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The nodal-line semiconductor Mn3Si2Te6 is generating enormous excitment due to the recent discovery of a field-driven insulator-to-metal transition and associated colossal magnetoresistance as well as evidence for a new type of quantum state involving chiral orbital currents. Strikingly, these qualities persist even in the absence of traditional Jahn-Teller distortions and double-exchange mechanisms, raising questions about exactly how and why magnetoresistance occurs along with conjecture as to the likely signatures of loop currents. Here, we measured the infrared response of Mn3Si2Te6 across the magnetic ordering and field-induced insulator-to-metal transitions in order to explore colossal magnetoresistance in the absence of Jahn-Teller and double-exchange interactions. Rather than a traditional metal with screened phonons, the field-driven insulator-to-metal transition leads to a weakly metallic state with localized carriers. Our spectral data are fit by a percolation model, providing evidence for electronic inhomogeneity and phase separation. Modeling also reveals a frequency-dependent threshold field for carriers contributing to colossal magnetoresistance which we discuss in terms of polaron formation, chiral orbital currents, and short-range spin fluctuations. These findings enhance the understanding of insulator-to-metal transitions in new settings and open the door to the design of unconventional colossal magnetoresistant materials. Field-driven insulator-to-metal transition and associated colossal magnetoresistance have been reported in the magnetic nodal-line semiconductor Mn3Si2Te6. Gu et al. measure infrared response across magnetic ordering and the transition, revealing a weakly metallic state instead of a traditional metallic state. [ABSTRACT FROM AUTHOR]

The nodal-line semiconductor Mn3Si2Te6 is generating enormous excitment due to the recent discovery of a field-driven insulator-to-metal transition and associated colossal magnetoresistance as well as evidence for a new type of quantum state involving chiral orbital currents. Strikingly, these qualities persist even in the absence of traditional Jahn-Teller distortions and double-exchange mechanisms, raising questions about exactly how and why magnetoresistance occurs along with conjecture as to the likely signatures of loop currents. Here, we measured the infrared response of Mn3Si2Te6 across the magnetic ordering and field-induced insulator-to-metal transitions in order to explore colossal magnetoresistance in the absence of Jahn-Teller and double-exchange interactions. Rather than a traditional metal with screened phonons, the field-driven insulator-to-metal transition leads to a weakly metallic state with localized carriers. Our spectral data are fit by a percolation model, providing evidence for electronic inhomogeneity and phase separation. Modeling also reveals a frequency-dependent threshold field for carriers contributing to colossal magnetoresistance which we discuss in terms of polaron formation, chiral orbital currents, and short-range spin fluctuations. These findings enhance the understanding of insulator-to-metal transitions in new settings and open the door to the design of unconventional colossal magnetoresistant materials. Field-driven insulator-to-metal transition and associated colossal magnetoresistance have been reported in the magnetic nodal-line semiconductor Mn3Si2Te6. Gu et al. measure infrared response across magnetic ordering and the transition, revealing a weakly metallic state instead of a traditional metallic state. [ABSTRACT FROM AUTHOR]

This paper critiques the restrictive criteria for germline genome editing recently proposed by Chin, Nguma, and Ahmad in this journal. While praising the authors for resisting fervent calls for an outright ban on clinical applications of the technology, this paper argues that their approach is nevertheless unduly restrictive, and may thus hinder technological progress. This response advocates for weighing potential benefits against risks without succumbing to excessive caution, proposing that ethical oversight combined with genetic scrutiny at the embryo stage post-editing can enable responsible use of the technology, ultimately reducing the burden of genetic diseases and enhancing human health, akin to how IVF transformed reproductive medicine despite strong initial opposition. [ABSTRACT FROM AUTHOR]

A lack of reliable winter hardiness has impeded the adoption of winter barley (Hordeum vulgare L.) in much of the northern United States. Direct selection for winter survival is time consuming and often unreliable. In addition, because survival is a binary trait, selection towards small quantitative gains can be difficult. One solution to these challenges is to identify indirect selection traits: anatomical or physiological characteristics which can be measured in the absence of winter stress, but which contribute to improved winter survival. Here, we survey a range of winter and spring barley, as well as winter wheat, winter rye, and perennial species of the genus Hordeum, all of which are more winter hardy than barley, to identify traits associated with winter survival. We identified several traits as promising candidates for selection. These included crown depth and leaf metaxylem diameter, which previous studies have identified as indirect selection traits. New candidates identified by our study include crown diameter and leaf midvein and blade thickness, as well as a suite of traits which suggest a pattern of reduced and efficient investment in above-ground structures. The effect of these traits on winter survival need to be validated and quantified by further experiments, but they represent a promising early step in a potentially valuable breeding strategy. [ABSTRACT FROM AUTHOR]

'Embodied cognition' suggests that our bodily experiences broadly shape our cognitive capabilities. We study how embodied experience affects the abstract physical problem-solving styles people use in a virtual task where embodiment does not affect action capabilities. We compare how groups with different embodied experience – 25 children and 35 adults with congenital limb differences versus 45 children and 40 adults born with two hands – perform this task, and find that while there is no difference in overall competence, the groups use different cognitive styles to find solutions. People born with limb differences think more before acting but take fewer attempts to reach solutions. Conversely, development affects the particular actions children use, as well as their persistence with their current strategy. Our findings suggest that while development alters action choices and persistence, differences in embodied experience drive changes in the acquisition of cognitive styles for balancing acting with thinking. [ABSTRACT FROM AUTHOR]

In a poorly understood yet recurring phenomenon, communities occupying diverse settings within a region may undertake large-scale migrations that cannot be easily attributed to single variables such as climate change. As a result, the study of these movements has increasingly focused on the distinct histories of localities to address how they may have articulated as large-scale abandonments. We adopt this micro-history perspective on the fourteenth to fifteenth century depopulation of a large portion of the North American Midwest and Southeast, popularly referred to as the Vacant Quarter. Our research on the Middle Cumberland drainage within the Vacant Quarter suggests that a significant exodus began slowly ca. 1300 CE; then, it accelerated extremely rapidly in the first half of the fifteenth century CE. This genesis of this trajectory seems to be related to a pattern of severe droughts, but it was brought to a close by social and demographic challenges such as endemic conflict and adverse health conditions. [ABSTRACT FROM AUTHOR]

This paper studies how public information regarding a firm's riskiness affects investors' incentives to acquire information about the firm and the firm's ability to learn decision-useful information from its price. I find that risk information complements investor learning by informing investors of when it is most lucrative to investigate the firm, thereby reducing liquidity. Furthermore, risk information causes the firm's price to contain more information when the firm's investment decisions have the greatest impact on its value, thereby improving real efficiency. Extensions of the model suggest that the impact of risk information on real efficiency may deteriorate when the firm's manager is excessively exposed to idiosyncratic risk, when the firm's shareholders are excessively averse to such risk, or when the disclosure concerns a "downside risk." In sum, my analysis suggests that information regarding firms' expected values and information regarding firms' risks significantly differ in their effects on the capital market. [ABSTRACT FROM AUTHOR]

GaN has been demonstrated as an important wide-bandgap semiconductor in many applications, especially in optoelectronic and high-power electronics. Two-dimensional (2D) GaN, with increased bandgap compared to the bulk counterpart, not only amplifies existing functionalities but also opens up fresh possibilities for compact electronics. Although several methods have recently been developed to synthesize 2D GaN, their practical application is hampered by either harsh growth conditions (e.g., high temperature and ultrahigh vacuum) or unsatisfactory performance due to grain boundaries. Here, we report the realization of few-nanometer-thick GaN crystals via in situ atomic substitution of layered GaS flakes at a relatively low temperature (590°C). GaN with tunable thickness from 50 nm down to 0.9 nm (~2 atomic layers) is achieved by applying the atomic substitution reaction to GaS with different numbers of layers. The obtained ultrathin GaN flakes retain the morphology inherited from the GaS flakes and show high crystallinity by transmission electron microscopy (TEM) characterization, while the thickness of GaN decreases to about 72% of the corresponding GaS flakes from the atomic force microscopy characterization. A time-dependent mechanism study reveals both horizontal and vertical conversion paths, with Ga2S3 as intermediate. Photoluminescence (PL) spectroscopy measurements show that the band edge PL of 2D ultrathin GaN is blue-shifted as compared with bulk GaN, suggesting that the bandgap increases with the decrease in thickness. This study provides a promising method for obtaining ultrathin, high-crystallinity GaN with tunable thicknesses, utilizing a minimal thermal budget. This breakthrough lays a solid foundation for future investigations into fundamental physics and potential device applications. [ABSTRACT FROM AUTHOR]

Kagomé metals are widely recognized, versatile platforms for exploring topological properties, unconventional electronic correlations, magnetic frustration, and superconductivity. In the RV6Sn6 family of materials (R = Sc, Y, Lu), ScV6Sn6 hosts an unusual charge density wave ground state as well as structural similarities with the AV3Sb5 system (A = K, Cs, Rb). In this work, we combine Raman scattering spectroscopy with first-principles lattice dynamics calculations to reveal phonon mixing processes in the charge density wave state of ScV6Sn6. In the low temperature phase, we find at least four new peaks in the vicinity of the V-containing totally symmetric mode near 240 cm−1 suggesting that the density wave acts to mix modes of P6/mmm and R 3 ¯ m symmetry - a result that we quantify by projecting phonons of the high symmetry state onto those of the lower symmetry structure. We also test the stability of the short-range ordered density wave state under compression and propose that both physical and chemical pressure quench the effect. We discuss these findings in terms of symmetry and the structure-property trends that can be unraveled in this system. [ABSTRACT FROM AUTHOR]

The increasing demand for fertility treatments has led to the rise of private clinics offering complementary and alternative medicine (CAM) treatments. The most frequently offered CAM infertility treatment is acupuncture. However, there is no good evidence to support the effectiveness of acupuncture in treating infertility. This study evaluates the scope of information provided by CAM fertility clinics in the UK. A content analysis was conducted on 200 websites of CAM fertility clinics in the UK that offer acupuncture as a treatment for infertility. Of the 48 clinics that met the eligibility criteria, the majority of the websites did not provide sufficient information on the efficacy, risks and success rates of acupuncture for infertility. This has the potential to infringe on patient autonomy, provide false hope and reduce the chances of pregnancy ever being achieved as fertility declines during the time course of ineffective acupuncture treatment. [ABSTRACT FROM AUTHOR]

We present here the life and the work of Paul A. Castelfranco (1921–2021), a very special person who was not only a top chemist of chlorophyll biosynthesis, but also made major contributions on fatty acid oxidation, acetate metabolism and cellular organization. He led an extraordinary and exemplary life as a human being. We present here both his personal life as well as his scientific life, which is followed by reminiscences by William Breidenbach, Kevin Smith, Alan Stemler, Ann Castelfranco, and John Castelfranco. As the subtitle of this Tribute implies, till the end Paul was a scientist par excellence, an intellectual with unlimited curiosity, a humanist, and a man of enduring religious faith. We all miss him dearly. [ABSTRACT FROM AUTHOR]

The dendroecology of larch (Larix gmelinii Rupr.) in the world’s northernmost forest provided insight into the complex relationship of tree growth, forest stand establishment, and changing eco-climatic factors. The Ary-Mas forest in the northern Siberia (72° + NL) is an ecological island, surrounded by tundra. We hypothesized that the environmental constraints that limit larch growth in this harsh habitat include soil moisture and winter winds as well as low air temperature. We constructed and analyzed the larch growth index (GI) chronology from the eighteenth century until 2019. We found that the larch GI depended on the air temperature, soil moisture anomalies, and winter wind speed, and that dependence was significantly different before and after the 2000s. Larch GI responded to the onset of climatic warming in the 1970s by a minor GI increase followed by a GI decrease until the end of 1990. Increased air temperature early in the growing season favored increased GI, whereas elevated winter wind speed negatively influenced larch growth. After warming in the 2000s, the length of the growing season increased by 15 days, and larch GI was sensitive to air temperature both early and late in the growing season. The adverse influence of winter winds has gradually decreased since the 1970s, becoming a minor factor in the 2000s. Soil moisture in “wet, cold soils” negatively influenced larch growth. Meanwhile, decreased soil moisture in the northern lowlands favored increased larch growth. We found that larch growth increases were strongly correlated with GPP and NPP (gross and net primary productivity) within the Ary-Mas site and for the central Siberian Arctic. We infer that this Arctic region continues to be a carbon sink. [ABSTRACT FROM AUTHOR]

In this paper, we propose a coupled system of complex Hessian equations which generalizes the equation for constant scalar curvature Kähler (cscK) metrics. We show this system can be realized variationally as the Euler–Lagrange equation of a Hessian version of the Mabuchi K-energy in an infinite dimensional space of k-Hessian potentials, which can be seen as an infinite dimensional Riemannian manifold with negative sectional curvature. Finally, we prove an a priori C 0 -estimate for this system which depends on the Entropy, which generalizes a fundamental result of Chen and Cheng [1] for cscK metrics. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the incidental prostate cancer (iPCa) detection rates of different embedding methods in a large, contemporary cohort of patients with bladder outlet obstruction (BOO) treated with transurethral surgery. We relied on an institutional tertiary-care database to identify BOO patients who underwent either transurethral loop resection or laser (Holmium:yttrium–aluminium garnet) enucleation of the prostate (HoLEP) between 01/2012 and 12/2019. Embedding methods differed with regard to the extent of the additional prostate tissue submitted following the first ten cassettes of primary embedding (cohort A: one [additional] cassette/10 g residual tissue vs. cohort B: complete embedding of the residual tissue). Detection rates of iPCa among the different embedding methods were compared. Subsequently, subgroup analyses by embedding protocol were repeated in HoLEP-treated patients only. In the overall cohort, the iPCa detection rate was 11% (46/420). In cohort A (n = 299), tissue embedding resulted in a median of 8 cassettes/patient (range 1–38) vs. a median of 15 (range 2–74) in cohort B (n = 121) (p <.001). The iPCa detection rate was 8% (23/299) and 19% (23/121) in cohort A vs. cohort B, respectively (p <.001). Virtual reduction of the number of tissue cassettes to ten cassettes resulted in a iPCa detection rate of 96% in both cohorts, missing one stage T1a/ISUP grade 1 carcinoma. Increasing the number of cassettes by two and eight cassettes, respectively, resulted in a detection rate of 100% in both cohorts without revealing high-grade carcinomas. Subgroup analyses in HoLEP patients confirmed these findings, demonstrated by a 100 vs. 96% iPCa detection rate following examination of the first ten cassettes, missing one case of T1a/ISUP 1. Examination of 8 additional cassettes resulted in a 100% detection rate. The extent of embedding of material obtained from transurethral prostate resection correlates with the iPCa detection rate. However, the submission of 10 cassettes appears to be a reasonable threshold to reduce resource utilization while maintaining secure cancer detection. [ABSTRACT FROM AUTHOR]

Purpose of review: Shift work is prevalent among the working population and is linked to an array of adverse health outcomes. This review summarizes current evidence on the relation between shift work and risk of obesity, with a particular emphasis on potential sex differences. Recent findings: Observational data strongly point towards an association between shift work and heightened risk of prevalent and incident obesity, and particularly abdominal obesity. Circadian misalignment and unhealthy lifestyle behaviors are the primary culprits mediating such association. As it pertains to sex differences in the impact of shift work on obesity, few studies have examined this aspect, and findings are conflicting. Summary: Shift work is an important risk factor for obesity, with likely multiple biological and behavioral mediators. However, whether there is a sex-dependent vulnerability to the obesogenic effects of shift work is unclear. This area presents opportunities for future research. [ABSTRACT FROM AUTHOR]

van der Waals solids are ideal platforms for the discovery of new states of matter and emergent properties under external stimuli. Under pressure, complex chalcogenides like MPS3 (M = Mn, Ni, Co, V) host sliding and structural transitions, insulator-to-metal transitions, the possibility of an orbitally-selective Mott state, piezochromism, and superconductivity. In this work, we bring together diamond anvil cell techniques, infrared and Raman scattering spectroscopies, and X-ray diffraction with a detailed symmetry analysis and first-principles calculations to uncover a series of high-pressure phases in NiPS3. Remarkably, we find five different states of matter between ambient conditions and 39 GPa—quite different than in the other MPS3 materials. Even more strikingly, infrared spectroscopy and X-ray diffraction combined with a symmetry analysis reveal both metallicity and loss of the inversion center above ~23 GPa suggesting that NiPS3 may be a polar metal with a P3m1 space group under these conditions and P1 symmetry under maximum compression. In addition to identifying a candidate polar metal ripe for further inquiry, we suggest that pressure may tune other complex chalcogenides into this elusive state. [ABSTRACT FROM AUTHOR]

We obtain sharp inequalities between the large scale asymptotic of the J functional with respect to the d 1 metric on the space of Kähler metrics. Applications regarding the initial value problem for geodesic rays are presented. [ABSTRACT FROM AUTHOR]

Enhancing the potency of mRNA therapeutics is an important objective for treating rare diseases, since it may enable lower and less-frequent dosing. Enzyme engineering can increase potency of mRNA therapeutics by improving the expression, half-life, and catalytic efficiency of the mRNA-encoded enzymes. However, sequence space is incomprehensibly vast, and methods to map sequence to function (computationally or experimentally) are inaccurate or time-/labor-intensive. Here, we present a novel, broadly applicable engineering method that combines deep latent variable modelling of sequence co-evolution with automated protein library design and construction to rapidly identify metabolic enzyme variants that are both more thermally stable and more catalytically active. We apply this approach to improve the potency of ornithine transcarbamylase (OTC), a urea cycle enzyme for which loss of catalytic activity causes a rare but serious metabolic disease. [ABSTRACT FROM AUTHOR]

Key message: Integration of multi-omics data improved prediction accuracies of oat agronomic and seed nutritional traits in multi-environment trials and distantly related populations in addition to the single-environment prediction. Multi-omics prediction has been shown to be superior to genomic prediction with genome-wide DNA-based genetic markers (G) for predicting phenotypes. However, most of the existing studies were based on historical datasets from one environment; therefore, they were unable to evaluate the efficiency of multi-omics prediction in multi-environment trials and distantly related populations. To fill those gaps, we designed a systematic experiment to collect omics data and evaluate 17 traits in two oat breeding populations planted in single and multiple environments. In the single-environment trial, transcriptomic BLUP (T), metabolomic BLUP (M), G + T, G + M, and G + T + M models showed greater prediction accuracy than GBLUP for 5, 10, 11, 17, and 17 traits, respectively, and metabolites generally performed better than transcripts when combined with SNPs. In the multi-environment trial, multi-trait models with omics data outperformed both counterpart multi-trait GBLUP models and single-environment omics models, and the highest prediction accuracy was achieved when modeling genetic covariance as an unstructured covariance model. We also demonstrated that omics data can be used to prioritize loci from one population with omics data to improve genomic prediction in a distantly related population using a two-kernel linear model that accommodated both likely casual loci with large-effect and loci that explain little or no phenotypic variance. We propose that the two-kernel linear model is superior to most genomic prediction models that assume each variant is equally likely to affect the trait and can be used to improve prediction accuracy for any trait with prior knowledge of genetic architecture. [ABSTRACT FROM AUTHOR]

Key message: Fine mapping of barley 6H pericentromeric region identified FHB QTL with opposite effects, and high grain protein content was associated with increased FHB severity. Resistance to Fusarium head blight (FHB), kernel discoloration (KD), deoxynivalenol (DON) accumulation and grain protein content (GPC) are important traits for breeding malting barley varieties. Previous work mapped a Chevron-derived FHB QTL to the pericentromeric region of 6H, coinciding with QTL for KD resistance and GPC. The Chevron allele reduced FHB and KD, but unfavorably increased GPC. To determine whether the correlations are caused by linkage or pleiotropy, a fine mapping approach was used to dissect the QTL underlying these quality and disease traits. Two populations, referred to as Gen10 and Gen10/Lacey, derived from a recombinant near-isogenic line (rNIL) were developed. Recombinants were phenotyped for FHB, KD, DON, GPC and other agronomic traits. Three FHB, two DON and two KD QTLs were identified. One of the three FHB QTLs, one DON QTL and one KD QTL were coincident with the GPC QTL, which contains the Hv-NAM1 locus affecting grain protein accumulation. The Chevron allele at the GPC QTL increased GPC and FHB and decreased DON and KD. The other two FHB QTL and the other DON and KD QTL were identified in the regions flanking the Hv-NAM1 locus, and the Chevron alleles decreased FHB, DON and KD. Our results suggested that the QTL associated with FHB, KD, DON and GPC in the pericentromeric region of 6H was controlled by both pleiotropy and tightly linked loci. The rNILs identified in this study with low FHB severity and moderate GPC may be used for breeding malting barley cultivars. [ABSTRACT FROM AUTHOR]

Growth in the surfing equipment industry has led to increased scientific interest in this area, yet no current paper has reviewed and synthesized the effects of equipment design on surfing. Therefore, the aims of this study were to: (1) assess the volume and type of scientific literature that is available to the authors specific to surfing equipment and design, (2) summarise all surfing equipment and design studies completed to date specific to outcome measures and key findings and (3) identify knowledge gaps in the topic of surfing equipment design. This review was conducted in accordance with the PRISMA scoping review guidelines. A total of seven electronic databases were searched (PubMed, Embase, CINAHL, SPORTDiscus, Web of Science, SCOPUS, and Ovid). Google Scholar was also searched for grey literature. Inclusion criteria were mention of surfing equipment and relevant surfing outcome measures (physiological and mechanical). Exclusion criteria were no full text availability and works not available in English. Results from these articles were then extracted, summarised and presented. A total of 17 articles were selected for review and organized by theme of board, wetsuit and fin. Fin and wetsuit design were the most prominent themes (seven studies each respectively). Most were written within the past 5 years and written in the USA. Fin design studies were largely computational, whereas board and wetsuit design were mostly field and laboratory based. Within each study theme there were consistencies in outcome measures and measuring devices. Board design studies focused on paddling efficiency (VO2 and HR). Wetsuit design studies primarily assessed thermoregulation, and less so muscle activation and paddling biomechanics. Fin design studies focused on fin shape and configuration to assess lift and drag properties. Three key themes of board, wetsuit and fin design were noted; from this the authors were able to identify several knowledge gaps such as a lack of standardisation in equipment controls and study design procedures. Alongside improving standardisation, the use of wave pools presents as an area of interest in future research. [ABSTRACT FROM AUTHOR]

Objectives: Although dating violence has been recognized as a major public health issue considering its high prevalence and deleterious consequences, little research has been conducted on the potential mechanisms through which dating violence is associated with negative psychological outcomes. The aim of this study was to test the mediational effect of dispositional mindfulness on the relationship between dating violence (victimization and perpetration), psychological distress, and self-esteem by including measures of both current and previous dating violence and by controlling for gender, age, and dating relationship length. Methods: The sample consisted of 227 adolescents (127 girls and 100 boys) aged between 15 and 17 old recruited in a small urban area. They completed measures of previous and current experiences of dating victimization and perpetration, the K10 psychological distress scale, the Self-Description Questionnaire which measures self-esteem, and the Child and Adolescent Mindfulness Measure. Results: The results showed that previous dating violence victimization was associated with lower dispositional mindfulness, which in turn was related to lower self-esteem and higher psychological distress, suggesting a mediation through dispositional mindfulness. However, in the integrative model, previous dating violence perpetration was not associated with dispositional mindfulness, self-esteem, or psychological distress. Conclusions: These results indicate the importance of previous dating violence victimization and its association with lower dispositional mindfulness, leading to lower self-esteem and higher psychological distress in teenagers. [ABSTRACT FROM AUTHOR]

Dumping plastic waste into landfills can lead to severe health and environmental problems. Plastic waste can be treated by the pyrolysis process to produce fuel. A techno-economic and feasibility assessment was performed for plastic-waste pyrolysis followed by hydrodeoxygenation to upgrade the fuel using the software Aspen Plus. A simulation was conducted using Aspen Plus to estimate the plant's mass and energy balance; it is assumed that 1,000 dry metric tons of plastic waste is processed per day. Plastic waste contains 40% polystyrene (PS), 20% polyethylene (PE), 20% polypropylene (PP), and 20% polyethylene terephthalate (PET). The process is simulated in five steps: pretreatment, pyrolysis, hydrogen production, and hydrodeoxygenation of oil and energy generation. The mass and the energy yields of this process are 36% and 42%, respectively. The capital investment of the plant and the production cost were calculated based on the Aspen Plus model. Based on the economic estimation, the capital investment of this process is $118 million and the production cost is $27 million. For the 20-year project, the minimum selling price (MSP) of the fuel was calculated to be $0.60/gal. Sensitivity analysis was performed to verify the economic assumptions on the MSP. The MSP is highly sensitive to the feedstock cost, plant capacity, and product yield. As the plant capacity or product yield increases, the MSP decreases significantly. [ABSTRACT FROM AUTHOR]

With the biodiversity crisis continuing unchecked, we need to establish levels and drivers of extinction risk, and reassessments over time, to effectively allocate conservation resources and track progress towards global conservation targets. Given that threat appears particularly high in freshwaters, we assessed the extinction risk of 1428 randomly selected freshwater molluscs using the IUCN Red List Categories and Criteria, as part of the Sampled Red List Index project. We show that close to one-third of species in our sample are estimated to be threatened with extinction, with highest levels of threat in the Nearctic, Palearctic and Australasia and among gastropods. Threat levels were higher in lotic than lentic systems. Pollution (chemical and physical) and the modification of natural systems (e.g. through damming and water abstraction) were the most frequently reported threats to freshwater molluscs, with some regional variation. Given that we found little spatial congruence between species richness patterns of freshwater molluscs and other freshwater taxa, apart from crayfish, new additional conservation priority areas emerged from our study. We discuss the implications of our findings for freshwater mollusc conservation, the adequacy of a sampled approach and important next steps to estimate trends in freshwater mollusc extinction risk over time. [ABSTRACT FROM AUTHOR]

This interpretative phenomenological analysis explores aid workers' understanding of identity and belonging through the transition from working in humanitarian aid to returning home. Semi-structured interviews were conducted with 10 participants who had returned to the UK after working in recently founded non-governmental organisations in Northern France between 2016 and 2019. Analysis of interview data identified four superordinate themes: (1) shared humanitarian identity, (2) limits and borders, (3) holding on to humanitarian identity and (4) redefining belonging and identity. Aid workers' belonging in humanitarian work settings is rooted in shared moral values and being able to fulfil a clearly defined role. Upon returning, aid workers struggled to reintegrate, manifesting as denial of having left humanitarian work, re-creation of the social setting and moral demarcation. Participants formed a new sense of belonging through redefining their social in-group. The study sheds light on a previously unexplored area of research, specifically characterised through the closeness of the international humanitarian setting and participants' homes. Findings suggest organisations can assist aid workers' re-entry by supporting professional distance in the field, and through opportunities that allow to sustain moral values post-mission. Future research should focus on the role of peer support in the re-entry process and the re-entry experiences of aid workers returning from comparable settings further afield (e.g. Greece). [ABSTRACT FROM AUTHOR]

An essential prerequisite for the efficient biomechanical tailoring of crops is to accurately relate mechanical behavior to compositional and morphological properties across different length scales. In this article, we develop a multiscale approach to predict macroscale stiffness and strength properties of crop stem materials from their hierarchical microstructure. We first discuss the experimental multiscale characterization based on microimaging (micro-CT, light microscopy, transmission electron microscopy) and chemical analysis, with a particular focus on oat stems. We then derive in detail a general micromechanics-based model of macroscale stiffness and strength. We specify our model for oats and validate it against a series of bending experiments that we conducted with oat stem samples. In the context of biomechanical tailoring, we demonstrate that our model can predict the effects of genetic modifications of microscale composition and morphology on macroscale mechanical properties of thale cress that is available in the literature. [ABSTRACT FROM AUTHOR]

Valorization of biomass-derived substrates via electrocatalytic hydrogenation-hydrogenolysis (ECH) is an attractive approach for selective production of organic chemicals. The electrocatalytic activity is strongly dependent on the surface coverage of adsorbed hydrogen radicals, which is a complex function of the catalytically active surface sites, electrolyte (pH and composition) and electrode potential. The performance of carbon-supported catalysts (Pt/C, Ru/C, Pd/C) was explored in the ECH of phenol and guaiacol in a stirred slurry electrochemical reactor where the cathode and anode compartments were separated by a Nafion® 117 membrane. Acid (H2SO4) and neutral (NaCl) catholytes were used. Pt/C showed superior activity in the acid-acid electrolyte pair, while the activity of Ru/C and Pd/C were significantly improved in the neutral-acid catholyte-anolyte pairs. By pairing neutral catholyte and acid anolyte, the anodic protons transported through the membrane can be effectively utilized for ECH reactions. In terms of reaction pathways for guaiacol ECH, ring saturation leading to 2-methoxycyclohexanol was generally the dominant pathway. However, for Pt/C in either 0.2 or 0.5 M NaCl catholyte paired with 0.5 M H2SO4 anolyte the demethoxylation–ring saturation pathway producing cyclohexanol and cyclohexanone was equally competitive at a constant superficial current density of -109 mA cm−2 and 50 0C. Efficient reductive upgrading of lignin model compounds can be achieved under mild conditions via electrocatalysis in the slurry reactor by exploiting synergistic effects between the catalyst and electrolyte. [ABSTRACT FROM AUTHOR]

Two prominent theoretical frameworks in moral psychology, Moral Foundations and Dual Process Theory, share a broad foundational assumption that individual differences in human morality are dispositional and in part due to genetic variation. The only published direct test of heritability, however, found little evidence of genetic influences on moral judgments using instrumentation approaches associated with Moral Foundations Theory. This raised questions about one of the core assumptions underpinning intuitionist theories of moral psychology. Here we examine the heritability of moral psychology using the moral dilemmas approach commonly used in Dual Process Theory research. Using such measures, we find consistent and significant evidence of heritability. These findings have important implications not only for understanding which measures do, or do not, tap into the genetically influenced aspects of moral decision-making, but in better establishing the utility and validity of different intuitionist theoretical frameworks and the source of why people differ in those frameworks. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the performance of radiological assessment categories and quantitative computational analysis of apparent diffusion coefficient (ADC) maps using variant machine learning algorithms to differentiate clinically significant versus insignificant prostate cancer (PCa). Methods: Retrospectively, 73 patients were included in the study. The patients (mean age, 66.3 ± 7.6 years) were examined with multiparametric MRI (mpMRI) prior to radical prostatectomy (n = 33) or targeted biopsy (n = 40). The index lesion was annotated in MRI ADC and the equivalent histologic slides according to the highest Gleason Grade Group (GrG). Volumes of interest (VOIs) were determined for each lesion and normal-appearing peripheral zone. VOIs were processed by radiomic analysis. For the classification of lesions according to their clinical significance (GrG ≥ 3), principal component (PC) analysis, univariate analysis (UA) with consecutive support vector machines, neural networks, and random forest analysis were performed. Results: PC analysis discriminated between benign and malignant prostate tissue. PC evaluation yielded no stratification of PCa lesions according to their clinical significance, but UA revealed differences in clinical assessment categories and radiomic features. We trained three classification models with fifteen feature subsets. We identified a subset of shape features which improved the diagnostic accuracy of the clinical assessment categories (maximum increase in diagnostic accuracy ΔAUC = + 0.05, p < 0.001) while also identifying combinations of features and models which reduced overall accuracy. Conclusions: The impact of radiomic features to differentiate PCa lesions according to their clinical significance remains controversial. It depends on feature selection and the employed machine learning algorithms. It can result in improvement or reduction of diagnostic performance. Key Points: • Quantitative imaging features differ between normal and malignant tissue of the peripheral zone in prostate cancer. • Radiomic feature analysis of clinical routine multiparametric MRI has the potential to improve the stratification of clinically significant versus insignificant prostate cancer lesions in the peripheral zone. • Certain combinations of standard multiparametric MRI reporting and assessment categories with feature subsets and machine learning algorithms reduced the diagnostic performance over standard clinical assessment categories alone. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer is the leading cause of cancer-related deaths in women younger than 40 years. We aim to evaluate cost as a barrier to care among female breast cancer patients diagnosed between 18 to 39 years. Methods: In early 2017, we distributed a survey to women diagnosed with breast cancer between the ages of 18 and 39 years, as identified by the central cancer registries of California, Georgia, North Carolina, and Florida. We used multivariable statistics to explore cost-related barriers to receiving breast cancer care for the 830 women that completed the survey. Results: About half of the women (47.4%) reported spending more on breast cancer care than expected, and almost two-thirds (65.3%) had not discussed costs with their care team. A third of the patients (31.8%) indicated forgoing care due to cost. Factors associated with not receiving anticipated care due to cost included age less than35 years at diagnosis, self-insurance, comorbid conditions, and late-stage diagnosis. Conclusion: Previous studies using breast cancer registry data have not included detailed insurance information and care received by young women. Young women with breast cancer frequently forgo breast cancer care due to cost. Our results highlight the potential for policies that facilitate optimal care for young breast cancer patients which could include the provision of comprehensive insurance coverage. [ABSTRACT FROM AUTHOR]

High β-glucan content is one of the main goals of oat breeding programs worldwide. However, the genomic regions and genes controlling β-glucan content in oats are not fully understood. In this sense, the objectives of this study were as follows: (i) to characterize structure and linkage disequilibrium (LD) in a panel of oat germplasm adapted to subtropical environments; and (ii) to identify genomic regions associated with oat β-glucan content. An oat panel with 413 genotypes was evaluated for β-glucan content under subtropical conditions in different years and genotyped using genotyping-by-sequencing. Population structure, LD, and genome-wide association (GWA) analyses were carried out. GWA mapping was performed for each year separately and in a multi-environment model. The UFRGS Oat Panel showed weak population structure and has great potential to elucidate many agronomic traits in subtropical environments. Seven quantitative trait loci (QTL) associated with β-glucan content were identified. These QTL are located on Mrg02, Mrg06, Mrg11, Mrg12, Mrg19, and Mrg20. The QTL located on Mrg02, Mrg06, and Mrg11 seem to be genomic regions syntenic with barley. The use of these QTL may be useful to accelerate the genetic progress of oat β-glucan content in subtropical environments. [ABSTRACT FROM AUTHOR]

UNESCO World Heritage Sites (WHS) are areas of outstanding universal value and conservation importance. They are, however, threatened by a variety of global change drivers, including biological invasions. We assessed the current status of biological invasions and their management in 241 natural and mixed WHS globally by reviewing documents collated by UNESCO and IUCN. We found that reports on the status of biological invasions in WHS were often irregular or inconsistent. Therefore, while some reports were very informative, they were hard to compare because no systematic method of reporting was followed. Our review revealed that almost 300 different invasive alien species (IAS) were considered as a threat to just over half of all WHS. Information on IAS management undertaken in WHS was available for fewer than half of the sites that listed IAS as a threat. There is clearly a need for an improved monitoring and reporting system for biological invasions in WHS and likely the same for other protected areas globally. To address this issue, we developed a new framework to guide monitoring and reporting of IAS in protected areas building on globally accepted standards for IAS assessments, and tested it on seven WHS. The framework requires the collation of information and reporting on pathways, alien species presence, impacts, and management, the estimation of future threats and management needs, assessments of knowledge and gaps, and, using all of this information allows for an overall threat score to be assigned to the protected area. This new framework should help to improve monitoring of IAS in protected areas moving forward. [ABSTRACT FROM AUTHOR]

Managing the impacts of invasive alien species (IAS) is a great societal challenge. A wide variety of terms have been used to describe the management of invasive alien species and the sequence in which they might be applied. This variety and lack of consistency creates uncertainty in the presentation and description of management in policy, science and practice. Here we expand on the existing description of the invasion process to develop an IAS management framework. We define the different forms of active management using a novel approach based on changes in species status, avoiding the need for stand-alone descriptions of management types, and provide a complete set of potential management activities. We propose a standardised set of management terminology as an emergent feature of this framework. We identified eight key forms of management: (1) pathway management, (2) interception, (3) limits to keeping, (4) secure keeping, (5) eradication, (6) complete reproductive removal, (7) containment and (8) suppression. We recognise four associated terms: prevention; captive management; rapid eradication; and long-term management, and note the use of impact mitigation and restoration as associated forms of management. We discuss the wider use of this framework and the supporting activities required to ensure management is well-targeted, cost-effective and makes best use of limited resources. [ABSTRACT FROM AUTHOR]

van der Waals materials are exceptionally responsive to external stimuli. Pressure-induced layer sliding, metallicity, and superconductivity are fascinating examples. Inspired by opportunities in this area, we combined high-pressure optical spectroscopies and first-principles calculations to reveal piezochromism in MnPS3. Dramatic color changes (green → yellow → red → black) take place as the charge gap shifts across the visible regime and into the near infrared, moving systematically toward closure at a rate of approximately −50 meV/GPa. This effect is quenched by the appearance of the insulator–metal transition. In addition to uncovering an intriguing and tunable functionality that is likely to appear in other complex chalcogenides, the discovery that piezochromism can be deterministically controlled at room temperature accelerates the development of technologies that take advantage of stress-activated modification of electronic structure. [ABSTRACT FROM AUTHOR]

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3–9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6–9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system. Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Mercury (Hg) in the environment has been receiving considerable attention in recent years, but little is known about Hg accumulation in trees. We analyzed Hg in tree rings from four tree species at the Hubbard Brook Experimental Forest in New Hampshire to determine whether Hg concentrations are more influenced by soil Hg concentrations, which have been stable or increasing due to the cumulative retention of historical atmospheric Hg deposition, or by atmospheric Hg deposition, which has declined in recent decades. Declining concentrations from the top to the bottom of the bole (p < 0.001) and from older to newer tree rings (p = 0.001) suggest that foliar uptake of Hg is more important than root uptake. Ten sugar maple clones planted in six blocks at the Heiberg Forest in New York State showed significant genetic control of sap Hg concentration (p = 0.02), which was not related to soil Hg concentration differences across blocks. Clones could differ in stomatal uptake, root uptake, or translocation of Hg. Better understanding of the source of Hg in wood is needed to forecast future changes in Hg cycling in forested ecosystems. [ABSTRACT FROM AUTHOR]

Key message: Association mapping study conducted in a population of 3490 elite barley breeding lines from ten barley breeding programs of the USA identified 12 QTLs for resistance/susceptibility to net form of net blotch. Breeding resistant varieties is the best management strategy for net form of net blotch (NFNB) in barley (Hordeum vulgare L.) caused by Pyrenophora teres f. teres (Ptt). Several resistance QTL have been previously identified in barley via linkage mapping and genome-wide association studies (GWAS). A GWAS conducted in a collection of advanced breeding lines (n = 3490) representing elite germplasm from ten barley breeding programs of the USA identified 42 unique marker-trait associations (MTA) for NFNB resistance. The lines were genotyped with 3072 SNP markers and phenotyped with four Ptt isolates in controlled environment. The lines were used to construct 13 different GWAS panels. Efficient mixed model association method with principal components and kinship was used for GWAS. Significance threshold for MTA was set at a false discovery rate of 0.05. Two, eight, six, one and 25 MTA were identified in chromosomes 1H, 3H, 4H, 5H and 6H, respectively. Based on genetic positions and linkage disequilibrium, these MTA's correspond to two, three, two, one and four QTLs in chromosome 1H, 3H, 4H, 5H and 6H, respectively. A comparison with previous linkage and GWAS studies revealed several previously identified and novel QTLs. Moreover, different genomic regions were found to be responsible for NFNB resistance in two-row versus six-row germplasm. The germplasm-specific SNP markers with additive effects and allelic distribution is reported to facilitate breeders in selection of markers for MAS to introgress novel net blotch resistance. [ABSTRACT FROM AUTHOR]

Purpose: Revision ACL surgery may be complicated by tunnel malposition and/or tunnel widening and often requires a staged treatment approach that includes bone grafting, a period of several months to allow bone graft incorporation and then definitive revision ACL reconstruction. The purpose of this study was to evaluate the results of a single-staged ACL revision reconstruction technique using a cylindrical dowel bone graft for patients who have existing posteriorly placed and/or widened tibial tunnels in the tibia at a minimum of 2 years follow-up.Methods: Between 2010 and 2014, patients undergoing single-stage revision ACL reconstruction with the described technique were prospectively enrolled and evaluated. At a minimum of 24 months, patients were evaluated by physical examination, multiple clinical outcome instruments including KOOS, Tegner and Lysholm, and preoperative and postoperative MRIs.Results: At a mean of 35.1 months, 18 consecutive patients had no revision surgery and no subjective knee instability. There were statistically significant improvements in the Tegner (median 2, interquartile range 2.25; p < 0.01), Lysholm (20.0 ± 15.0; p < 0.01), KOOS symptoms scale (12.9 ± 11.8; p < 0.01), KOOS pain scale (15.4 ± 18.7; p < 0.01), KOOS ADL scale (13.5 ± 19.0; p < 0.01), KOOS sports scale (32.8 ± 26.4; p < 0.01), and KOOS QoL scale (18.1 ± 16.9; p < 0.01). Postoperative MRI demonstrated statistically significant anteriorization of the tibial tunnel and a statistically significant decrease in tunnel widening.Conclusion: Revision ACL reconstruction utilizing a single-staged tibial tunnel grafting technique resulted in improved knee pain, function, and stability at a minimum of 24-month follow-up.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Many children with autism spectrum disorder (ASD) have sleep disorders. Face-to-face (F2F) sessions have empowered parents to help their child sleep. Our goal was whether online technologies could provide similar improvements in children's sleep while also improving parents' quality of life. Identical programs were taught in two sessions to F2F and online parents. Measurements were compared from baseline to 4 and 8 weeks post teaching sessions. Twenty-three participants completed the program. Parent quality of life improved for both groups. Parent fatigue scores were improved and sustained for the online group. The total sleep score improved for both groups, while the online group had sustained decreases in night wakings. Online methods can conveniently help improve sleep for children with ASD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API-API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib). Tramadol and celecoxib pharmacokinetics are modified after CTC administration versus administration of reference products. This randomised, open-label, crossover, phase 1 study assessed CTC pharmacokinetics, dose proportionality, safety and tolerability in Japanese and Caucasian subjects.Methods: CTC (100, 150 and 200 mg) was administered orally to healthy Japanese/Caucasian subjects. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were determined pre-dose and up to 48 h post-dose. Maximum observed plasma concentration (Cmax), and area under the plasma concentration-time curve from dosing to last measurable concentration (AUCt) and from dosing extrapolated to infinity (AUC∞) were evaluated. Dose proportionality was assessed in a dose-adjusted bioavailability analysis of variance and in a power model. Inter-cohort comparability of pharmacokinetic exposure was confirmed if the ratio (Japanese cohort/Caucasian cohort) of geometric least-squares means and corresponding 90% confidence intervals were 80-125%. Post hoc weight-adjusted comparability analyses were performed. Safety was assessed throughout.Results: Sixty subjects (21 males/9 females per cohort) were randomised; 57 completed the study. Cohorts were age and BMI matched; there were expected inter-cohort weight differences. Exposure to each analyte increased in both cohorts with increasing CTC dose. Tramadol's pharmacokinetic exposure was comparable between cohorts after adjusting for body weight; the pharmacokinetic exposure of O-desmethyltramadol and celecoxib was increased in Japanese subjects.Conclusions: Differences in pharmacokinetics were not sufficient to suggest that CTC dose adjustment is required in Japanese subjects.Clinical Trial Registration: EudraCT: 2015-003071-29. [ABSTRACT FROM AUTHOR]

Pattern recognition in imaging data by >300,000 players of a global, online, commercial computer game is combined with deep learning to improve the accuracy of annotation of subcellular protein localization.Pattern recognition and classification of images are key challenges throughout the life sciences. We combined two approaches for large-scale classification of fluorescence microscopy images. First, using the publicly available data set from the Cell Atlas of the Human Protein Atlas (HPA), we integrated an image-classification task into a mainstream video game (EVE Online) as a mini-game, named Project Discovery. Participation by 322,006 gamers over 1 year provided nearly 33 million classifications of subcellular localization patterns, including patterns that were not previously annotated by the HPA. Second, we used deep learning to build an automated Localization Cellular Annotation Tool (Loc-CAT). This tool classifies proteins into 29 subcellular localization patterns and can deal efficiently with multi-localization proteins, performing robustly across different cell types. Combining the annotations of gamers and deep learning, we applied transfer learning to create a boosted learner that can characterize subcellular protein distribution with F1 score of 0.72. We found that engaging players of commercial computer games provided data that augmented deep learning and enabled scalable and readily improved image classification. [ABSTRACT FROM AUTHOR]

Alkaloid concentration of perennial ryegrass herbage is affected by endophyte strain and host plant genotype. However, previous studies suggest that associations between host and endophyte also depends on environmental conditions, especially those affecting nutrient reserves and that water-soluble carbohydrate (WSC) concentration of perennial ryegrass plants may influence grass-endophyte associations. In this study a single transgenic event, with altered expression of fructosyltransferase genes to produce high WSC and biomass, has been crossed into a range of cultivar backgrounds with varying Epichloë endophyte strains. The effect of the association between the transgenic trait and alkaloid production was assessed and compared with transgene free control populations. In the vast-majority of comparisons there was no significant difference between alkaloid concentrations of transgenic and non-transgenic plants within the same cultivar and endophyte backgrounds. There was no significant difference between GOI+ (gene of interest positive) and GOI− (gene of interest negative) populations in Janthritrem response. Peramine concentration was not different between GOI+ and GOI− for 10 of the 12 endophytes-cultivar combinations. Cultivar Trojan infected with NEA6 and Alto with SE (standard endophyte) exhibited higher peramine and lolitrem B (only for Alto SE) concentration, in the control GOI− compared with GOI+. Similarly, cultivar Trojan infected with NEA6 and Alto with NEA3 presented higher ergovaline concentration in GOI−. Differences in alkaloid concentration may be attributable to an indirect effect in the modulation of fungal biomass. These results conclude that the presence of this transgenic insertion, does not alter the risk (toxicity) of the endophyte-grass associations. Endophyte-host interactions are complex and further research into associations with high WSC plant should be performed in a case by case basis. [ABSTRACT FROM AUTHOR]

Background and Objective: Co-Crystal of Tramadol-Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions.Methods: Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed.Results: Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O-desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration-time curve to infinity (AUC∞) were within the pre-defined range for comparative bioavailability (80-125%). For celecoxib, Cmax and AUC∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98-146.49) and 129.34% (121.78-137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions.Conclusions: As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability.Clinical trial registration number: 152052 (registered with the Therapeutic Products Directorate of Health Canada) [ABSTRACT FROM AUTHOR]