Timing Of Expansion Research Articles

Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage.

Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR>1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3-3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5-14) h vs. 10 (IQR 7-16) h, p=0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6-14)h vs. 12 (8-19)h, p=0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.

Phylogeography of a widespread small carnivore, the western spotted skunk (Spilogale gracilis) reveals temporally variable signatures of isolation across western North America.

We analyzed phylogeographic patterns in the western spotted skunk, Spilogale gracilis Merriam, 1890 (Carnivora: Mephitidae) in relation to historical events associated with Pre‐Pleistocene Divergence (PPD) and Quaternary climate change (QCC) using mitochondrial DNA from 97 individuals distributed across Western North America. Divergence times were generated using BEAST to estimate when isolation in putative refugia occurred. Patterns and timing of demographic expansion was performed using Bayesian skyline plot. Putative climatic refugia resulting from Quaternary climate change were identified using paleoecological niche modeling and divergence dates compared to major vicariant events associated with Pre‐Pleistocene conditions. We recovered three major mitochondrial clades corresponding to western North America (California, Baja, and across the Great Basin), east‐central North America (Texas, central Mexico, New Mexico), and southwestern Arizona/northwestern Mexico. Time to most recent common ancestor for S. gracilis occurred ~1.36 Ma. Divergence times for each major clade occurred between 0.25 and 0.12 Ma, with signature of population expansion occurring 0.15 and 0.10 Ma. Ecological niche models identified three potential climatic refugia during the Last Interglacial, (1) west coast of California and Oregon, (2) northwestern Mexico, and (3) southern Texas/northeastern Mexico as well as two refugia during the Last Glacial Maximum, (1) western USA and (2) southern Texas/northeastern Mexico. This study supports PPD in shaping species‐level diversity compared to QCC‐driven changes at the intraspecific level for Spilogale, similar to the patterns reported for other small mammals (e.g., rodents and bats). Phylogeographic patterns also appear to have been shaped by both habitat and river vicariance, especially across the desert southwest. Further, continuing climate change during the Holocene coupled with anthropogenic modifications during the Anthropocene appears to be removing both of these barriers to current dispersal of western spotted skunks.

Broad-scale lake expansion and flooding inundates essential wood bison habitat

Understanding the interaction between the response of a complex ecosystem to climate change and the protection of vulnerable wildlife species is essential for conservation efforts. In the Northwest Territories (Canada), the recent movement of the Mackenzie wood bison herd (Bison bison athabascae) out of their designated territory has been postulated as a response to the loss of essential habitat following regional lake expansion. We show that the proportion of this landscape occupied by water doubled since 1986 and the timing of lake expansion corresponds to bison movements out of the Mackenzie Bison Sanctuary. Historical reconstructions using proxy data in dated sediment cores show that the scale of recent lake expansion is unmatched over at least the last several hundred years. We conclude that recent lake expansion represents a fundamental alteration of the structure and function of this ecosystem and its use by Mackenzie wood bison, in response to climate change.

Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency

Prenatal maternal infection and maternal iron deficiency during pregnancy are 2 early environmental insults associated with increased risk for schizophrenia in offspring. Substantial evidence suggests that abnormalities in inhibitory γ-aminobutyric acid (GABA) interneuron function, especially in the parvalbumin subtype of GABA interneuron, both developmentally and in adulthood, may contribute mechanistically to cognitive deficits and psychotic symptoms in schizophrenia. This study used a rat model to test whether prenatal immune activation with lipopolysaccharide (LPS; at gestation days, GD, 15 and 16) or maternal iron deficiency (from GD2 to postnatal day P7) or the combination of both insults alters major subtypes of GABAergic interneurons (parvalbumin, somatostatin, cholecystokinin) in brain regions relevant to schizophrenia (medial and dorsolateral prefrontal cortex [PFC], hippocampal CA1 and dentate gyrus, ventral subiculum) in offspring at P14 or P28. Prenatal LPS treatment significantly increased the density of parvalbumin-immunoreactive neurons at P14 in the medial PFC, dorsolateral PFC, and ventral subiculum of offspring born from iron-sufficient but not iron-deficient dams. Prenatal LPS also increased cholecystokinin neuron density in the medial PFC at P28, under both iron-sufficient and iron-deficient conditions. We observed a large increase in parvalbumin neuron density from P14 to P28 in the medial PFC and subiculum across all birth groups, that was not observed in other brain regions, and significant decreases in somatostatin neuron density from P14 to P28 in all brain regions examined across all birth groups, indicating differential developmental trajectories for parvalbumin and somatostatin neurons in various brain regions during this early postnatal period. Thus, it appears that the medial PFC and ventral subiculum, brain regions involved in circuitry modulating ventral tegmental dopamine and nucleus accumbens activities, may be regions vulnerable to effects of prenatal LPS on specific subpopulations of interneurons. It is known that the timing of maturation and expansion of parvalbumin neurons in early development provides threshold levels of inhibition that trigger critical periods for cortical plasticity, leading to long-term circuit consolidation. Thus, our finding of increased parvalbumin neuron density at early developmental times might suggest a mechanism by which an acute prenatal insult like LPS exposure could produce long-term changes in prefrontal cortical or subicular function.

Using Cosmogenic 10Be Exposure Dating and Lichenometry to Constrain Holocene Glaciation in the Central Brooks Range, Alaska

ABSTRACTWe compile new and previously published lichenometric and cosmogenic 10Be moraine ages to summarize the timing of Holocene glacier expansions in the Brooks Range, Arctic Alaska. Foundational lichenometric studies suggested that glaciers likely grew to their Holocene maxima as early as the middle Holocene, followed by several episodes of moraine building prior to, and throughout, the last millennium. Previously published 10Be ages on Holocene moraine boulders from the north-central Brooks Range constrain the culmination of maximum Holocene glacier advances between 4.6 ka and 2.6 ka. New 10Be ages of moraine boulders from two different valleys in the central Brooks Range published here show that maximum Holocene glacial extents in these valleys were reached by 3.5 ka and ca. 2.6 ka, supporting previous studies showing that Holocene maximum, or near-maximum, glacial extents in the Brooks Range occurred prior to the Little Ice Age. However, in-depth reconciliations between glacier extent and local and regional climate are hampered by uncertainties associated with both lichenometry and 10Be dating.

How do State Crime Policies Affect Other States? The Externalities of State DNA Database Laws

State and local governments control most criminal justice policy in the United States, without regard for potential effects on other states. Lenient state policies might draw in criminals from other states, whereas harsh state policies might drive criminals away to other states. Alternatively, harsh policies might deter or incapacitate criminals who would otherwise migrate to neighboring states and commit crimes there. Thus the effects of a state’s policies extend beyond its borders, but these effects could be positive or negative. This paper estimates the externalities of DNA databases. I exploit variation in the timing of database expansions as exogenous shocks to the sizes of state databases, to measure the cross-state effect of database size. The federal government seems to think externalities are positive, since it subsidizes state-level database expansions. I find instead that externalities are negative: increasing the number of other-state profiles increases own-state crime, so that approximately 10 percent of DNA databases’ crime-reducing effect is due to states’ displacing crime to other states. Effects are larger for nearby states. This result is consistent with the hypothesis that offenders respond rationally to state policies by moving to places where they are less likely to get caught for their crimes.

The Effects of DNA Databases on Crime

Every US state has a database of criminal offenders' DNA profiles. These databases receive widespread attention in the media and popular culture, but there has been no rigorous analysis of their impact on crime. This paper intends to fill that gap. I exploit the details and timing of state DNA database expansions in two ways, first to address the effects of DNA profiling on individuals' subsequent criminal behavior and then to address the aggregate effects on crime rates. I show that DNA databases deter crime by profiled offenders, reduce crime rates, and are more cost-effective than traditional law enforcement tools. (JEL H76, K42)

PMHC affinity controls duration of CD8+ T cell-DC interactions and imprints timing of effector differentiation versus expansion.

During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC) affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulated factor 4) induction and timing of effector differentiation, as low affinity-primed T cells acquired cytotoxic activity earlier than high affinity-primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity-stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.

Evaluating the timing of former glacier expansions in the Tian Shan: A key step towards robust spatial correlations

The timing of past glaciation across the Tian Shan provides a proxy for past climate change in this critical area. Correlating glacial stages across the region is difficult but cosmogenic exposure ...

CGG-repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell-derived neurons

BackgroundFragile X syndrome (FXS), a common cause of intellectual disability and autism, results from the expansion of a CGG-repeat tract in the 5′ untranslated region of the FMR1 gene to >200 repeats. Such expanded alleles, known as full mutation (FM) alleles, are epigenetically silenced in differentiated cells thus resulting in the loss of FMRP, a protein important for learning and memory. The timing of repeat expansion and FMR1 gene silencing is controversial.MethodsWe monitored the repeat size and methylation status of FMR1 alleles with expanded CGG repeats in patient-derived induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) that were grown for extended period of time either as stem cells or differentiated into neurons. We used a PCR assay optimized for the amplification of large CGG repeats for sizing, and a quantitative methylation-specific PCR for the analysis of FMR1 promoter methylation. The FMR1 mRNA levels were analyzed by qRT-PCR. FMRP levels were determined by western blotting and immunofluorescence. Chromatin immunoprecipitation was used to study the association of repressive histone marks with the FMR1 gene in FXS ESCs.ResultsWe show here that while FMR1 gene silencing can be seen in FXS embryonic stem cells (ESCs), some silenced alleles contract and when the repeat number drops below ~400, DNA methylation erodes, even when the repeat number remains >200. The resultant active alleles do not show the large step-wise expansions seen in stem cells from other repeat expansion diseases. Furthermore, there may be selection against large active alleles and these alleles do not expand further or become silenced on neuronal differentiation.ConclusionsOur data support the hypotheses that (i) large expansions occur prezygotically or in the very early embryo, (ii) large unmethylated alleles may be deleterious in stem cells, (iii) methylation can occur on alleles with >400 repeats very early in embryogenesis, and (iv) expansion and contraction may occur by different mechanisms. Our data also suggest that the threshold for stable methylation of FM alleles may be higher than previously thought. A higher threshold might explain why some carriers of FM alleles escape methylation. It may also provide a simple explanation for why silencing has not been observed in mouse models with >200 repeats.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0105-9) contains supplementary material, which is available to authorized users.

The Changing Face of Neolithic and Bronze Age Ireland: A Big Data Approach to the Settlement and Burial Records

This paper synthesizes and discusses the spatial and temporal patterns of archaeological sites in Ireland, spanning the Neolithic period and the Bronze Age transition (4300–1900 cal BC), in order to explore the timing and implications of the main changes that occurred in the archaeological record of that period. Large amounts of new data are sourced from unpublished developer-led excavations and combined with national archives, published excavations and online databases. Bayesian radiocarbon models and context- and sample-sensitive summed radiocarbon probabilities are used to examine the dataset. The study captures the scale and timing of the initial expansion of Early Neolithic settlement and the ensuing attenuation of all such activity—an apparent boom-and-bust cycle. The Late Neolithic and Chalcolithic periods are characterised by a resurgence and diversification of activity. Contextualisation and spatial analysis of radiocarbon data reveals finer-scale patterning than is usually possible with summed-probability approaches: the boom-and-bust models of prehistoric populations may, in fact, be a misinterpretation of more subtle demographic changes occurring at the same time as cultural change and attendant differences in the archaeological record.

Constraints on timing and magnitude of early global expansion of the Moon from topographic features in linear gravity anomaly areas

AbstractGravity data obtained from the Gravity Recovery and Interior Laboratory have revealed linear gravity anomalies (LGAs) formed by the early global expansion of the Moon and subsequent magma intrusion. In this study, using Lunar Orbiter Laser Altimeter topographic data, we investigated topographic profiles across LGAs to verify that they were formed by extensional tectonics. We found that 17 of the 20 LGAs investigated exhibited a valley structure, suggesting that they were formed by tensile stress. Assuming that these topographic depressions accompanied graben formation, the increase in the lunar radius is estimated to be on the order of several tens of meters. On the other hand, assuming that these topographic depressions accompanied flexure of elastic lithosphere due to the LGA load, the elastic thickness during the LGA formation is estimated as ~10 km. The crater frequencies in the vicinity of LGAs indicate that the peak tectonic activity occurred before the basin‐forming epoch.

Factors associated with birth outcomes from cryopreserved blastocysts: experience from 4,597 autologous transfers of 7,597 cryopreserved blastocysts

To evaluate factors associated with cryopreserved blastocyst transfer birth outcomes, including age, expansion time, cryopreservation protocol, cryodamage, and number of embryos transferred. Retrospective cohort study. Private infertility practice. Cryopreserved blastocyst transfer patients from January 2003 to April2012. None. Birth per transfer and children per embryo. Overall live birth per transfer was 32%, with 17% twin births and 0.3% triplets. Live birth per transfer was significantly higher for vitrification compared with slow-freeze (day 5 cryopreservation: 47% vs. 35%; day 6 cryopreservation: 46% vs. 24%), as was live born children per transferred embryo (39% vs. 29% for day 5; 36% vs. 18% for day 6). Birth rates declined only slightly with increasing age at cryopreservation through 37years, followed by an increasingly rapid decline in success with increasing age thereafter. Live birth rates declined rapidly (49%-18% for vitrification and 37%-10% for slow-freeze) as the percentage of intact cells after cryopreservation decreased from 95%-100% to 70%-79%, with almost no births when the percentage of intact cells was <70%. Increasing numbers of embryos per transfer were associated with significant increase in live birth per transfer but significant decrease in children per transferred embryo. Birth rates were much lower for blastocysts with delayed expansion on day 7 (10% per transfer). Birth outcomes from cryopreserved blastocyst transfer are influenced by age, timing of expansion, cryopreservation protocol, visible cryodamage, and the number of embryos transferred. Vitrification substantially improves outcomes versus slow freezing.

Effect of external volume expansion on the survival of fat grafts.

Introduction:External volume expansion (EVE) is one method, which has been utilised for increasing the survival of adipose tissue grafts. EVE releases positive pressure from the graft and also induces intense levels of edema that decreases diffusion of metabolites essential for graft survival initially. The ideal timing of external volume expansion in relation to the injection of the fat to facilitate survival is not yet clear.Aims and Objectives:This study was undertaken to evaluate and compare the efficacy of external volume expansion applied at variable time points in relation to the injection of the fat.Materials and Methods:Athymic mouse was the animal model and human lipo-aspirate mixed with PRP was used as graft. An indigenous dome shaped silicone device was fabricated to deliver a negative pressure of -30 mm of Hg. The EVE was applied at variable time intervals. At the end of 4 weeks visual, histological and radiological features of the injected fat were compared. The adipose tissue was stained with human vimentin to ascertain the origin of the retained fat.Results:All the grafts, which had EVE, had significantly better volume retention and vascularity. The groups which underwent a delayed EVE or prior expansion followed by concomitant graft injection and expansion showed the most optimal vascularity and graft retention.Conclusions:A delayed EVE or prior expansion followed by concomitant graft injection and expansion may be the most ideal combinations to optimize graft take. However, on account of the relatively small sample size, there was a limitation in drawing statistically significant conclusions for certain variables.

An optimization framework for the integrated planning of generation and transmission expansion in interconnected power systems

Energy, and particularly electricity, has played and will continue to play a very important role in the development of human society. Electricity, which is the most flexible and manageable energy form, is currently used in a variety of activities and applications. For instance, electricity is used for heating, cooling, lighting, and for operating electronic appliances and electric vehicles. Nowadays, given the rapid development and commercialization of technologies and devices that rely on electricity, electricity demand is increasing faster than overall primary energy supply. Consequently, the design and planning of power systems is becoming a progressively more important issue in order to provide affordable, reliable and sustainable energy in timely fashion, not only in developed countries but particularly in developing economies where electricity demand is increasing even faster.Power systems are networks of electrical devices, such as power plants, transformers, and transmission lines, used to produce, transmit, and supply electricity. The design and planning of such systems require the selection of generation technologies, along with the capacity, location, and timing of generation and transmission capacity expansions to meet electricity demand over a long-term horizon. This manuscript presents a comprehensive optimization framework for the design and planning of interconnected power systems, including the integration of generation and transmission capacity expansion planning. The proposed framework also considers renewable energies, carbon capture and sequestration (CCS) technologies, demand-side management (DSM), as well as reserve and CO2 emission constraints. The novelty of this framework relies on an integrated assessment of the aforementioned features, which can reveal possible interactions and synergies within the power system. Moreover, the capabilities of the proposed framework are demonstrated using a suite of case studies inspired by a real-world power system, including “business as usual” and “CO2 mitigation policy” scenarios. These case studies illustrated the adaptability and effectiveness of the framework at dealing with typical situations that can arise in designing and planning power systems.

Influence of geology and human activity on the genetic structure and demography of the Oriental fire-bellied toad (Bombina orientalis)

The Oriental fire-bellied toad (Bombina orientalis) is a commonly used study organism, but knowledge of its evolutionary history is incomplete. We analyze sequence data from four genetic markers (mtDNA genes encoding cytochrome c oxidase subunit I, cytochrome b, and 12S–16S rRNA; nuDNA gene encoding recombination activating gene 2) from 188 individuals across its range in Northeast Asia to elucidate phylogeographic patterns and to identify the historic events that shaped its evolutionary history. Although morphologically similar across its range, B. orientalis exhibits phylogeographic structure, which we infer was shaped by geologic, climatic, and anthropogenic events. Phylogenetic and divergence-dating analyses recover four genetically distinct groups of B. orientalis: Lineage 1—Shandong Province and Beijing (China); Lineage 2—Bukhan Mountain (Korea); Lineage 3—Russia, Northeast China, and northern South Korea; and Lineage 4—South Korea. Lineage 2 was previously unknown. Additionally, we discover an area of secondary contact on the Korean Peninsula, and infer a single dispersal event as the origin of the insular Jeju population. Skyline plots estimate different population histories for the four lineages: Lineages 1 and 2 experienced population decreases, Lineage 3 remained stable, while Lineage 4 experienced a sharp increase during the Holocene. The timing of the population expansion of Lineage 4 coincides with the advent of rice cultivation, which may have facilitated the increase in population size by providing additional breeding habitat.

Phase 1 Biomarker Analysis of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B-cell malignancies (Kochenderfer et al. Blood 2012, JCO 2014, ASH 2014). In the NCI study, anti-CD19 CAR T cells expanded within 1 week of administration and generally cleared the peripheral blood within 2 months. Anti-CD19 CAR T cell infusion resulted in rapid elevation and subsequent resolution of circulating cytokines and chemokines within 3 weeks (Bot et al. ASCO 2015). KTE-C19 utilizes the same anti-CD19 CAR construct investigated at the NCI, manufactured using an optimized 6-8 day process (Better et al. ASCO 2014). Preliminary characterization of KTE-C19 expansion and serum pharmacodynamic (PD) markers from ZUMA-1 are presented.Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (1 x 106 minimum) CAR-positive T cells/kg body weight after undergoing a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. KTE-C19 was characterized pre- and post-infusion by multiparameter flow cytometry for CAR expression and major phenotypic markers. KTE-C19 expansion and clearance was also monitored by multiparameter flow cytometry and quantitative PCR (qPCR) at weeks 1, 2, 4 and months 3 and 6 respectively. Forty one analytes from serum samples were evaluated by EMD Millipore Luminex® xMAP® multiplex assays at Days -5 (prior to conditioning chemotherapy), 0, 1, 3, 5, 7, 14 and 28 for a broad panel of cytokines, chemokines and immune effector related markers. Maximum fold increase (MFI) was defined as the maximum fold change of measured analytes above baseline (Day -5). Time to maximum value and time to resolution were calculated among subjects with increases after commencement of conditioning chemotherapy. Comparisons of fold increase were not adjusted for multiplicity.Results: As of 28 July 2015, 6 subjects have received KTE-C19. Three subjects had post-infusion samples evaluable for CAR T-cell expansion by qPCR. Peak levels occurred within 7 days and KTE-C19 was detectable at 1 month. Additional qPCR monitoring is ongoing. Circulating cytokines, chemokines and immune effector markers have been evaluated in 4 subjects. Samples post conditioning and pre-KTE-C19 infusion showed significant increases in the levels of IL-15 (p<0.005) and MCP-1 (p<0.030). Cytokine and chemokine levels achieved their peak levels 1-10 days post KTE-C19 infusion and returned to baseline generally within 3 weeks. Key pro-inflammatory markers were substantially upregulated as indicated in the table. Additional monitoring of KTE-C19 persistence (by qPCR), phenotype and activation status of CAR T cells is ongoing. Updated results will be presented. Pre-infusion characterization of KTE-C19 with respect to CAR expression and T-cell subsets including CD4, CD8, naïve, central memory and effector memory are presented in a separate ASH abstract.Conclusion: Six subjects with refractory aggressive NHL have received KTE-C19. CAR T cells expanded substantially and persisted through at least 1 month in 3 subjects evaluated to date. Pro-inflammatory, immune-homeostatic cytokines and chemokines peaked within 2 weeks. Timing of peak KTE-C19 expansion and serum cytokine profiles and clearance in this multicenter study with an optimized, shortened manufacturing process were consistent with results of the NCI study. This first biomarker analysis of ZUMA-1 demonstrates the PD activity of KTE-C19 and will help optimize future CAR T cell therapy. Clinical trial: NCT02348216. Table 1MFI (range)Time to Maximum Median Days (range)Time to ResolutionaMedian Days (range)IL-6141 (17, 1010)5 (3, 9)18.5 (9, 28)IFN-gamma167 (8, 4387)4 (3, 5)9 (7, 10)CRP27 (1, 57)5 (3, 5)7 (7, 13)IL-1522 (12, 55)2 (1, 7)9 (9, 9)IL-27 (1, 31)1 (1, 3)5 (3, 5)IL-10132 (3, 561)5 (5, 5)9 (7, 11)MCP-116 (2, 25)2 (1, 5)7 (3, 10)Granzyme B42 (27, 773)5 (5, 7)8.5 (7, 14)a Time to resolution is the first post-KTE-C19 infusion day at which the level was ≤ 2x baseline. DisclosuresRossi:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Off Label Use: Tocilizumab for the management of CRS . Go:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Locke:Kite Pharma: Other: Scientific Advisory Boards. Bartlett:Insight: Research Funding; Janssen: Research Funding; Kite: Research Funding; Medimmune: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Colgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Siddiqi:Pharmacyclics/Jannsen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Elias:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Bot:Kite Pharma: Employment, Equity Ownership.

Asynchronous onset of eutrophication among shallow prairie lakes of the Northern Great Plains, Alberta, Canada

Coherent timing of agricultural expansion, fertilizer application, atmospheric nutrient deposition, and accelerated global warming is expected to promote synchronous fertilization of regional surface waters and coherent development of algal blooms and lake eutrophication. While broad-scale cyanobacterial expansion is evident in global meta-analyses, little is known of whether lakes in discrete catchments within a common lake district also exhibit coherent water quality degradation through anthropogenic forcing. Consequently, the primary goal of this study was to determine whether agricultural development since ca. 1900, accelerated use of fertilizer since 1960, atmospheric deposition of reactive N, or regional climate warming has resulted in coherent patterns of eutrophication of surface waters in southern Alberta, Canada. Unexpectedly, analysis of sedimentary pigments as an index of changes in total algal abundance since ca. 1850 revealed that while total algal abundance (as β-carotene, pheophytin a) increased in nine of 10 lakes over 150 years, the onset of eutrophication varied by a century and was asynchronous across basins. Similarly, analysis of temporal sequences with least-squares regression revealed that the relative abundance of cyanobacteria (echinenone) either decreased or did not change significantly in eight of the lakes since ca. 1850, whereas purple sulfur bacteria (as okenone) increased significantly in seven study sites. These patterns are consistent with the catchment filter hypothesis, which posits that lakes exhibit unique responses to common forcing associated with the influx of mass as water, nutrients, or particles.

Objectively Quantifying Radiation Esophagitis With Novel Computed Tomography–Based Metrics

To study radiation-induced esophageal expansion as an objective measure of radiation esophagitis in patients with non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy. Eighty-five patients had weekly intra-treatment CT imaging and esophagitis scoring according to Common Terminlogy Criteria for Adverse Events 4.0, (24 Grade 0, 45 Grade 2, and 16 Grade 3). Nineteen esophageal expansion metrics based on mean, maximum, spatial length, and volume of expansion were calculated as voxel-based relative volume change, using the Jacobian determinant from deformable image registration between the planning and weekly CTs. An anatomic variability correction method was validated and applied to these metrics to reduce uncertainty. An analysis of expansion metrics and radiation esophagitis grade was conducted using normal tissue complication probability from univariate logistic regression and Spearman rank for grade 2 and grade 3 esophagitis endpoints, as well as the timing of expansion and esophagitis grade. Metrics' performance in classifying esophagitis was tested with receiver operating characteristic analysis. Expansion increased with esophagitis grade. Thirteen of 19 expansion metrics had receiver operating characteristic area under the curve values >0.80 for both grade 2 and grade 3 esophagitis endpoints, with the highest performance from maximum axial expansion (MaxExp1) and esophageal length with axial expansion ≥30% (LenExp30%) with area under the curve values of 0.93 and 0.91 for grade 2, 0.90 and 0.90 for grade 3 esophagitis, respectively. Esophageal expansion may be a suitable objective measure of esophagitis, particularly maximum axial esophageal expansion and esophageal length with axial expansion ≥30%, with 2.1 Jacobian value and 98.6 mm as the metric value for 50% probability of grade 3 esophagitis. The uncertainty in esophageal Jacobian calculations can be reduced with anatomic correction methods.

Genetic Differentiation in Insular Lowland Rainforests: Insights from Historical Demographic Patterns in Philippine Birds.

Phylogeographic studies of Philippine birds support that deep genetic structure occurs across continuous lowland forests within islands, despite the lack of obvious contemporary isolation mechanisms. To examine the pattern and tempo of diversification within Philippine island forests, and test if common mechanisms are responsible for observed differentiation, we focused on three co-distributed lowland bird taxa endemic to Greater Luzon and Greater Negros-Panay: Blue-headed Fantail (Rhipidura cyaniceps), White-browed Shama (Copsychus luzoniensis), and Lemon-throated Leaf-Warbler (Phylloscopus cebuensis). Each species has two described subspecies within Greater Luzon, and a single described subspecies on Greater Negros/Panay. Each of the three focal species showed a common geographic pattern of two monophyletic groups in Greater Luzon sister to a third monophyletic group found in Greater Negros-Panay, suggesting that common or similar biogeographic processes may have produced similar distributions. However, studied species displayed variable levels of mitochondrial DNA differentiation between clades, and genetic differentiation within Luzon was not necessarily concordant with described subspecies boundaries. Population genetic parameters for the three species suggested both rapid population growth from small numbers and geographic expansion across Luzon Island. Estimates of the timing of population expansion further supported that these events occurred asynchronously throughout the Pleistocene in the focal species, demanding particular explanations for differentiation, and support that co-distribution may be secondarily congruent.