Large spherical balloons are a promising new option for deploying extremely large, yet light-weight mirrors for strato-spheric and space-based applications. However, their lack of a rigid, precise structure presents a unique challenge for optically correcting nonspherical distortions, particularly at shorter wavelengths. In this paper, we present the design and characterization of a lab prototype for a 10-m aperture telescope for observing the water vapor emission line at 538 mu m (557 GHz), as well as considerations for future flight-worthy versions.

O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder

Objectives: Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. Design: Multicenter prospective study of in-hospital cardiac arrest. Setting: Five medical centers in the United States and the United Kingdom. Patients: Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1–2. Interventions: Cerebral oximetry monitoring. Measurements and Main Results: Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1–2 at discharge. Higher mean ± sd regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1–2 versus cerebral performance category 3–5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69–0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94–100) and 100% negative predictive value (95% CI, 79–100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95–100) and 93% positive predictive value (95% CI, 66–100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1–2 (area under the curve, 0.79; 95% CI, 0.70–0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46–95), 72% specificity (95% CI, 65–79), and 98% negative predictive value (95% CI, 93–100) for cerebral performance category 1–2. Conclusions: Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes.

The In Vessel Viewing System (IVVS) will be one of the essential machine diagnostic systems at ITER to provide information about the status of in-vessel and plasma facing components and to evaluate the dust inside the Vacuum Vessel. The current design consists of six scanning probes and their deployment systems, which are placed in dedicated ports at the divertor level. These units are located in resident guiding tubes 10 m long, which allow the IVVS probes to go from their storage location to the scanning position by means of a simple straight translation. Moreover, each resident tube is supported inside the corresponding Vacuum Vessel and Cryostat port extensions, which are part of the primary confinement barrier. As the Vacuum Vessel and the Cryostat will move with respect to each other during operation (especially during baking) and during incidents and accidents (disruptions, vertical displacement events, seismic events), the structural integrity of the resident tube and the surrounding vacuum boundaries would be compromised if the required flexibility and supports are not appropriately assured. This paper focuses on the integration of the present design of the IVVS into the Vacuum Vessel and Cryostat environment. It presents the adopted strategy to withstand all the main interfacing loads without damaging the confinement barriers and the corresponding analysis supporting it. (C) 2015 Elsevier B.V. All rights reserved.

Background: Cardiac arrest (CA) is associated with morbidity and mortality due to cerebral ischemia. We therefore tested the hypothesis that higher regional cerebral oxygenation (rSO2) during resuscitation is associated with improved return of spontaneous circulation (ROSC), survival and neurological outcomes at hospital discharge. We further examined the validity of rSO2 as a test to predict these outcomes. Methods: Multicenter prospective study of in-hospital CA (IHCA). Inclusion criteria: IHCA, age≥18 years, Prolonged CPR≥5 minutes. Patients were recruited consecutively during working hours between 08/2011-09/2014. Survival with a favorable neurological outcome was defined as a Cerebral Performance Category (CPC)1-2. Results: Among 504 IHCA events, 183 (36%) met inclusion criteria. Overall 62/183 (33.9%) achieved ROSC, while 13/183(7.1%) achieved CPC1-2 at discharge. Higher mean±SD rSO2 was associated with ROSC vs. no ROSC (51.8±11.2% vs. 40.9±12.3%) and CPC1-2 vs. CPC3-5 (56.1±10.0% vs. 43.8±12.8%), both P<0.001). Mean rSO2 during the last 5 minutes of CPR best predicted ROSC (AUC=0.76:95% CI:0.69-0.83); rSO2≥25% provided 100% sensitivity (95%CI:94%-100%), 100% negative predictive value (NPV) (95%CI:79%-100%); rSO2 ≥65% provided: 99% specificity (95%CI:95%-100%), 93% positive predictive value (PPV) (95%CI:66%-100%) for ROSC. Time with rSO2>50% during CPR best predicted CPC1-2 (AUC=0.79: 95%CI:0.70-0.88). Specifically, ≥60% CPR time with rSO2>50% provided 77% sensitivity (95%CI:46%-95%), 72% specificity (95%CI:65%-79%) and 98% NPV (95%CI: 93%-100%) for CPC1-2. Conclusions: Cerebral oximetry allows real-time non-invasive cerebral oxygenation monitoring during CPR. Higher cerebral oxygenation during CPR is associated with ROSC and neurologically favorable survival to hospital discharge. Achieving higher rSO2 during resuscitation may optimize the chances of CA favorable outcomes.

We report on a 4.7 THz heterodyne receiver being developed to fly on the Stratospheric Terahertz Observatory (STO-2) balloon platform. The receiver is based on a single pixel hot electron bolometer (HEB) mixer pumped by a 4.7 THz 3rd order distributed feedback quantum cascade laser (QCL) as local oscillator and is designed for high resolution spectroscopy of the astronomically important neutral oxygen (OI) line at 4.745 THz. We describe the expected receiver performance and outline novel approaches to QCL amplitude and frequency/phase stabilization.

Abstract Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by augmented myelopoiesis leading to increased red cell mass with frequent excessive proliferation of other myeloid lineages. Over 95% of PV patients harbor JAK2V617F mutation, which confers proliferative advantage to affected myeloid progenitors. JAK2V617F, which is thought to be necessary but not sufficient for the disease, is often associated with acquired uniparental disomy on chromosome 9p (9pUPD). To better understand the underlying molecular basis of PV, we performed whole-exome sequencing and DNA copy-number analysis of 31 JAK2V617F-positive patients and further investigated the evolution of somatic mutations using longitudinal samples. In addition to JAK2 V617F and 9pUPD, we identified recurrent somatic mutation in an additional 5 genes including ASXL1, TET2, DNMT3A, and SF3B1 and recurrent DNA copy-number alterations at 1q and 18p. Forty-two percent of patients had at least one somatic mutation in an epigenetic modifier gene, and 23% of patients harbored mutation in RTK/RAS, RNA processing pathways, tumor suppressors and protein kinases. In 4 of 31 cases, variant allele abundance suggested somatic mutations of ASXL1, DNMT3A and SF3B1 may have preceded JAK2V617F. Interestingly, in 7 PV patients mutations also present in COSMIC were shared between the patients’ T-cell controls and granulocytes: 4 NF1, 2 ASXL1, and one each in TET2, IDH2, and DNMT3A, suggesting these genes mutated early in hematopoietic development. Absence of JAK2V617F in these T-cells ruled out cross-contamination of cell lineages. In an additional 4 cases, a minor JAK2V617F subclone acquired new mutations in DNMT3A, SF3B1, SMARCA2, and TET2 during PV progression. In summary, seventy percent of patients had mutation of at least one gene important to development of myeloid neoplasms, other than JAK2V617F. Our data reveal that these mutations, in particular NF1, may have arisen in some cases early in hematopoiesis but also in some patients during progression after diagnosis. These results suggest that the order of mutation is not as important as the total mutational burden in the development of PV. Citation Format: David A. Wheeler, Linghua Wang, Sabina Swierczek, Kimberly Hickman, Jennifer A. Drummond, Donna Muzny, Richard A. Gibbs, Joseph Prchal. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2014-LB-311

Letter to the Editor JAK2V617F mutation is the most common somatic event observed in patients with myeloproliferative neoplasms (MPN)1-4. JAK2V617F is found in over 95% of patients with polycythemia vera (PV), 55% of essential thrombocytosis and 65% of primary myelofibrosis. Homozygous JAK2V617F is present in about half of PV patients whereas it is rarely seen in other MPNs3, 5, 6. Patients bearing homozygous JAK2V617F tend to have a longer duration of disease2, higher hemoglobin levels, increased incidence of pruritis7 and are more likely to progress to post-PV myelofibrosis8. Homozygous JAK2V617F is shown to result from mitotic recombination, leading to acquired uniparental disomy (aUPD) on chromosome 9p9. It was reported that JAK2 46/1 (GGCC) haplotype may predispose carriers to JAK2 mutation10-12, and JAK2V617F facilitates the acquisition of homozygous JAK29, 13. Challenging this view was a single study reporting 9p aUPD in two PV subjects with wild-type JAK214, suggesting that in these two individuals, 9p aUPD might have preceded JAK2V617F. However, the relationship between JAK2V617F and 9p aUPD, the frequency and stability of existing PV genotypes has yet to be systematically defined in a larger PV cohort. To address this, we performed whole-exome sequencing and SNP array in 31 PV patients, and further validated our findings in two additional cohorts totaling 59 patients (Supplementary Methods). In addition, we investigated the stability of PV genotypes using 36 longitudinal samples. The allelic fraction of JAK2V617F in granulocytes (GNC), measured by sequencing, varied from 0.01 to 1.0 (Figure 1). 9p aUPD spanning JAK2 locus was present in 48% of patients in the discovery set. The fraction of genomes harboring 9p aUPD in a given GNC sample, varied from 0.08 to 1.0 (Figure 1). Based on the quantitative relationship between JAK2V617F allelic fraction and the fraction of genomes harboring 9p aUPD, we defined 4 PV subgroups and validated this finding in extended two cohorts (Figure 1). Across the three cohorts, 42% of patients harbored JAK2V617F in a heterozygous state without detectable 9p aUPD (Subgroup I); 45% of patients had JAK2V617F with an allelic fraction in direct proportion to the level of 9p aUPD (Subgroup II; homozygous JAK2V617F); 10% of patients harbored 9p aUPD at approximately twice the level of the JAK2V617F allelic burden (Subgroup III; aUPD with heterozygous JAK2V617F). Although any single patient in Subgroup III, taken in isolation, could be explained as a mixture of cells from Subgroup I and II, the best explanation for the pattern of Subgroup III across these patients is that JAK2V617F and 9p aUPD reside in the same cell with heterozygous JAK2V617F in all such patients. Thus, Subgroup III reported in this study comprises a novel subtype that has not been previously described. Three patients (3%) exhibited trisomy of 9p, generating 2 copies of JAK2V617F allele (Subgroup IV). The number of patients in Subgroup IV was too small and thus this group was not evaluated further. Figure 1 The mutational pattern of JAK2V617F and 9p aUPD We then investigated the stability of each PV genotype using longitudinal samples. The JAK2V617:9p aUPD ratio remained stable in, 11 of 17 patients, although the JAK2V617 allele burden itself varied (Figure 2A). In contrast, 6 of 17 patients changed their JAK2V617 Subgroup membership. Patients PV1, PV16, and PV27 progressed from prognostically more favorable heterozygous JAK2V617F to less favorable homozygous JAK2V617F clones (Figures 2B-C). For example, patient PV27 was a mixture of Subgroup-I and -II clones at the first timepoint but four years later only Subgroup-II clone was apparent. However, patients PV2, PV28 and PV31 transformed their JAK2 genotypes and gained new clones (Figures 2D-E). The Subgroup-II clone in PV2 was eliminated, possibly as a result of treatment, and a new Subgroup-III clone emerged. It was interesting that PV28 and PV31 transformed to myelofibrosis (MF) whereas none of the other 14 patients with stable or progressed JAK2 genotype showed phenotype transformation. It has been suggested that patients with homozygous JAK2V617F were more likely to develop post-PV MF2, a propensity we also observed in the Subgroup-II patients (Supplementary Figure 1). Among those 11 Subgroup-II patients that transformed to MF, we have longitudinal samples collected for two patients PV28 and PV31. We observed that, in both patients, there was an outgrowth of a new Subgroup-I clone (Figure 2D). However, we could not establish the sequential order of these two events. Figure 2 The stability of JAK2 genotypes We propose four pathways leading to PV (Figure 2F) to explain these results. PV stem cells or their self-renewing progenitors, in the majority of patients, acquire JAK2V617F first. Approximately half of them remain stable in this configuration (Subgroup I). Others in this pathway duplicate JAK2 by one of two different mechanisms: a minor fraction duplicated JAK2V617F-bearing chromosome to produce trisomy 9p (Subgroup IV). Almost half of the patients in Subgroup I duplicate JAK2V617F allele via mitotic recombination to produce 9p aUPD (Subgroup II). We observed progression from Subgroup I to II in two patients, but the factors controlling the progression could not be ascertained by our analysis. 10% of patients acquire 9p aUPD first followed by JAK2V617F mutation, yielding patients in Subgroup III. Although the 9p aUPD cell with wild-type JAK2 has been reported in one case study14, we did not observe 9p aUPD alone in our unselected 3 cohorts, suggesting it might be asymptomatic until acquisition of JAK2V617F. We found that, in a single female patient which was not included in these 3 cohorts, her granulocytes showed almost complete 9p aUPD with a low JAK2V617F allelic burden (0.24), indicating the majority of PV clone was composed of 9p aUPD (Supplementary Figure 2). Further, this female was heterozygous for X-chromosome FHL1 gene and her granulocytes were clonal using a transactional clonality assay15. This patient is probably in a transient state from 9p aUPD with wild-type JAK2 to Subgroup III. Since we observed more patients in Subgroup III, it suggests that acquiring the JAK2V617F mutation would provide a proliferative advantage. It was reported that JAK2 46/1 (GGCC) haplotype may predispose carriers to JAK2 mutation10-12, but we didn't observe any significant difference in the frequency of this haplotype across 3 subgroups (Supplementary Figure 3). The 9p aUPD region, in any given patient, includes many genes (Supplementary Figure 4). In the mitotic recombination event(s) leading to generation of aUPD, both common and rare alleles may be lost. We reasoned that genes with recurrent loss of wild-type alleles within aUPD regions underwent selection for the PV phenotype. Forty-eight genes lost their wild-type alleles in at least 3 patients (Supplementary Figure 5). Among them, 9 genes were related to cell division, 7 in transcriptional regulation, 4 in epigenetic regulation and 3 genes were potential tumor suppressors. KDM4C and SMARCA2, whichare involved in histone modification and chromatin remodeling, are among them. Moreover, 6 of the top 10 genes (Supplementary Table 1) play a functional role in regulation of cell division. Among them, DOCK8, a gene involved in intracellular signaling networks, also had a somatic loss-of-function mutation and a novel germline variant. Recent evaluation of recurrent loss of heterozygosity in 3131 tumors in the absence of clear driver mutations led Elledge and coworkers to hypothesize the existence of cancer gene islands16. These are regions harboring multiple cancer genes that act in a coordinated fashion within the cancer cell to produce a strong tumorigenic effect. Thus, our observations may suggest that genes in 9p aUPD region other than JAK2 could also contribute to PV pathophysiology. Heretofore, the zygosity of the JAK2V617F has been estimated by the allele burden with an arbitrary threshold of >0.5 for homozygous and <0.5 for heterozygotes. This approach assumed a pure tumor cell population, which often is not the case. In this study, we account for tumor cell purity by comparing JAK2V617F to the level of 9p aUPD in the cell, rather than the absolute allele burden, leading to more accurate determination of mutant JAK2 zygosity. With this more accurate measure of JAK2 mutant zygosity, we observe that most patients can be classified in to one of 3 subgroups (Figure 1), setting the stage for more precise analysis of prognostic value of JAK2 zygosity, as well as improved resolution of the clonal status of a patient's tumor. For the first time, we investigated the clonal stability of these PV genotypes. Two thirds of the patients were apparently stable in their PV clone for at least two years. Patients of all subgroups were represented among the stable patients. One third of the patients exhibited clonal changes, with emergence of both prognostically more or less favorable JAK2V617F patterns (Figure 2B-E). However, our samples size is too small to investigate the factors controlling the stability of clones but the role of treatment regimen in clonal stability is clearly an important question. Further study of the clinical properties of a larger cohort of Subgroup III patients, compared to Subgroup I and II, is required to elucidate the contribution of 9p and the cancer genes therein in PV pathogenesis. This novel perspective on the molecular basis of the evolution of PV should lead to a better understanding of the roles of JAK2V617F and 9p aUPD in this disease.

Background: Real time recognition of the quality of brain oxygen delivery is critical during resuscitation. Although end tidal CO2 monitoring (ETCO2) has been proposed as a marker of organ perfusio...

The exploitation of ITER tokamak will require diagnostics for machine protection, inputs to plasma control systems, evaluation and analysis of plasma parameters and performances.The equatorial visible/infrared wide angle viewing system and the radial neutron camera are the two main diagnostics of Procurement Package 11 (PP11), one of the diagnostic procurements under the responsibility of Europe, which also contains Equatorial Port Plug I and seven other diagnostics supplied by Europe or other ITER partners and integrated in the same Port Plug. Significant progress has recently been made in the development of the equatorial visible/infrared wide angle viewing system and the radial neutron camera.This paper gives an overview of the major technical achievements on these two diagnostics and points out the urgent needed R&D activities. (C) 2008 Elsevier B.V. All rights reserved.