Diffraction enhanced imaging utilizing a laser produced x-ray source.

Image formation by Fresnel diffraction utilizes both absorption and phase-contrast to measure electron density profiles. The low spatial and spectral coherence requirements allow the technique to be performed with a laser-produced x-ray source coupled with a narrow slit. This makes it an excellent candidate for probing interfaces between materials at extreme conditions, which can only be generated at large-scale laser or pulsed power facilities. Here, we present the results from a proof-of-principle experiment demonstrating an effective ∼2 µm laser-generated source at the OMEGA Laser Facility. This was achieved using slits of 1 × 30 µm2 and 2 × 40 µm2 geometry, which were milled into 30 µm thick Ta plates. Combining these slits with a vanadium He-like 5.2 keV source created a 1D imaging system capable of micrometer-scale resolution. The principal obstacles to achieving an effective 1 µm source are the slit tilt and taper-where the use of a tapered slit is necessary to increase the alignment tolerance. We demonstrate an effective source size by imaging a 2 ± 0.2 µm radius tungsten wire.

Serum OPG/TRAIL ratio predicts the presence of cardiovascular disease in people with type 2 diabetes mellitus.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk. METHODS: In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA. RESULTS: People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%. CONCLUSION: This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

Impact and legacy of the highly cited paper by Blaxter and Clapperton (1965) 'Prediction of the amount of methane produced by ruminants [Br J Nutr 19, 511-522]'.

The paper by K. L. Blaxter and J. L. Clapperton (1965) 'Prediction of the amount of methane produced by ruminants. Br J Nutr 19, 511-522' has been cited 656 times according to Web of Science and continues to be cited with increasing frequency to the present day. The analysis described in the paper, or meta-analysis as it would be known now, is of methane production from cattle and sheep based on forty-eight trials using closed-circuit respiration chambers, all carried out at the Hannah Research Institute, Ayr, UK, between 1955 and 1965. Methane emissions per unit of diet fed were shown to vary depending on diet, level of feeding and individual animal. As such, previous notions that methane emissions were essentially proportional to energy intake were set aside. The main reasons for the paper's continuing citation are the set of equations that can be used to predict methane emissions from ruminants when the technically demanding respiration chambers are unavailable, and that it was the first definitive study to describe the complexities of methane emissions with respect to animals and diets. The paper thus provided abundant insights of the relations between ruminant methane emissions and nutritional biology, and rumen microbiology, in particular, that have informed countless research projects in the intervening half-century. Given the importance of methane as a greenhouse gas in the climate change scenario, these insights are at least as relevant today as they were in 1965.

Elimination of human rabies in Goa, India through an integrated One Health approach.

Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention 'very cost-effective' by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.

Demonstration of plasma mirror capability for the OMEGA Extended Performance laser system.

A plasma mirror platform was developed for the OMEGA-EP facility to redirect beams, thus enabling more flexible experimental configurations as well as a platform that can be used in the future to improve laser contrast. The plasma mirror reflected a short pulse focusing beam at 22.5° angle of incidence onto a 12.5 µm thick Cu foil, generating Bremsstrahlung and kα x rays, and accelerating ions and relativistic electrons. By measuring these secondary sources, the plasma mirror key performance metrics of integrated reflectivity and optical quality are inferred. It is shown that for a 5 ± 2 ps, 310 J laser pulse, the plasma mirror integrated reflectivity was 62 ± 13% at an operating fluence of 1670 J cm-2, and that the resultant short pulse driven particle acceleration and x-ray generation indicate that the on target intensity was 3.1 × 1018 W cm-2, which is indicative of a good post-plasma mirror interaction beam optical quality. By deriving the plasma mirror performance metrics from the secondary source scalings, it was simultaneously demonstrated that the plasma mirror is ready for adoption in short pulse particle acceleration and high energy photon generation experiments using the OMEGA-EP system.

Toward an integrated platform for characterizing laser-driven, isochorically heated plasmas with 1 µm spatial resolution.

Warm dense matter is a region of phase space that is of high interest to multiple scientific communities ranging from astrophysics to inertial confinement fusion. Further understanding of the conditions and properties of this complex state of matter necessitates experimental benchmarking of the current theoretical models. We discuss the development of an x-ray radiography platform designed to measure warm dense matter transport properties at large laser facilities such as the OMEGA Laser Facility. Our platform, Fresnel diffractive radiography, allows for high spatial resolution imaging of isochorically heated targets, resulting in notable diffractive effects at sharp density gradients that are influenced by transport properties such as thermal conductivity. We discuss initial results, highlighting the capabilities of the platform in measuring diffractive features with micrometer-level spatial resolution.

Light microscopic observations of the ruminal papillae of cattle on diets with divergent forage to cereal ratios.

High levels of supplementation with cereal increases production rates in cattle but can increase incidence of disease, ranging from mild indigestion to acute ruminal acidosis and death. Therefore, there is motivation to determine biological markers which can be used to identify whether animals have been, or are being fed, sufficient or excessive cereals. This study aimed to describe light microscopic findings from animals being fed diverse dietary cereal proportions and to test the performance of a novel rumen epithelial scoring system. Rumen wall tissue samples were obtained from the abattoir from 195 cattle from 11 Scottish farms and processed for histological examination. Light microscopic examination was used to characterise ruminal epithelial response to dietary challenge. Secondary objectives included describing the distribution of immune-related cells in bovine ruminal epithelium and assessing the use of a modified Elastin Martius Scarlet Blue stain (EMSB) for histological examination of the rumen epithelium. Cells staining positive for cluster of differentiation 3 were distributed mainly in the lower layers of the stratum basale and were found in higher densities in animals offered lower cereal proportion diets. Cells staining positive for major histocompatibility complex class 2 (MHCII) were most common in perivascular locations and in the junction between the lower stratum basale and the propria-submucosa. The density of MHCII positive staining cells was higher in animals on lower cereal diets. The level of supplementation with cereal was also associated with the thickness of the stratum corneum (SCT) and stratum granulosum (SGT), the integrity of the stratum corneum and sloughing of cornified cells. There were no advantages in using EMSB stain over haematoxylin and eosin (H&E) in this scoring system. We concluded that a scoring system that included only SCT, SGT and a measure of the loss of appearance of intercellular space allowed differentiation of groups of animals according to the level of cereal supplementation.

'The names have changed, but the game's the same': artificial intelligence and racial policy in the USA.

Like the Operations Research models used to justify the ethnic cleansing of minority voting blocs in 1970's New York City, AI 'risk assessment' systems for individuals will be used to reinforce longstanding power relations between ethnic groups within the USA. From the perspective of African-Americans and their abolitionist allies, the central problem with AI risk assessment does not involve 'corrective' stabilization of an inadvertently unstable system. On the contrary, that system's de-facto-if sometimes camouflaged-purpose is enforcing the stability of historic patterns of racial oppression, constitutional formalities notwithstanding. AI, like 'OR' before it, becomes, then, simply another tactic in a persistent strategy aimed at reinforcing a stable cultural trajectory with roots deep in human slavery. To the archetypic question 'what is to be done?' is the archetypic answer: build countervailing power.

Genomic Analysis of Limosilactobacillus fermentum ATCC 23271, a Potential Probiotic Strain with Anti-Candida Activity.

Limosilactobacillus fermentum (ATCC 23271) was originally isolated from the human intestine and has displayed antimicrobial activity, primarily against Candida species. Complete genome sequencing and comparative analyses were performed to elucidate the genetic basis underlying its probiotic potential. The ATCC 23271 genome was found to contain 2,193,335 bp, with 2123 protein-coding sequences. Phylogenetic analysis revealed that the ATCC 23271 strain shares 941 gene clusters with six other probiotic strains of L. fermentum. Putative genes known to confer probiotic properties have been identified in the genome, including genes related to adhesion, tolerance to acidic pH and bile salts, tolerance to oxidative stress, and metabolism and transport of sugars and other compounds. A search for bacteriocin genes revealed a sequence 48% similar to that of enterolysin A, a protein from Enterococcus faecalis. However, in vitro assays confirmed that the strain has inhibitory activity on the growth of Candida species and also interferes with their adhesion to HeLa cells. In silico analyses demonstrated a high probability of the protein with antimicrobial activity. Our data reveal the genome features of L. fermentum ATCC 23271, which may provide insight into its future use given the functional benefits, especially against Candida infections.

Converting existing optical detectors into fast x-ray detectors.

The very short burn time and small size of burning plasmas created at advanced laser-fusion facilities will require high-spatial-resolution imaging diagnostics with fast time resolution. These instruments will need to function in an environment of extremely large neutron fluxes that will cause conventional diagnostics to fail because of radiation damage and induced background levels. One solution to this challenge is to perform an ultrafast conversion of the x-ray signals into the optical regime before the neutrons are able to reach the detector and then to relay image the signal out of the chamber and into a shielded bunker, protected from the effects of these neutrons. With this goal in mind, the OMEGA laser was used to demonstrate high-temporal-resolution x-ray imaging by using an x-ray snout to image an imploding backlighter capsule onto a semiconductor. The semiconductor was simultaneously probed with the existing velocity interferometry system for any surface reflector (VISAR) diagnostic, which uses an optical streak camera and provided a one-dimensional image of the phase in the semiconductor as a function of time. The phase induced in the semiconductor was linearly proportional to the x-ray emission from the backlighter capsule. This approach would then allow a sacrificial semiconductor to be attached at the end of an optical train with the VISAR and optical streak camera placed in a shielded bunker to operate in a high neutron environment and obtain time-dependent one-dimensional x-ray images or time-dependent x-ray spectra from a burning plasma.

The rumen microbiome: balancing food security and environmental impacts.

Ruminants produce edible products and contribute to food security. They house a complex rumen microbial community that enables the host to digest their plant feed through microbial-mediated fermentation. However, the rumen microbiome is also responsible for the production of one of the most potent greenhouse gases, methane, and contributes about 18% of its total anthropogenic emissions. Conventional methods to lower methane production by ruminants have proved successful, but to a limited and often temporary extent. An increased understanding of the host-microbiome interactions has led to the development of new mitigation strategies. In this Review we describe the composition, ecology and metabolism of the rumen microbiome, and the impact on host physiology and the environment. We also discuss the most pertinent methane mitigation strategies that emerged to balance food security and environmental impacts.

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Comparison of methods to predict feed intake and residual feed intake using behavioral and metabolite data in addition to classical performance variables.

Predicting dry matter intake (DMI) and feed efficiency by leveraging the use of data streams available on farm could aid efforts to improve the feed efficiency of dairy cattle. Residual feed intake (RFI) is the difference between predicted and observed feed intake after accounting for body size, body weight change, and milk production, making it a valuable metric for feed efficiency research. Our objective was to develop and evaluate DMI and RFI prediction models using multiple linear regression (MLR), partial least squares regression, artificial neural networks, and stacked ensembles using different combinations of cow descriptive, performance, sensor-derived behavioral (SMARTBOW; Zoetis), and blood metabolite data. Data were collected from mid-lactation Holstein cows (n = 124; 102 multiparous, 22 primiparous) split equally between 2 replicates of 45-d duration with ad libitum access to feed. Within each predictive approach, 4 data streams were added in sequence: dataset M (week of lactation, parity, milk yield, and milk components), dataset MB (dataset M plus body condition score and metabolic body weight), dataset MBS (dataset MB plus sensor-derived behavioral variables), and dataset MBSP (dataset MBS plus physiological blood metabolites). The combination of 4 datasets and 4 analytical approaches resulted in 16 analyses of DMI and RFI, using variables averaged within cow across the study period. Additional models using weekly averaged data within cow and study were built using all predictive approaches for datasets M, MB, and MBS. Model performance was assessed using the coefficient of determination, concordance correlation coefficient, and root mean square error of prediction. Predictive models of DMI performed similarly across all approaches, and models using dataset MBS had the greatest model performance. The best approach-dataset combination was MLR-dataset MBS, although several models performed similarly. Weekly DMI models had the greatest performance with MLR and partial least squares regression approaches. Dataset MBS models had incrementally better performance than datasets MB and M. Within each approach-dataset combination, models with DMI averaged over the study period had slightly greater model performance than DMI averaged weekly. Predictive performance of all RFI models was poor, but slight improvements when using MLR applied to dataset MBS suggest that rumination and activity behaviors may explain some of the variation in RFI. Overall, similar performance of MLR, compared with machine learning techniques, indicates MLR may be sufficient to predict DMI. The improvement in model performance with each additional data stream supports the idea of integrating data streams to improve model predictions and farm management decisions.

Metagenomic analysis of the cow, sheep, reindeer and red deer rumen.

The rumen microbiota comprises a community of microorganisms which specialise in the degradation of complex carbohydrates from plant-based feed. These microbes play a highly important role in ruminant nutrition and could also act as sources of industrially useful enzymes. In this study, we performed a metagenomic analysis of samples taken from the ruminal contents of cow (Bos Taurus), sheep (Ovis aries), reindeer (Rangifer tarandus) and red deer (Cervus elaphus). We constructed 391 metagenome-assembled genomes originating from 16 microbial phyla. We compared our genomes to other publically available microbial genomes and found that they contained 279 novel species. We also found significant differences between the microbiota of different ruminant species in terms of the abundance of microbial taxonomies, carbohydrate-active enzyme genes and KEGG orthologs. We present a dataset of rumen-derived genomes which in combination with other publicly-available rumen genomes can be used as a reference dataset in future metagenomic studies.

Using biodosimetry to enhance the public health response to a nuclear incident.

Radiation Biodosimetry is a continually developing clinical diagnostic field, which focuses on biological markers that proportionally change in relationship to the amount of ionizing radiation absorbed. Examples of host marker response include changes in white cell count, specific proteins in circulation, RNAs in white blood cells, or chromosome fidelity in affected lymphocytes. Measurements of radiation biomarkers correlate with the approximate radiation dose absorbed and indirectly provide an assessment of the likelihood of developing acute radiation syndrome. The aim of this review is to summarize four biodosimetry programs that are in advanced development, later pipeline stages with funding from the Biomedical Advanced Research and Development Authority (BARDA), an agency under the Assistant Secretary for Preparedness and Response (ASPR) in the U.S. Department of Health and Human Services (HHS). With BARDA financial support, biodosimetry diagnostic assays in development will inform patient management, improve health and psychosocial outcomes, and save lives after a nuclear disaster. These tests include an SRI International developed rapid on-site screening test requiring only a finger stick of blood to triage those who have received little or no radiation from those who have received clinically significant levels of radiation and need further immediate patient management. In addition, multiple laboratory-based, high-throughput quantitative tests, currently under development by MRIGlobal, DxTerity, and ASELL, will more accurately define dose levels and possibly predict cellular and organ-damage and other longer-term effects of radiation. In the future, when clinical and analytical validation of these assays is complete, the data is reviewed by the FDA, and agency use status is obtained, rapid triage and laboratory-based biodosimetry test results will enable emergency medical teams to do the most good for the largest number of people after a nuclear blast.

Trainee experience in diagnosis and management of personality disorders.

The diagnosis and management of personality disorders continues to evolve and develop alongside psychiatry internationally, however, not always in a linear fashion. Trainees working in a variety of clinical areas have regular exposure to personality disorder presentations. Psychiatry training bodies continue to adapt their training structure and curriculum, however, there seems to be a lack of sufficient emphasis with regards this area. We are now embarking on a new diagnostic system for personality disorders; this may impact on our clinical practice and perspective of these patients. The role of psychiatrists in diagnosing and managing personality disorders can be unclear at times and may benefit from on-going reflection and standardization.

Identification of Complex Rumen Microbiome Interaction Within Diverse Functional Niches as Mechanisms Affecting the Variation of Methane Emissions in Bovine.

A network analysis including relative abundances of all ruminal microbial genera (archaea, bacteria, fungi, and protists) and their genes was performed to improve our understanding of how the interactions within the ruminal microbiome affects methane emissions (CH4). Metagenomics and CH4 data were available from 63 bovines of a two-breed rotational cross, offered two basal diets. Co-abundance network analysis revealed 10 clusters of functional niches. The most abundant hydrogenotrophic Methanobacteriales with key microbial genes involved in methanogenesis occupied a different functional niche (i.e., "methanogenesis" cluster) than methylotrophic Methanomassiliicoccales (Candidatus Methanomethylophylus) and acetogens (Blautia). Fungi and protists clustered together and other plant fiber degraders like Fibrobacter occupied a seperate cluster. A Partial Least Squares analysis approach to predict CH4 variation in each cluster showed the methanogenesis cluster had the best prediction ability (57.3%). However, the most important explanatory variables in this cluster were genes involved in complex carbohydrate degradation, metabolism of sugars and amino acids and Candidatus Azobacteroides carrying nitrogen fixation genes, but not methanogenic archaea and their genes. The cluster containing Fibrobacter, isolated from other microorganisms, was positively associated with CH4 and explained 49.8% of its variability, showing fermentative advantages compared to other bacteria and fungi in providing substrates (e.g., formate) for methanogenesis. In other clusters, genes with enhancing effect on CH4 were related to lactate and butyrate (Butyrivibrio and Pseudobutyrivibrio) production and simple amino acids metabolism. In comparison, ruminal genes negatively related to CH4 were involved in carbohydrate degradation via lactate and succinate and synthesis of more complex amino acids by γ-Proteobacteria. When analyzing low- and high-methane emitters data in separate networks, competition between methanogens in the methanogenesis cluster was uncovered by a broader diversity of methanogens involved in the three methanogenesis pathways and larger interactions within and between communities in low compared to high emitters. Generally, our results suggest that differences in CH4 are mainly explained by other microbial communities and their activities rather than being only methanogens-driven. Our study provides insight into the interactions of the rumen microbial communities and their genes by uncovering functional niches affecting CH4, which will benefit the development of efficient CH4 mitigation strategies.