Technical guide on documentation requirements for open market contract acquisitions of information resources

A guide is presented to assist requestors in formulating and submitting the required Complete Package for Information Resources (IR) acquisitions. Advance discussions with cognizant procurement personnel are strongly recommended for complex IR requirements or for those requestors new to the acquisition process. Open Market means the requirement either is not available on GSA Schedule Contract or exceeds the $300,000 threshold and/or the quantity Maximum Order Limitation of the GSA Schedule Contract. Only open market contract acquisitions (i.e., in excess of the$25,000 small purchase threshold), are addressed

Isolation and characterisation of polymorphic microsatellite loci for studies of the big blue octopus, Octopus cyanea

The big blue octopus, Octopus cyanea, occurs on coral reefs throughout the Indo-Pacific region from East Africa to the Hawaiian Islands, wherein it is of great ecological and socio-economic importance. However, many components of its intraspecific biodiversity, such as population structure, are unresolved due to a lack of informative genetic markers. To address this issue, which may compromise conservation and sustainability efforts, the development and characterisation of the first species-specific microsatellite loci for O. cyanea are described here. The eight loci were characterised by the genotyping of 40 adults from Madagascar, which revealed an average of 13.5 alleles per locus (range 9?18). The observed and expected heterozygosity per locus ranged from 0.432 to 0.949 and from 0.481 to 0.989, respectively. No evidence of linkage disequilibrium was detected between pairs of loci. Genotype proportions at six loci conformed to Hardy?Weinberg equilibrium expectations, with two loci exhibiting significant heterozygote deficits. These loci are applicable to multiple areas of eco-evolutionary research and, thus, represent a valuable resource for future studies of O. cyaneapublishersversionPeer reviewe

Impact of the Holocene Transgression on the Atlantic Coastline of Nova Scotia

As analogs for impact of a future sea-level rise on the coast of Nova Scotia (eastern Canada), geological data and information on relative sea-level changes are examined at three different time scales. Relative sea level rose swiftly during the early Holocene, at a maximum rate of 11 m/ka at 7500 radiocarbon years BP. Freshwater, salt-marsh, and estuarine sediments that formed during this period have been located on the inner shelf. After 5000 BP the rate slackened to about 2 m/ka. Despite overall submergence and coastal retreat since that time, gravel barriers have persisted where large amounts of sediment have been added to the littoral system by erosion of glacial deposits. The barriers often display evidence of early progradational phases in the form of gravel beach ridges, partly or wholly submerged in lagoons behind contemporary storm beaches. Tide-gauge data from the past century show submergence rates averaging 3.5 mm/a, well in excess of the longterm trend. The response of the coastline to this rapid rise is complex. Unconsolidated cliffs (bluffs) retreat at up to 5 m/a during initial exposure to wave attack and during extreme storm events, but at lesser rates (8 m/a) in some locations, but low elsewhere, in some cases showing almost no movement over the past 10 years, and neighbouring beaches are sometimes observed to behave in completely different ways. Sediment released by coastal erosion finds its way into nearby estuaries, causing growth of flood-tidal deltas and marsh aggradation. If a global rise in sea level occurs, the processes of erosion and sedimentation operating along the coast of Nova Scotia during the Holocene are expected to continue in a similar fashion, but rates of change will increase at many locations.Les données géologiques et les connaissances sur les changements du niveau marin relatif sont étudiées à trois échelles temporelles en tant qu'analogues des conséquences d'une future hausse du niveau marin sur la côte de la Nouvelle-Écosse. Le niveau marin relatif s'est rapidement élevé au cours de l'Holocène inférieur, jusqu'au taux maximal de 11 m/ka à 7500 BP. Des sédiments estuariens ou issus de marais salants et d'eau douce datant de cette période ont été localisés sur le plateau continental intérieur. Après 5000 BP le taux a diminué jusqu'à 2 m/ka. En dépit de la submersion de la région côtière et de son dégagement subséquent, les cordons littoraux de gravier ont persisté là où de grandes quantités de sédiments ont été mis en place sur le littoral par érosion des dépôts glaciaires. Les cordons montrent souvent des indices de phases de progression sous la forme de crêtes de graviers, partiellement ou entièrement submergés dans les lagunes situées derrière les plages de tempêtes contemporaines. Les données marégraphiques du siècle dernier font ressortir un taux de submersion d'environ 3,5 mm/a, taux nettement plus élevé que celui de la tendance à long terme. La réponse du littoral à cette hausse rapide est complexe. Les falaises non consolidées peuvent reculer jusqu'à 5 m/a au début de leur exposition aux fortes vagues et pendant les plus fortes tempêtes et à un rythme beaucoup plus lent (8 m/a) par endroits, lent ailleurs; certaines plages sont presque immobiles depuis 10 ans, alors que les plages voisines se comportent de façon tout à fait différente. Les sédiments libérés par l'érosion littorale se retrouvent dans les estuaires les plus proches, provoquant l'expansion des deltas d'inondation et l'extension des marais. Si une hausse globale du niveau marin survenait, les processus d'érosion et de sédimentation qui se sont manifestés le long de la côte de la Nouvelle-Écosse pendant l'Holocène agiront de façon semblable, mais le rythme des changements augmentera dans plusieurs sites

Understanding implementation success: protocol for an in-depth, mixed-methods process evaluation of a cluster randomised controlled trial testing methods to improve detection of Lynch syndrome in Australian hospitals.

INTRODUCTION:In multisite intervention trials, implementation success often varies widely across settings. Process evaluations are crucial to interpreting trial outcomes and understanding contextual factors and causal chains necessary for successful implementation. Lynch syndrome is a hereditary cancer predisposition conferring an increased risk of colorectal, endometrial and other cancer types. Despite systematic screening protocols to identify Lynch syndrome, the condition remains largely underdiagnosed. The Hide and Seek Project ('HaSP') is a cluster randomised controlled trial determining the effectiveness of two approaches to improving Lynch syndrome detection at eight Australian hospital networks. To enhance widespread implementation of optimal Lynch syndrome identification, there is a need to understand not only what works, but also why, in what contexts, and at what costs. Here we describe an in-depth investigation of factors influencing successful implementation of procedures evaluated in the HaSP trial. METHODS AND ANALYSIS:A mixed-methods, theory-driven process evaluation will be undertaken in parallel to the HaSP trial. Data will include: interviews of Implementation Leads and Lynch syndrome stakeholders, pre-post implementation questionnaires, audio analysis of meetings and focus groups, observation of multidisciplinary team meetings, fidelity checklists and project log analysis. Results will be triangulated and coded, drawing on the Theoretical Domains Framework, Consolidated Framework for Implementation Research and Proctor's implementation outcomes. ETHICS AND DISSEMINATION:Use of a theory-based process evaluation will enhance interpretation and generalisability of HaSP trial findings, and contribute to the implementation research field by furthering understanding of the conditions necessary for implementation success. Ethical approval has been granted and results will be disseminated via publications in peer-reviewed journals and conference presentations. At trial completion, key findings will be fed back to sites to enable refinement of intervention strategies, both in the context of Lynch syndrome and for the possible generalisability of intervention components in other genetic and broader clinical specialties. HASP TRIAL REGISTRATION NUMBER:Australian New Zealand Clinical Trials Registry (Identifier: ACTRN12618001072202). Registered 27 June 2018. http://www.ANZCTR.org.au/ACTRN12618001072202.aspx

Colorimetric and Longitudinal Analysis of Leukocoria in Recreational Photographs of Children with Retinoblastoma

Retinoblastoma is the most common primary intraocular tumor in children. The first sign that is often reported by parents is the appearance of recurrent leukocoria (i.e., “white eye”) in recreational photographs. A quantitative definition or scale of leukocoria – as it appears during recreational photography – has not been established, and the amount of clinical information contained in a leukocoric image (collected by a parent) remains unknown. Moreover, the hypothesis that photographic leukocoria can be a sign of early stage retinoblastoma has not been tested for even a single patient. This study used commercially available software (Adobe Photoshop®) and standard color space conversion algorithms (operable in Microsoft Excel®) to quantify leukocoria in actual “baby pictures” of 9 children with retinoblastoma (that were collected by parents during recreational activities i.e., in nonclinical settings). One particular patient with bilateral retinoblastoma (“Patient Zero”) was photographed >7, 000 times by his parents (who are authors of this study) over three years: from birth, through diagnosis, treatment, and remission. This large set of photographs allowed us to determine the longitudinal and lateral frequency of leukocoria throughout the patient's life. This study establishes: (i) that leukocoria can emerge at a low frequency in early-stage retinoblastoma and increase in frequency during disease progression, but decrease upon disease regression, (ii) that Hue, Saturation and Value (i.e., HSV color space) are suitable metrics for quantifying the intensity of retinoblastoma-linked leukocoria; (iii) that different sets of intraocular retinoblastoma tumors can produce distinct leukocoric reflections; and (iv) the Saturation-Value plane of HSV color space represents a convenient scale for quantifying and classifying pupillary reflections as they appear during recreational photography

INTEGRAL and RXTE observations of accreting millisecond pulsar IGR J00291+5934 in outburst

Simultaneous observations of the accretion-powered millisecond pulsar IGR J00291+5934 by International Gamma-Ray Astrophysics Laboratory and Rossi X-ray Timing Explorer during the 2004 December outburst are analysed. The average spectrum is well described by thermal Comptonization with an electron temperature of 50 keV and Thomson optical depth tau_T ~ 1 in a slab geometry. The spectral shape is almost constant during the outburst. We detect a spin-up of the pulsar with nudot=8.4x10E-13 Hz/s. The ISGRI data reveal the pulsation of X-rays at a period of 1.67 milliseconds up to ~150 keV. The pulsed fraction is shown to increase from 6 per cent at 6 keV to 12--20 per cent at 100 keV. This is naturally explained by the action of the Doppler effect the exponentially cutoff Comptonization spectrum from the hot spot. The nearly sinusoidal pulses show soft lags with complex energy dependence, increasing up to 7 keV, then decreasing to 15 keV, and seemingly saturating at higher energies.Comment: 11 pages, 8 figures, 3 tables, accepted for publication on A&

Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells

Background Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with multiple roles in tumour growth, cell invasion and metastasis. We have previously established GSK-3 as an upstream regulator of PD-1 gene expression in CD8 + T cells and demonstrated that GSK-3 inhibition is as effective as anti-PD-1 mAb blockade in controlling tumour growth. Elraglusib (9-ING-41) is a specific small-molecule inhibitor of GSK-3β with clinical activity in patients with advanced cancers, including a patient with refractory melanoma whose response provided the rationale for the current study. Methods The B16 melanoma mouse model was used to observe the effect of elraglusib on tumour growth either as a single agent or in combination (simultaneously and sequentially) with anti-PD-1 mAb treatment. B16 tumour cells were implanted in either the flank, brain or both locations, and Kaplan–Meier plots were used to depict survival and significance determined using log rank tests. Expression of the immune checkpoint molecules, TIGIT, LAG-3 and PD-1, was evaluated using flow cytometry alongside expression of the chemokine receptor, CXCR3. Further evaluation of PD-1 expression was determined through RT-qPCR and immunohistochemistry. Results We demonstrated that elraglusib has a suppressive effect against melanoma as a single agent and enhanced anti-PD-1 therapy. There was a synergistic effect when elraglusib was used in combination with anti-PD-1 mAb, and an even greater effect when used as sequential therapy. Suppression of tumour growth was associated with a reduced expression of immune checkpoint molecules, PD-1, TIGIT and LAG-3 with upregulation of CXCR3 expression. Conclusions These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182)

Benefit-Cost Analysis of FEMA Hazard Mitigation Grants

Mitigation ameliorates the impact of natural hazards on communities by reducing loss of life and injury, property and environmental damage, and social and economic disruption. The potential to reduce these losses brings many benefits, but every mitigation activity has a cost that must be considered in our world of limited resources. In principle benefit-cost analysis (BCA) can be used to assess a mitigation activity’s expected net benefits (discounted future benefits less discounted costs), but in practice this often proves difficult. This paper reports on a study that refined BCA methodologies and applied them to a national statistical sample of FEMA mitigation activities over a ten-year period for earthquake, flood, and wind hazards. The results indicate that the overall benefit-cost ratio for FEMA mitigation grants is about 4 to 1, though the ratio varies according to hazard and mitigation type.

In the shadow of coal: How large-scale industries contributed to present-day regional differences in personality and well-being

Recent research has identified regional variation of personality traits within countries but we know little about the underlying drivers of this variation. We propose that the Industrial Revolution, as a key era in the history of industrialized nations, has led to a persistent clustering of well-being outcomes and personality traits associated with psychological adversity via processes of selective migration and socialization. Analyzing data from England and Wales, we examine relationships between the historical employment share in large-scale coal-based industries (coal mining and steam-powered manufacturing industries that used this coal as fuel for their steam engines) and today’s regional variation in personality and well- being. Even after controlling for possible historical confounds (historical energy supply, education, wealth, geology, climate, population density), we find that the historical local dominance of large-scale coal-based industries predicts today’s markers of psychological adversity (lower Conscientiousness [and order facet scores], higher Neuroticism [and anxiety and depression facet scores], lower activity [an Extraversion facet], and lower life satisfaction and life expectancy). An instrumental variable analysis, using the historical location of coalfields, supports the causal assumption behind these effects (with the exception of life satisfaction). Further analyses focusing on mechanisms hint at the roles of selective migration and persisting economic hardship. Finally, a robustness check in the U.S. replicates the effect of the historical concentration of large-scale industries on today’s levels of psychological adversity. Taken together, the results show how today’s regional patterns of personality and well-being may have their roots in major societal changes underway decades or centuries earlier

Bone turnover and metabolite responses to exercise in people with and without long-duration type 1 diabetes: a case-control study

INTRODUCTION: Exercise acutely alters markers of bone resorption and formation. As risk of fracture is increased in patients with type 1 diabetes, understanding if exercise-induced bone turnover is affected within this population is prudent. We assessed bone turnover responses to acute exercise in individuals with long-duration type 1 diabetes and matched controls. RESEARCH DESIGN AND METHODS: Participants with type 1 diabetes (n=15; age: 38.7±13.3; glycosylated hemoglobin: 60.5±6.7 mmol/mol; diabetes duration: 19.3±11.4 years) and age-matched, fitness-matched, and body mass index-matched controls (n=15) completed 45 min of incline walking (60% peak oxygen uptake). Blood samples were collected at baseline and immediately, 30 min, and 60 min postexercise. Markers of bone resorption (β-C-terminal cross-linked telopeptide of type 1 collagen, β-CTx) and formation (procollagen type-1 amino-terminal propeptide, P1NP), parathyroid hormone (PTH), phosphate, and calcium (albumin-adjusted and ionized) were measured. Data (mean±SD) were analyzed by a mixed-model analysis of variance. RESULTS: Baseline concentrations of P1NP and β-CTx were comparable between participants with type 1 diabetes and controls. P1NP did not change with exercise (p=0.20) but β-CTx decreased (p0.39). Participants with type 1 diabetes had reduced albumin and ionized calcium at all sample points (p<0.01). CONCLUSIONS: Following exercise, participants with type 1 diabetes displayed similar time-course changes in markers of bone formation and associated metabolites, but an attenuated suppression in bone resorption. The reduced albumin and ionized calcium may have implications for future bone health. Further investigation of the interactions between type 1 diabetes, differing modalities and intensities of exercise, and bone health is warranted