass herbicide fb a POST herbicide based on field scouting resulted in less control of velvetleaf and morningglory species, corn yield, and economic return compared with a PRE broad-spectrum herbicide application fb scouting. Cultivation after a PRE broad-spectrum herbicide application increased weed control and corn yield compared with the herbicide applied alone, but economic return was not increased. An early-postemergence herbicide application fb cultivation resulted in the highest level of broadleaf weed control, the highest corn yield, and the greatest economic return compared with all other strategies. Weed control based on scouting proved to be useful in reducing the effect of weed escapes on corn yield and increased economic return compared with PRE herbicide application alone. However, economic return was not greater than the PRE fb planned POST or total POST strategies.
The Middle Jurassic is a poorly sampled time interval for non-pelagic neosuchian crocodyliforms, which obscures our understanding of the origin and early evolution of major clades. Here we report a lower jaw from the Middle Jurassic (Bathonian) Duntulm Formation of the Isle of Skye, Scotland, UK, which consists of an isolated and incomplete left dentary and part of the splenial. Morphologically, the Skye specimen closely resembles the Cretaceous neosuchians Pachycheilosuchus and Pietraroiasuchus, in having a proportionally short mandibular symphysis, shallow dentary alveoli and inferred weakly heterodont dentition. It differs from other crocodyliforms in that the Meckelian canal is dorsoventrally expanded posterior to the mandibular symphysis and drastically constricted at the 7th alveolus. The new specimen, together with the presence of Theriosuchus sp. from the Valtos Formation and indeterminate neosuchians from the Kilmaluag Formation, indicates the presence of a previously unrecognised, diverse crocodyliform fauna in the Middle Jurassic of Skye, and Europe more generally. Small-bodied neosuchians were present, and ecologically and taxonomically diverse, in nearshore environments in the Middle Jurassic of the UK.
The recently developed three-dimensional electron microscopic (EM) method of serial block-face scanning electron microscopy (SBEM) has rapidly established itself as a powerful imaging approach. Volume EM imaging with this scanning electron microscopy (SEM) method requires intense staining of biological specimens with heavy metals to allow sufficient back-scatter electron signal and also to render specimens sufficiently conductive to control charging artifacts. These more extreme heavy metal staining protocols render specimens light opaque and make it much more difficult to track and identify regions of interest (ROIs) for the SBEM imaging process than for a typical thin section transmission electron microscopy correlative light and electron microscopy study. We present a strategy employing X-ray microscopy (XRM) both for tracking ROIs and for increasing the efficiency of the workflow used for typical projects undertaken with SBEM. XRM was found to reveal an impressive level of detail in tissue heavily stained for SBEM imaging, allowing for the identification of tissue landmarks that can be subsequently used to guide data collection in the SEM. Furthermore, specific labeling of individual cells using diaminobenzidine is detectable in XRM volumes. We demonstrate that tungsten carbide particles or upconverting nanophosphor particles can be used as fiducial markers to further increase the precision and efficiency of SBEM imaging.
The seventh annual Teaching and Learning Conference (TLC) was held in Philadelphia, Pennsylvania, from February 5 to 7, 2010, with 224 attendees onsite. The theme for the meeting was “Advancing Excellence in Teaching Political Science.” Using the working-group model, the TLC track format encourages in-depth discussion and debate on research dealing with the scholarship of teaching and learning.
As we have noted before, the WG-IR was created following a Joint Commission Meeting at the IAU General Assembly in Baltimore in 1988, a meeting that provided both diagnosis and prescription for the perceived ailments of infrared photometry at the time. The results were summarized in Milone (1989). The challenges involve how to explain the failure to systematically achieve the milli-magnitude precision expected of infrared photometry and an apparent 3% limit on system transformability. The proposed solution was to re-define the broadband Johnson system, the passbands of which had proven so unsatisfactory that over time effectively different systems proliferated although bearing the same JHKLMNQ designations; the new system needed to be better positioned and centered in the atmospheric windows of the Earth's atmosphere, and the variable water vapour content of the atmosphere needed to be measured in real time to better correct for atmospheric extinction.