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We present a dataset of 1,119 radiocarbon dates and their contexts for Oaxaca, Mexico, a best effort to include all published dates, plus hundreds of unpublished samples. We illustrate its potential and limitations with five examples: (1) dated stratigraphy in stream cutbanks show how aggradation, downcutting, and stability responded to global climate and human activities; (2) 14C samples from Late/Terminal Formative contexts allow interregional comparisons of temple and palace construction, use, and abandonment; (3) new 14C dates provide better understanding of events during the Late Classic/Epiclassic, a problematic time in the ceramic chronology; (4) individual Classic/Postclassic residential contexts had long durations—several hundred years; and (5) model constraints from other data permit refinement at times of calibration curve deviation, as during AD 1400–1600. We recommend further chronological refinement with best-practice standards, new samples, existing collections, and statistical modeling.
Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods
T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results
PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).
Conclusions
PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.
An alternative to an “all or none” approach to contact precautions for patients with MRSA carriage may be a “risk-tailored” approach – using gloves and gowns only for certain high-risk activities, locations, or roles.
Methods:
We distributed a discrete choice experiment to healthcare personnel (HCPs) in three cities. Respondents were presented with eight choice sets, each consisting of two hypothetical policy options for glove and gown use to prevent MRSA transmission. In each comparison, respondents selected their preferred option. Using mixed logit modeling we calculated utility derived from each policy component, probability of uptake for the most favored policies, and heterogeneity in preferences based on HCP role.
Results:
In total, 326 HCPs completed the survey. 237 (54%) respondents reported wearing gloves and gowns ‘all the time’ when required. Respondents’ preferred policy with the highest utility score was to use gloves and gown for all HCPs roles (utility, 0.17; 95% CI, 0.12 to 0.23), in high-risk settings (utility, 0.12; 95% CI 0.07–0.18), when touching the patient (utility, 0.11; 95% CI 0.06–0.17). Sixty-three percent (95% CI 60–66) would support a risk-tailored approach over an approach where contact precautions are used by all HCPs in all settings and for all activities. Support varied by HCP role (p < 0.02), with the strongest probability of support from physicians and advanced practice providers (77%, 95% CI 72%–82%) and the least support from environmental services personnel (45%, 95% CI 37%–53%).
Conclusions:
This discrete choice survey demonstrates that most HCPs prefer a risk-tailored approach to contact precautions when caring for patients with MRSA.
Objectives/Goals: Trainees in clinical and translational science (CTS) must learn to effectively communicate their research ideas and findings to a range of audiences. As part of our science communication curriculum, we developed ORAL and WRITTEN science communication rubrics for our trainees to use across their courses and research activities. Methods/Study Population: The Tufts CTS Graduate Program is the training core of the Tufts CTSI and its associated pre- and post-doctoral T32 awards. Approximately 10 trainees with a range of backgrounds (e.g., physicians, medical students, master’s-level researchers, and basic science PhDs) matriculate each year. Faculty members and staff with expertise in science communication and pedagogy formed a committee to develop the rubrics. Because oral and written communication require different skills, we developed separate rubrics for each. We reviewed our current science communication curriculum, reviewed existing communication rubrics, and identified common mistakes students make. Following pilot testing by students and faculty pilot for one semester, we modified the rubrics based on informal feedback. Results/Anticipated Results: Both rubrics include a section to identify the target audience and specific items organized by theme. Oral rubric themes include presentation content, slides, verbal communication, nonverbal communication, and following instructions. Written rubric themes include overall, manuscript/proposal sections, and following instructions. The rubrics serve as feedback tools for faculty and students to evaluate work others produce and as self-evaluation tools. Feedback elements include a 4-point rating for each rubric item, open text feedback for each theme, and an open text holistic assessment. We now use the rubrics in our study design course, which features student presentations of planned research, and in our writing course. We anticipate collecting formal student feedback to further evaluate the rubrics. Discussion/Significance of Impact: Our rubrics can supplement existing science communication training and can be integrated into all CTS coursework and research activities. For future clinical and translational scientists to have the greatest impact, they must learn to effectively communicate findings to multiple audiences, ranging from experts in their field to the general public.
Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and infertility, we conducted a genome-wide association study (GWAS) on mothers of spontaneous DZ twins (MoDZT) versus controls (3273 cases, 24,009 controls). This is a follow-up study to the Australia/New Zealand (ANZ) component of that previously reported (Mbarek et al., 2016), with a sample size almost twice that of the entire discovery sample meta-analysed in the previous article (and five times the ANZ contribution to that), resulting from newly available additional genotyping and representing a significant increase in power. We compare analyses with and without male controls and show unequivocally that it is better to include male controls who have been screened for recent family history, than to use only female controls. Results from the SNP based GWAS identified four genomewide significant signals, including one novel region, ZFPM1 (Zinc Finger Protein, FOG Family Member 1), on chromosome 16. Previous signals near FSHB (Follicle Stimulating Hormone beta subunit) and SMAD3 (SMAD Family Member 3) were also replicated (Mbarek et al., 2016). We also ran the GWAS with a dominance model that identified a further locus ADRB2 on chr 5. These results have been contributed to the International Twinning Genetics Consortium for inclusion in the next GWAS meta-analysis (Mbarek et al., in press).
Ice-crystal fabric can induce mechanical anisotropy that significantly affects flow, but ice-flow models generally do not include fabric development or its effect upon flow. Here, we incorporate a new spectral expansion of fabric, and more complete description of its evolution, into the ice-flow model Elmer/Ice. This approach allows us to model the effect of both lattice rotation and migration recrystallization on large-scale ice flow. The fabric evolution is coupled to flow using an unapproximated non-linear orthotropic rheology that better describes deformation when the stress and fabric states are misaligned. These improvements are most relevant for simulating dynamically interesting areas, where recrystallization can be important, tuning data are scarce and rapid flow can lead to misalignment between stress and fabric. We validate the model by comparing simulated fabric to ice-core and phase-sensitive radar measurements on a transect across Dome C, East Antarctica. With appropriately tuned rates for recrystallization, the model is able to reproduce observations of fabric. However, these tuned rates differ from those previously derived from laboratory experiments, suggesting a need to better understand how recrystallization acts differently in the laboratory compared to natural settings.
Children need to be repeatedly and consistently exposed to a variety of vegetables from an early age to achieve an increase in vegetable intake. A focus on enjoyment and learning to like eating vegetables at an early age is critical to forming favourable lifelong eating habits. Coordinated work is needed to ensure vegetables are available and promoted in a range of settings, using evidence-based initiatives, to create an environment that will support children’s acceptance of vegetables. This will help to facilitate increased intake and ultimately realise the associated health benefits. The challenges and evidence base for a new approach are described.
OBJECTIVES/GOALS: We aim to discover safer and more effective therapeutics for CNS disorders. Current therapeutic development is hindered by dosing out drugs for safe consumption. By identifying proteins with narrow functional roles in the brain (i.e., behavioral control), we can develop drugs targeting these proteins for improved treatment safety and efficacy. METHODS/STUDY POPULATION: We focused on an evolutionarily new, non-neuronal, non-synaptic glutamate signaling mechanism, system xc- (Sxc). Sxc activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc). To confirm Sxc mutation, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on behavioral control, such as impulse control and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on behavioral control were impaired. MSxc rats displayed deficits in impulse control and behavioral flexibility. We hypothesize that MSxc rats will also show deficits in response inhibition using the stop signal reaction time task, a common metric used in clinical populations. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on impulse control, without impacting development or simple brain function. These results show the potential of targeting Sxc to restore behavioral control without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.
Cover crops (CCs) have shown great potential for suppressing annual weeds within agronomic cropping systems across the United States. However, the weed suppressive potential of CCs may be moderated by environmental and management factors that are specific to certain geographic areas and their associated characteristics. This may be particularly true within the U.S. Southeast, where higher mean annual temperature and precipitation generate favorable conditions for both CC and weed growth. To understand the effects of this regional context on CCs and weeds, a meta-analysis examining paired comparisons of weed biomass and/or weed density under CC and bare ground conditions from studies conducted within the Southeast was conducted. Data were identified and extracted from 28 journal articles in which weed biomass and/or weed density were measured along with cash crop yield data, if they were provided. Fourteen studies provided 142 comparisons for weed biomass; 23 studies provided 139 comparisons for weed density; and 22 studies, pooled over both weed response variables, provided 144 comparisons for cash crop yield. CCs had a negative effect on weed density (P = 0.0016) but no effect on either weed biomass (P = 0.16) or cash crop yield (P = 0.88). The mean relative reduction in weed density under CCs was 44%. Subsequent analyses indicated that CC biomass was the key factor associated with this reduction. Weed density suppression was linearly related to CC biomass; a 50% decrease in weed density was associated with 6,600 kg ha−1 of CC biomass. Edaphic, geographic, and other management factors had no bearing on this suppressive effect. This highlights the importance of generating adequate CC biomass if weed suppression is the primary objective of CC use and the potential for CCs to reduce weed density over diverse soil, climate, and farm management conditions.
We compare different ways the bulk flow nonlinearity of glacier ice can be captured in an orthotropic rheology. Specifically, we compare the unapproximated orthotropic rheology, derived from plastic potential theory, to existing approximations that assume either the nonlinear viscosity or fluidity is identical to that of Glen's isotropic flow law. We find, overall, a reasonable agreement between the three orthotropic rheologies, and with existing Dye 3 ice-core deformation tests, although assuming Glen's viscosity provides the best approximation to the unapproximated rheology. Our results therefore suggest that previous studies based on either approximation to the orthotropic rheology are on relatively safe ground in the sense that both approximations generally agree with the unapproximated rheology and experimental data. Finally, we provide the forward and inverse analytical forms of all three rheologies for use in future numerical ice-flow modelling.
OBJECTIVES/GOALS: We aim to determine whether non-neuronal, non-synaptic glutamate signaling mechanisms can be targeted to produce highly specific, narrow changes in brain function that would benefit CNS disorders. To do this, we investigated cognitive changes produced through manipulating the activity of the astrocytic glutamate release mechanism system xc-. METHODS/STUDY POPULATION: System xc- (Sxc) activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc rats). To confirm a lack of Sxc activity, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on executive function, such as cognitive flexibility, impulse control, decision-making, and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on executive function were impaired. MSxc rats displayed deficits in cocaine reinstatement and attentional set-shifting. We anticipate MSxc rats to also show impairments in decision-making in the rat gambling task and response inhibition in the stop-signal reaction time task. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on executive function without impacting development or simple brain function. These results highlight the potential of targeting Sxc to enhance cognition without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.
The utilization of remote sensing in agriculture has great potential to change the methods of field scouting for weeds. Previous remote sensing research has been focused on the ability to detect and differentiate between species. However, these studies have not addressed weed density variability throughout a field. Furthermore, the impact of changing phenology of crops and weeds within and between growing seasons has not been investigated. To address these research gaps, field studies were conducted in 2016 and 2017 at the Horticultural Crops Research Station near Clinton, NC. Two problematic weed species, Palmer amaranth (Amaranthus palmeri S. Watson) and large crabgrass [Digitaria sanguinalis (L.) Scop.], were planted at four densities in soybean [Glycine max (L.) Merr.]. Additionally, these weed densities were grown in the presence and absence of the crop to determine the influence of crop presence on the detection and discrimination of weed species and density. Hyperspectral data were collected over various phenological time points in each year. Differentiation between plant species and weed density was not consistent across cropping systems, phenology, or season. Weed species were distinguishable across more spectra when no soybean was present. In 2016, weed species were not distinguishable, while in 2017, differentiation occurred at 4 wk after planting (WAP) and 15 WAP when weeds were present with soybean. When soybean was not present, differentiation occurred only at 5 WAP in 2016 and at 3 WAP through 15 WAP in 2017. Differentiation between weed densities did occur in both years with and without soybean present, but weed density could be differentiated across more spectra when soybean was not present. This study demonstrates that weed and crop reflectance is dynamic throughout the season and that spectral reflectance can be affected by weed species and density.
Analysis of patterns of faulting and hydrogeology, stratigraphic and sedimentologic studies, and luminescence dating of aeolian deposits in China Lake basin provide new perspectives on the origins and development of Late Holocene dunes and sand ramps in the seismically active Indian Wells Valley of eastern California. Aeolian dune and sand sheet deposits were sourced from alluvial material derived from granitic rocks of the south-eastern Sierra Nevada and are concentrated in areas with sand-stabilizing phreatophyte vegetation influenced by high groundwater levels along the active oblique-normal Little Lake and Paxton Ranch faults, which locally form barriers to groundwater flow. Three episodes of sand accumulation are recognized (2.1 ± 0.1 to 2.0 ± 0.1 ka, 1.8 ± 0.2 to 1.6 ± 0.2 ka, and 1.2 ± 0.1 to 0.9 ± 0.1 ka) during conditions in which sediment supplied to the basin during periods of enhanced rainfall and runoff was subsequently reworked by wind into dunes and sand ramps at the transition to more arid periods. Understanding the role tectonics plays in influencing the hydrogeology of seismically active lake basins provides insights to accurately interpret landscape evolution and any inferences made on past hydroclimate variability in a region.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
We investigate the errors caused by neglecting the crystal-orientation fabric when inferring the basal friction coefficient field, and whether such errors can be alleviated by inferring an isotropic enhancement factor field to compensate for missing fabric information. We calculate the steady states that arise from ice flowing over a sticky spot and a bedrock bump using a vertical-slab numerical ice-flow model, consisting of a Weertman sliding law and the anisotropic Johnson flow law, coupled to a spectral fabric model of lattice rotation and dynamic recrystallisation. Given the steady or transient states as input for a canonical adjoint-based inversion, we find that Glen's isotropic flow law cannot necessarily be used to infer the true basal drag or friction coefficient field, which are obscured by the orientation fabric, thus potentially affecting vertically integrated mass fluxes. By inverting for an equivalent isotropic enhancement factor, a more accurate mass flux can be recovered, suggesting that joint inversions for basal friction and the isotropic flow-rate factor may be able to compensate for mechanical anisotropies caused by the fabric. Thus, in addition to other sources of rheological uncertainty, fabric might complicate attempts to relate subglacial conditions to basal properties inferred from an inversion relying on Glen's law.
In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.
Methods
Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.
Results
All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.
Conclusions
Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.
Funding
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.