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Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels.
Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels.
Overweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28–3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7–2.41), while depression also contributed a significant risk (OR 1.09, 0.27–2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels.
Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.
ABSTRACT IMPACT: Predicting therapeutic responses in GBM. OBJECTIVES/GOALS: The goal of this team approach is to integrate mathematical models of glioblastoma (GBM) infiltrating myeloid cells that contribute to the immunosuppressive phenotype in glioma with experimental data to predict therapeutic responses to combined chemokine receptor and immune checkpoint blockade. METHODS/STUDY POPULATION: Orthotopic murine KR158-luc gliomas were established in fluorescent reporter CCR2WT/RFP CX3CR1WT/GFP mice. Subsequently, an anti-CD31 injection was administered to label the vasculature. Fluorescent imaging and quantification of anti-CD3 stained sections were performed on a range of tumor sizes to acquire vasculature, tumor, T cell, and myeloid cell densities. In parallel, a system of ordinary differential equations was formulated based on biological assumptions to evaluate the change over time of tumor cells, T cells, and infiltrating myeloid cells. The model was then refined and validated by experimental results. RESULTS/ANTICIPATED RESULTS: Fluorescent imaging and quantification revealed a correlation between tumor size and abundance of (CX3CR1+, CCR2-) and (CX3CR1+, CCR2+) myeloid cell populations in the tumor microenvironment. The density of these cell populations and vasculature remained constant as the tumors increased in size. Computer simulations of the mathematical model will predict tumor, myeloid, and T cell dynamics. These simulations will be particularly useful to uncover information regarding myeloid cell dynamics, such as cell entry time into the tumor microenvironment. Parameter sensitivity analysis of the model will inform us of the biological processes driving these tumor-immune cell dynamics. DISCUSSION/SIGNIFICANCE OF FINDINGS: GBM is a challenge as current intervention are ineffective. This study improves the understanding of glioma infiltrating myeloid cells and their impact on tumor progression. The data will serve as a basis for quantitatively predicting therapeutic responses of a novel combination treatment.
The El Cañizar de Villarquemado pollen record covers the last part of MIS 6 to the Late Holocene. We use Tolerance-Weighted Averaging Partial Least Squares (TWA-PLS) to reconstruct mean temperature of the coldest month (MTCO) and growing degree days above 0°C (GDD0) and the ratio of annual precipitation to annual potential evapotranspiration (MI), accounting for the ecophysiological effect of changing CO2 on water-use efficiency. Rapid summer warming occurred during the Zeifen-Kattegat Oscillation at the transition to MIS 5. Summers were cold during MIS 4 and MIS 2, but some intervals of MIS 3 had summers as warm as the warmest phases of MIS 5 or the Holocene. Winter temperatures declined from MIS 4 to MIS 2. Changes in temperature seasonality within MIS 5 and MIS 1 are consistent with insolation seasonality changes. Conditions became progressively more humid during MIS 5, and MIS 4 was also humid, although MIS 3 was more arid. Changes in MI and GDD0 are anti-correlated, with increased MI during summer warming intervals. Comparison with other records shows glacial-interglacial changes were not unform across the circum-Mediterranean region, but available quantitative reconstructions are insufficient to determine if east-west differences reflect the circulation-driven precipitation dipole seen in recent decades.
Most techniques for pollen-based quantitative climate reconstruction use modern assemblages as a reference data set. We examine the implication of methodological choices in the selection and treatment of the reference data set for climate reconstructions using Weighted Averaging Partial Least Squares (WA-PLS) regression and records of the last glacial period from Europe. We show that the training data set used is important because it determines the climate space sampled. The range and continuity of sampling along the climate gradient is more important than sampling density. Reconstruction uncertainties are generally reduced when more taxa are included, but combining related taxa that are poorly sampled in the data set to a higher taxonomic level provides more stable reconstructions. Excluding taxa that are climatically insensitive, or systematically overrepresented in fossil pollen assemblages because of known biases in pollen production or transport, makes no significant difference to the reconstructions. However, the exclusion of taxa overrepresented because of preservation issues does produce an improvement. These findings are relevant not only for WA-PLS reconstructions but also for similar approaches using modern assemblage reference data. There is no universal solution to these issues, but we propose a number of checks to evaluate the robustness of pollen-based reconstructions.
Single nucleotide polymorphisms (SNPs) contribute small increases in risk for late-onset Alzheimer's disease (LOAD). LOAD SNPs cluster around genes with similar biological functions (pathways). Polygenic risk scores (PRS) aggregate the effect of SNPs genome-wide. However, this approach has not been widely used for SNPs within specific pathways.
We investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.
We mapped SNPs to genes within 8 pathways implicated in LOAD. For our polygenic analysis, the discovery sample comprised 13,831 LOAD cases and 29,877 controls. LOAD risk alleles for SNPs in our 8 pathways were identified at a P-value threshold of 0.5. Pathway-specific PRS were calculated in a target sample of 3332 cases and 9832 controls. The genetic data were pruned with R2 > 0.2 while retaining the SNPs most significantly associated with AD. We tested whether pathway-specific PRS were associated with LOAD using logistic regression, adjusting for age, sex, country, and principal components. We report the proportion of variance in liability explained by each pathway.
The most strongly associated pathways were the immune response (NSNPs = 9304, = 5.63 × 10−19, R2 = 0.04) and hemostasis (NSNPs = 7832, P = 5.47 × 10−7, R2 = 0.015). Regulation of endocytosis, hematopoietic cell lineage, cholesterol transport, clathrin and protein folding were also significantly associated but accounted for less than 1% of the variance. With APOE excluded, all pathways remained significant except proteasome-ubiquitin activity and protein folding.
Genetic risk for LOAD can be split into contributions from different biological pathways. These offer a means to explore disease mechanisms and to stratify patients.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
We present a detailed overview of the cosmological surveys that we aim to carry out with Phase 1 of the Square Kilometre Array (SKA1) and the science that they will enable. We highlight three main surveys: a medium-deep continuum weak lensing and low-redshift spectroscopic HI galaxy survey over 5 000 deg2; a wide and deep continuum galaxy and HI intensity mapping (IM) survey over 20 000 deg2 from
$z = 0.35$
to 3; and a deep, high-redshift HI IM survey over 100 deg2 from
$z = 3$
to 6. Taken together, these surveys will achieve an array of important scientific goals: measuring the equation of state of dark energy out to
$z \sim 3$
with percent-level precision measurements of the cosmic expansion rate; constraining possible deviations from General Relativity on cosmological scales by measuring the growth rate of structure through multiple independent methods; mapping the structure of the Universe on the largest accessible scales, thus constraining fundamental properties such as isotropy, homogeneity, and non-Gaussianity; and measuring the HI density and bias out to
$z = 6$
. These surveys will also provide highly complementary clustering and weak lensing measurements that have independent systematic uncertainties to those of optical and near-infrared (NIR) surveys like Euclid, LSST, and WFIRST leading to a multitude of synergies that can improve constraints significantly beyond what optical or radio surveys can achieve on their own. This document, the 2018 Red Book, provides reference technical specifications, cosmological parameter forecasts, and an overview of relevant systematic effects for the three key surveys and will be regularly updated by the Cosmology Science Working Group in the run up to start of operations and the Key Science Programme of SKA1.
The Square Kilometre Array (SKA) is a planned large radio interferometer designed to operate over a wide range of frequencies, and with an order of magnitude greater sensitivity and survey speed than any current radio telescope. The SKA will address many important topics in astronomy, ranging from planet formation to distant galaxies. However, in this work, we consider the perspective of the SKA as a facility for studying physics. We review four areas in which the SKA is expected to make major contributions to our understanding of fundamental physics: cosmic dawn and reionisation; gravity and gravitational radiation; cosmology and dark energy; and dark matter and astroparticle physics. These discussions demonstrate that the SKA will be a spectacular physics machine, which will provide many new breakthroughs and novel insights on matter, energy, and spacetime.
Although there are many views on the nature of wisdom, a common thread emerging in philosophical, folk, and scientific discourse is the importance of wise reflection or “reasoning” for sound judgment. In this chapter, we briefly highlight this common thread in historical perspectives on wisdom before moving on to discuss its further development through contemporary personality- and performance-oriented traditions in the empirical study of wisdom. These empirical traditions serve as forerunners to the recent methodological and experimental innovations in the study of wise reasoning. We detail the strengths and weaknesses of existing measures of wisdom, and the subsequent development and validation of the Situated Wise Reasoning Scale to address the limitations of previous approaches. We highlight work demonstrating the importance of the situation for measuring wise reasoning. Further, we address cultural differences in wise reasoning, and highlight ways to boost people’s propensity to reason wisely. Finally, we outline some of the theoretical and practical implications of wise reasoning for wisdom writ large.
Leaf colour characteristics of 730 sweetpotato, Ipomoea batatas (L.) Lam. (Convolvulaceae), plant introduction (PI) accessions from the USDA sweetpotato germplasm collection were evaluated during 2012–2014. Colorimetry data for the abaxial and adaxial leaf surfaces were recorded using a tristimulus colorimeter and the CIE 1976 L*a*b* and CIE L*C*h* colour spaces. Most accessions (725 of 730 PIs) had dark-to-medium green leaves, but two PIs had totally purple leaves, and three PIs had yellow or yellow-green (chartreuse) leaves. For mature, field-grown green leaves, values for the red-green coordinate (a*) averaged −12.4 for the adaxial and −10.4 for the abaxial leaf surface. Values for the blue-yellow coordinate (b*) averaged 17.2 for the adaxial and 17.3 for the abaxial leaf surface. Hue angle (h*) for green leaves averaged 120.9° for the adaxial and 126.2° for the abaxial leaf surface. Colour saturation (Chroma, C*) averaged 21.3 for the adaxial and 20.2 for the abaxial leaf surface. Lightness (L*) averaged 35.4 for the adaxial and 47.2 for the abaxial leaf surface of green leaves. Late in the season, over one-half (53.9%) of the 730 PIs showed some level of purple pigmentation in the leaf lamina. Late-season purple leaves were collected and colour coordinates were recorded for 118 PIs grown in the field. For purple leaves, values for a*, b*, C*, L* and h* averaged 2.3, 6.2, 7.9, 28.2 and 64.4° for the adaxial surface and −1.0, 12.7, 13.9, 43.1 and 87.0° for the abaxial leaf surface, respectively.
Cambodia supports populations of three Critically Endangered vulture species that are believed to have become isolated from the rest of the species’ global range. Until recently Cambodia’s vulture populations had remained stable. However a recent spike in the number of reports of the use of poisons in hunting practices suggests the need to re-evaluate the conservation situation in Cambodia. Population trend analysis showed that since 2010 populations of the White-rumped Vulture Gyps bengalensis and Red-headed Vulture Sarcogyps calvus have declined, while the Slender-billed Vulture Gyps tenuirostris may also have started to decline since 2013. These trends are supported by evidence of reduced nesting success. A survey of veterinary drug availability revealed that diclofenac, the non-steroid anti-inflammatory drug responsible for vulture declines in South Asia was not available for sale in any of the 74 pharmacies surveyed. However, a poisoned Slender-billed Vulture tested positive for carbofuran in toxicology tests. This provides the first evidence of a vulture mortality resulting from carbofuran in Cambodia. The findings suggest the urgent need to tackle use of carbamate pesticides in hunting. Proposed conservation actions are: a) prevention of poisoning through national bans on harmful carbamate pesticides and diclofenac and education campaigns to reduce demand and use; b) training of personnel in priority protected areas in detection and response to poisoning incidents; c) maintenance of a safe and reliable food source through vulture restaurants to ensure short-term survival, and d) protection and restoration of large areas of deciduous dipterocarp forests to enable long-term species recovery.
Hereditary haemorrhagic telangiectasia is an autosomal dominant condition, characterised by mucocutaneous telangiectasia, aneurysm and arteriovenous malformations. Thalidomide has been used as a therapeutic strategy for refractory epistaxis in hereditary haemorrhagic telangiectasia patients. This review set out to examine the evidence for using thalidomide in the management of refractory epistaxis in hereditary haemorrhagic telangiectasia patients.
A systematic search of the available literature was performed using Medline, Embase, Cochrane Library and NHS Evidence databases, from inception to December 2017. The search terms used included: hereditary haemorrhagic telangiectasia (HHT), Osler-Weber-Rendu syndrome, epistaxis, haemorrhage and thalidomide.
All studies using thalidomide therapy showed a reduction in the frequency and duration of epistaxis, as early as four weeks post-therapy. In addition, thalidomide therapy was shown to increase median haemoglobin levels and reduce blood transfusion dependence.
Current available evidence suggests that low-dose thalidomide is effective in transiently reducing epistaxis frequency and duration. Further studies are required to establish a treatment regimen to prevent side effects.
Effective integrated weed management in agricultural landscapes depends on the ability to identify and manage processes that drive weed dynamics. The current study reports the effects of grazing management and crop rotation strategies on the seedbank and emerged weed flora in an integrated crop-livestock system (ICLS) experiment during a 12-year period under no-tillage in sub-tropical southern Brazil. During winter, Italian ryegrass cover crops were grazed by sheep: grazing management treatments included two stocking methods (continuous and rotational) and two forage allowances (10 and 20 kg of herbage dry matter available per 100 kg animal live weight). During summer, the crop rotation treatments involved either soybean-maize or soybean-soybean in succession with winter-grazed cover crops. The treatments were part of a factorial randomized complete block design. Treatment effects were evaluated on the weed seedbank and emerged weed flora populations during winter-grazed cover crop and summer crop growth as well as during the harvest phase. The current results demonstrate that crop rotation and grazing management exhibited interactive effects on the determination of weed outcomes in an ICLS. However, overall, compared with moderate forage allowance, high forage allowance during the winter-grazed cover crop caused lower emerged weed flora in subsequent crops (20% reduction during crop growth and 90% reduction at crop harvest) and 48% reduction in seedbank size. High forage allowance promoted more residue from winter-grazed cover crop biomass, which remained during the summer crop phases and probably resulted in a physical barrier to weed emergence.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
This paper reports on: (1) an evaluation of a common elements treatment approach (CETA) developed for comorbid presentations of depression, anxiety, traumatic stress, and/or externalizing symptoms among children in three Somali refugee camps on the Ethiopian/Somali border, and (2) an evaluation of implementation factors from the perspective of staff, lay providers, and families who engaged in the intervention.
This project was conducted in three refugee camps and utilized locally validated mental health instruments for internalizing, externalizing, and posttraumatic stress (PTS) symptoms. Participants were recruited from either a validity study or from referrals from social workers within International Rescue Committee Programs. Lay providers delivered CETA to youth (CETA-Youth) and families, and symptoms were re-assessed post-treatment. Providers and families responded to a semi-structured interview to assess implementation factors.
Children who participated in the CETA-Youth open trial reported significant decreases in symptoms of internalizing (d = 1.37), externalizing (d = 0.85), and posttraumatic stress (d = 1.71), and improvements in well-being (d = 0.75). Caregivers also reported significant decreases in child symptoms. Qualitative results were positive toward the acceptability and appropriateness of treatment, and its feasibility.
This project is the first to examine a common elements approach (CETA: defined as flexible delivery of elements, order, and dosing) with children and caregivers in a low-resource setting with delivery by lay providers. CETA-Youth may offer an effective treatment that is easier to implement and scale-up versus multiple focal interventions. A fullscale randomized clinical trial is warranted.
The majority of fast radio bursts (FRBs) are poorly localised, hindering their potential scientific yield as galactic, intergalactic, and cosmological probes. LOFT-e, a digital backend for the U.K.’s e-MERLIN seven-telescope interferometer will provide commensal search and real-time detection of FRBs, taking full advantage of its field of view (FoV), sensitivity, and observation time. Upon burst detection, LOFT-e will store raw data offline, enabling the sub-arcsecond localisation provided by e-MERLIN and expanding the pool of localised FRBs. The high-time resolution backend will additionally introduce pulsar observing capabilities to e-MERLIN.