The Rat Genome Database (RGD, https://rgd.mcw.edu) has evolved from simply a resource for rat genetic markers, maps, and genes, by adding multiple genomic data types, extensive disease and phenotype annotations, and developing tools to effectively mine, analyze and visualize the available data, to empower investigators in their hypothesis-driven research. Leveraging its robust and flexible infrastructure, RGD has added data for human and eight other model organisms (mouse, 13-lined ground squirrel, chinchilla, naked mole rat, dog, pig, African green monkey/vervet, and bonobo) besides rat to enhance its translational aspect. This article presents an overview of the database with the most recent additions to RGD's genome, variant and quantitative phenotype data. We also briefly introduce VCMap, an updated tool that explores synteny between species as an improvement to RGD's suite of tools, followed by a discussion regarding the refinements to the existing PhenoMiner tool that assists researchers in finding and comparing quantitative data across rat strains. Collectively, RGD focuses on providing a continuously improving, consistent, and high-quality data resource for researchers while advancing data reproducibility and fulfilling FAIR data principles.

Holocene environmental change in the northern and central Nile Valley was controlled primarily by shifts in the Intertropical Convergence Zone over time, leading to changes in aridity and water availability for early occupants of the region. Although local environmental changes may help to motivate societal changes such as those in settlement patterns or technological productions, evidence from pedogenic carbonates at Sai Island, in northern Sudan, indicate that the most significant environmental changes predated a key shift in local food production from foraging to pastoralism. Changes in local environmental conditions from a wetter and more diverse vegetative context to a more arid and C 4 ‐dominant landscape occurred during the occupation of Khartoum Variant foragers, whereas later Abkan pastoralists arrived without any notable differences in the region compared to the environments inhabited by the most recent foragers. The lack of an external environmental driver for food production changes at Sai suggests that other, potentially cultural factors were more important in these economic decisions in the mid‐Holocene.

The laboratory rat,Rattus norvegicus, has been used in biomedical research for more than 150 years, and in many cases remains the model of choice for studies of physiology, behavior, and complex human disease. This book provides detailed information on a number of methodologies that can be used in rat. This chapter gives an introduction to rat as a species and as a biomedical model, providing historical information, a brief introduction to the current state of rat research, and a perspective on the future of rat as a model for

— The Rat Genome Database (RGD) has been annotating genes, QTLs, and strains to disease terms for over 15 years. During that time the controlled vocabulary used for disease curation has changed a few times. The changes were necessitated because no single vocabulary or ontology was freely accessible and complete enough to cover all of the disease states described in the biomedical literature. The first disease vocabulary

Today, Bir Tarfawi, Kharga and Dakhleh Oases all sit in Egypt's hyperarid Western Desert. A dearth of naturally occurring surface water coupled with <= 0.1 mm/y of precipitation, and evaporation rates > 2 m/y make Bir Tarfawi uninhabitable today, while Dakhleh and Kharga depend on borehole water to support human inhabitation. Yet in scattered locations dotting the Quaternary surfaces and deposits near each oasis, Paleolithic artefacts, fossil ungulate teeth, and snails record times when surface water did exist in wetlands, small ponds, and even large lakes. At Bir Tarfawi in Marine Isotope Stages (MIS) 5, 7, and 13, wetlands or small lakes supported freshwater snails, large herbivores, and hominins. Dakhleh Oasis hosted a large lake in MIS 6 that provided a deep reliable water supply for many millennia subsequently. ESR dates on fossils and tufa dates show thriving lacustrine and terrestrial ecosystems at Dakhleh during MIS 5, 7, 9,11, and 17, and in shorter episodes in MIS 1, 2, 3, 6, and 12. At Kharga Oasis, springs discharged along the Libyan Escarpment edge, but the water was ponded in small basins dammed within tufa deposits. These dated deposits and fossils attest that water existed there in MIS 2-11, and one spot dating to 2.3 Ma. This proxy evidence suggest that, thanks to higher rainfall and/or groundwater tables, sufficient water persisted for much of the Pleistocene, supporting food resources, like large herbivores and molluscs, to thrive and enabling hominin habitation. and activity in the Western Desert. (C) 2017 Elsevier Ltd. All rights reserved.

In the northeastern Sahara, electron spin resonance (ESR) dating of when animals lived documents their habitability in Dakhleh Oasis, Egypt. A Middle Pleistocene paleolake(s) covered >1700 km(2). At eastern Locality Dak348, 10 m thick, remnant lacustrine marls yielded Pleistocene fauna, rare artefacts, and plant casts. No obvious unconformity exists within these deposits. From upper horizons, a hartebeest tooth ESR dated at 195 +/- 11 ka, correlates with Marine Isotope Stage (MIS) 7, while molluscs from a stratigraphically higher horizon averaged 89 +/- 10 ka, correlating with MIS 5a/b. At western Locality Dak006, upslope deflation has left a temporally mixed surficial lag. Numerous lagged tooth fragments, independently dated by ESR, correlate with MIS 5 through 17. Fragments from a slope sand unit correlate with MIS stages 3 through 6. One bovid tooth associated with Younger Middle Stone Age artefacts in the base of the sand dated at 84 +/- 7 ka (MIS 5a/b). Molluscs from Romano-Byzantine backdirt at a breached artesian vent dated to 8-15 +/- 1 ka, suggesting that ponds formed during MIS 1 and 2. Even without well defined sedimentary contexts, ESR frequency data indicate that the oasis was habitable for herbivores during at least twelve stages in the Mid-Late Quaternary, and, therefore, likely also for humans. (C) 2015 Elsevier Ltd and INQUA. All rights reserved.

G. Caton-Thompson and E. W. Gardner designated new Pleistocene cultural units at Kharga Oasis in the 1930’s: both were originally termed ‘pre-Sebilian’, but were later locally named the ‘Levalloiso-Khargan’ and ‘Khargan’ industries. High on the Bulaq scarp face, a puzzling cluster of stone ‘alignments’ was discovered in 1931–32, with a reported, but discounted, association with ‘Levalloiso-Khargan’ artefacts. Gardner excavated some features in 1933. Members of the Kharga Oasis Prehistory Project relocated ‘Site J’ in January 2011, and verified the reported Khargan associations with the features. In 2008, the project found structural features associated with Khargan artefacts in the northern Gebel Yebsa survey area, confirming earlier finds in the southern oases of Kurkur and Dungul. Evidence there, and that found in Kharga and Dakhleh oases, is now designated as the Khargan Complex. The associated built stone features of the included cultural units appear to be unique in Late Pleistocene Africa, especially at Bulaq.

There is an urgent need for improved therapies for children with high‐risk neuroblastoma where survival rates remain low. MYCN amplification is the most common genomic change associated with aggressive neuroblastoma and drugs targeting PI3K/AKT/mTOR, to activate MYCN oncoprotein degradation, are entering clinical evaluation. Our aim was to develop and validate pharmacodynamic (PD) biomarkers to evaluate both proof of mechanism and proof of concept for drugs that block PI3K/AKT/mTOR pathway activity in children with neuroblastoma. We have addressed the issue of limited access to tumor biopsies for quantitative detection of protein biomarkers by optimizing a three‐color fluorescence activated cell sorting (FACS) method to purify CD45−/GD2+/CD56+ neuroblastoma cells from bone marrow. We then developed a novel quantitative measurement of MYCN protein in these isolated neuroblastoma cells, providing the potential to demonstrate proof of concept for drugs that inhibit PI3K/AKT/mTOR signaling in this disease. In addition we have established quantitative detection of three biomarkers for AKT pathway activity (phosphorylated and total AKT, GSK3β and P70S6K) in surrogate platelet‐rich plasma (PRP) from pediatric patients. Together our new approach to neuroblastoma cell isolation for protein detection and suite of PD assays provides for the first time the opportunity for robust, quantitative measurement of protein‐based PD biomarkers in this pediatric patient population. These will be ideal tools to support clinical evaluation of PI3K/AKT/mTOR pathway drugs and their ability to target MYCN oncoprotein in upcoming clinical trials in neuroblastoma.

The gold standard definitive treatment for early stage nonmelanoma skin cancers (NMSC) is surgery. However, depending on tumor location, margins, and comorbidities, noninvasive modalities such as radiation may be preferred. Historically, superficial x-rays were most commonly used to treat NMSC. Recently, the use of hypofractionated HDR brachytherapy has increased, likely due to easier treatment setup and fewer treatments. We use a modern version of brachytherapy, the '3D topographic applicator brachytherapy' (3TAB) to treat NMSC since 2010. This study compares local control, toxicities, and number of treatments of x-rays vs 3TAB at our institution using matched pair analysis. 59 consecutive early stage NMSC lesions were treated with x-rays from 1999-2010 and were matched with respect to age, stage, histology, and site to 59 lesions in the 3TAB group selected from 252 lesions treated between 2010 to 2013. The x-ray group was treated with 100 kVp to a dose 40-54 Gy/10-20 fxs, based on size and depth of lesion. For 3TAB, a custom applicator was made using thermoplastic mold with HAM or Freiburg flap. A 3D optimized plan to 3 mm depth was created to deliver 40 Gy in 8 fxs, 2/wk over 4 weeks. Acute toxicity was graded by RTOG criteria for 3TAB, and for x-rays; grading was based on interpretation of follow-up notes. Chronic toxicity was graded by the presence or lack of toxicity. Cohorts were compared using Chi-square and Wilcoxon signed-rank test. Outlined in Table 1. No significant difference was seen in local control and chronic toxicity between the x-ray and the 3TAB cohorts. However, there was a significant difference in acute toxicity (P <0.0001) and number of treatments, with 3TAB having less acute toxicity and fewer fractions. At the completion of treatment, 22 (37.3%) lesions in the x-ray group and 2 (3.4%) lesions in the 3TAB group had G3 dermatitis, requiring a 2-week break for 3 (5.1%) lesions in the x-ray group, and 0 (0%) in the 3TAB group. In 3TAB group, 2 (3.3%) lesions received 7/8 planned treatments. For majority of lesions in both groups, acute toxicity subsided within 3 months. In this study, 3TAB offers similar local control and chronic toxicity with fewer treatments and less acute toxicity thus potentially promising to be a better modality.Poster Viewing Abstracts 3586; Table 1ParametersNumber (%) or Mean (Range)X-ray Group N=593TAB group N=59P valueAge (yrs)76 (50-94)80 (58-98)NSSite H&N Non H&N50 (84.7)50 (84.7)NS9 (15.3)9 (15.3)Histology BCC SCC Bowen's disease35 (59.3)35 (59.3)NS20 (33.9)20 (33.9)4 (6.8)4 (6.8)Stage0 I II4 (6.8)4 (6.8)NS42 (71.2)42 (71.2)13 (22.0)13 (22.0)# of Treatments17 (10-26)8F/U (mo)34.618.9Median: 24.0Median: 19.3Status at last F/UNED Local Recurrence5959NS00Acute ToxicityG1 G2 G317 (28.8)27 (45.8)<0.000120 (33.9)30 (50.8)22 (37.3)2 (3.4)Chronic Toxicity13 (22.0)10 (16.9) Open table in a new tab

There is an urgent need for improved therapies for children with high-risk neuroblastoma where survival rates remain low. MYCN amplification is the most common genomic change associated with aggressive neuroblastoma and drugs targeting PI3K/AKT/mTOR, to activate MYCN oncoprotein degradation, are entering clinical evaluation. Our aim was to develop and validate pharmacodynamic (PD) biomarkers to evaluate both proof of mechanism and proof of concept for drugs that block PI3K/AKT/mTOR pathway activity in children with neuroblastoma. We have addressed the issue of limited access to tumor biopsies for quantitative detection of protein biomarkers by optimizing a three-color fluorescence activated cell sorting (FACS) method to purify CD45-/GD2+/CD56+ neuroblastoma cells from bone marrow. We then developed a novel quantitative measurement of MYCN protein in these isolated neuroblastoma cells, providing the potential to demonstrate proof of concept for drugs that inhibit PI3K/AKT/mTOR signaling in this disease. In addition we have established quantitative detection of three biomarkers for AKT pathway activity (phosphorylated and total AKT, GSK3β and P70S6K) in surrogate platelet-rich plasma (PRP) from pediatric patients. Together our new approach to neuroblastoma cell isolation for protein detection and suite of PD assays provides for the first time the opportunity for robust, quantitative measurement of protein-based PD biomarkers in this pediatric patient population. These will be ideal tools to support clinical evaluation of PI3K/AKT/mTOR pathway drugs and their ability to target MYCN oncoprotein in upcoming clinical trials in neuroblastoma.

During 2007 and 2008 it is likely that millions of patients in the US received heparin contaminated (CH) with oversulfated chondroitin sulfate, which was associated with anaphylactoid reactions. We tested the hypothesis that CH was associated with serious morbidity, mortality, intensive care unit (ICU) stay and heparin-induced thrombocytopenia following adult cardiac surgery.We conducted a single center, retrospective, propensity-matched cohort study during the period of CH and the equivalent time frame in the three preceding or the two following years. Perioperative data were obtained from the institutional record of the Society of Thoracic Surgeons National Database, for which the data collection is prospective, standardized and performed by independent investigators. After matching, logistic regression was performed to evaluate the independent effect of CH on the composite adverse outcome (myocardial infarction, stroke, pneumonia, dialysis, cardiac arrest) and on mortality. Cox regression was used to determine the association between CH and ICU length of stay. The 1∶5 matched groups included 220 patients potentially exposed to CH and 918 controls. There were more adverse outcomes in the exposed cohort (20.9% versus 12.0%; difference = 8.9%; 95% CI 3.6% to 15.1%, P < 0.001) with an odds ratio for CH of 2.0 (95% CI, 1.4 to 3.0, P < 0.001). In the exposed group there was a non-significant increase in mortality (5.9% versus 3.5%, difference = 2.4%; 95% CI, -0.4 to 3.5%, P = 0.1), the median ICU stay was longer by 14.1 hours (interquartile range -26.6 to 79.8, S = 3299, P = 0.0004) with an estimated hazard ratio for CH of 1.2 (95% CI, 1.0 to 1.4, P = 0.04). There was no difference in nadir platelet counts between cohorts.The results from this single center study suggest the possibility that contaminated heparin might have contributed to serious morbidity following cardiac surgery.

BACKGROUND: β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.

Accretionary desert pavements on the eastern Libyan Plateau of central Egypt support a rich Middle and Upper Paleolithic artifact assemblage exhibiting intensive blank production and minimal tool production. These assemblages appear to be in primary context with numerous examples of lithic refits showing on‐site lithic production. However, the smallest (length ≤2.5 cm) archaeological fragments are recovered at a much lower rate on this desert pavement surface than expected given comparable data from lithic assemblages in cave and shelter contexts in France. Excavation of archaeological contexts on the Libyan Plateau reveals the loss of small artifact fragments into the subsurface due to aeolian accumulation of silts, whereas geomorphic examination of desert pavement surfaces suggests a potential for relatively isolated bioturbation as a source of lateral and vertical disturbance of desert pavement surfaces over small areas. Archaeologists should be aware of the potential for long‐term assemblage stability as well as small artifact burial in surficial desert pavement contexts.

BACKGROUND:Pump thrombosis in patients with left ventricular assist devices (LVADs) continues to present treatment challenges. Anti-coagulation strategies used to treat this complication are empiric and without firm data for guidance. The addition of a platelet glycoprotein IIb/IIIa inhibitor to intravenous anti-coagulation has been suggested by several case series and recent guidelines. The aim of this study was to evaluate our use of eptifibatide for the treatment of suspected pump thrombus/thrombosis. METHODS:This retrospective, single-center cohort study was performed at Barnes-Jewish Hospital. The medical informatics system was queried to identify all LVAD patients who received eptifibatide for suspected pump thrombus/thrombosis from January 1, 2011, through April 30, 2013. RESULTS:A total of 17 patients (16 HeartMate II [Thoratec, Pleasanton, CA], 1 HeartWare [HeartWare International Inc, Framingham, MA]) with 22 separate administration attempts received eptifibatide (dose range, 0.1-2 μg/kg/min) for suspected pump thrombus/thrombosis presenting as one or more of the following findings: elevated lactate dehydrogenase, decreased haptoglobin, elevated plasma free hemoglobin, LVAD dysfunction, or new, persistently high LVAD power. The mean time from device implantation to eptifibatide therapy was 47.34 days (range, 3.88-397.67 days). Of the 22 attempts, 5 (22.7%) resulted in resolution of 1 or more patient-specific indicators of LVAD thrombus/thrombosis. Three patients (17.6%) had resolution of an indicator while also remaining free from continued hemolysis, death, pump exchange, or emergent heart transplant. Bleeding events were common, with 11 patients (64.7%) experiencing bleeding during the infusion. Seven patients (41.2%) died, with intraparenchymal hemorrhage as the cause of death in 2 patients. Pump exchange was performed in 3 patients. CONCLUSIONS:Our limited experience indicates the risk of using eptifibatide outweighs the proposed benefit of salvaging the existing LVAD in the setting of suspected pump thrombus/thrombosis at our institution.

The residual carbon content and carbon edge flux in JET have been assessed by three independent diagnostic techniques after start of plasma operation with the ITER-Like Wall (ILW) with beryllium first wall and tungsten divertor: (i) in-situ measurements with optical spectroscopy on low ionisation stages of carbon, (ii) charge-exchange recombination spectroscopy, and (iii) residual gas composition analysis in dedicated global gas balance experiments. Direct comparison experiments in L-mode discharges were carried out between references from the previously installed material configuration with plasma-facing components made of carbon-fibre composite (JET-CFC) and the JET-ILW. The temporal evolution of the C divertor flux since installation of the ILW has been studied in the ohmic phase of dedicated monitoring discharges which have been executed regularly throughout the experimental exploitation so far (60000 plasma seconds). The C flux behaviour in the divertor can be divided in three phases: initial fast drop, moderate reduction phase, and a long lasting phase with almost constant C flux. The Be flux in both divertor legs mirrors the behaviour of C. All experiments and diagnostic techniques demonstrate a strong reduction in C fluxes and C content of more than one order of magnitude with respect to JET-CFC which is in line with the reduction in long-term fuel retention due to co-deposition. There is no evidence of an increase in residual carbon in time, thus no indication that a damage of the thin tungsten coatings on CFC substrate in the divertor occurred.

Kharga Oasis, in Egypt's hyperarid Western Desert, today lacks naturally occurring surface water. Near Kharga, large tufa deposits ranging from a few hectares to more than 10 km(2) in area dot the edge of the Libyan Plateau. These, and lacustrine sediment, record intervals during the Pleistocene when wetlands, ponds, and small freshwater lakes provided water to enable herbivore and human inhabitation. Along with Pleistocene fossils, archaeological finds in the area include artifacts from Earlier Stone Age, Middle Stone Age, Later Stone Age, and younger cultural materials. ESR analysis was used to date freshwater mollusc shells (Melanoides tuberculata and Gyraulus) found in tufas and lake silts at Wadi Midauwara, Matana, and Bulaq. In some units, multiple gastropod populations from different times have been preserved as a mixed deposit, while several others appear to only preserve a single population. The mollusc dates suggest that freshwater existed sporadically at Bulaq and Matana during Marine (Oxygen) Isotope Stages (MIS) 2 and 4. At Midauwara, standing freshwater existed during the MIS 7/6 and 6/5e boundaries, and repeatedly in MIS 5-2. Molluscs and water also existed during the earliest Pleistocene, at similar to 2.4 +/- 0.4 Ma, which could have enabled the first hominin migration out of Africa via the Western Desert.