104 research outputs found
An efficient semiparametric maxima estimator of the extremal index
The extremal index , a measure of the degree of local dependence in
the extremes of a stationary process, plays an important role in extreme value
analyses. We estimate semiparametrically, using the relationship
between the distribution of block maxima and the marginal distribution of a
process to define a semiparametric model. We show that these semiparametric
estimators are simpler and substantially more efficient than their parametric
counterparts. We seek to improve efficiency further using maxima over sliding
blocks. A simulation study shows that the semiparametric estimators are
competitive with the leading estimators. An application to sea-surge heights
combines inferences about with a standard extreme value analysis of
block maxima to estimate marginal quantiles.Comment: 17 pages, 7 figures. Minor edits made to version 1 prior to journal
publication. The final publication is available at Springer via
http://dx.doi.org/10.1007/s10687-015-0221-
Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.
BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made
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Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy
An Interconverting Family of Coordination Cages and a meso-Helicate; Effects of Temperature, Concentration, and Solvent on the Product Distribution of a Self-Assembly Process
The
self-assembly between a water-soluble bis-bidentate ligand
L<sup>18w</sup> and Co(II) salts in water affords three high-spin
Co(II) products: a dinuclear <i>meso</i>-helicate [Co<sub>2</sub>(L<sup>18w</sup>)<sub>3</sub>]X<sub>4</sub>; a tetrahedral
cage [Co<sub>4</sub>(L<sup>18w</sup>)<sub>6</sub>]X<sub>8</sub>; and
a dodecanuclear truncated-tetrahedral cage [Co<sub>12</sub>(L<sup>18w</sup>)<sub>18</sub>]X<sub>24</sub> (X = BF<sub>4</sub> or ClO<sub>4</sub>). All three products were crystallized under different conditions
and structurally characterized. In [Co<sub>2</sub>(L<sup>18w</sup>)<sub>3</sub>]X<sub>4</sub> all three bridging ligands span a pair
of metal ions; in the two larger products, there is a metal ion at
each vertex of the Co<sub>4</sub> or Co<sub>12</sub> polyhedral cage
array with a bridging ligand spanning a pair of metal ions along every
edge. All three structural types are known: what is unusual here is
the presence of all three from the same reaction. The assemblies <b>Co</b><sub><b>2</b></sub>, <b>Co</b><sub><b>4</b></sub>, and <b>Co</b><sub><b>12</b></sub> are in slow
equilibrium (hours/days) in aqueous solution, and this can be conveniently
monitored by <sup>1</sup>H NMR spectroscopy because (i) the paramagnetism
of Co(II) disperses the signals over a range of ca. 200 ppm and (ii)
the different symmetries of the three species give characteristically
different numbers of independent <sup>1</sup>H NMR signals, which
makes identification easy. From temperature- and concentration-dependent <sup>1</sup>H NMR studies it is clear that increasing temperature and
increasing dilution favors fragmentation to give a larger proportion
of the smaller assemblies for entropic reasons. High concentrations
and low temperature favor the larger assembly despite the unfavorable
entropic and electrostatic factors associated with its formation.
We suggest that this arises from the hydrophobic effect: reorganization
of several smaller complexes into one larger one results in a smaller
proportion of the hydrophobic ligand surface being exposed to water,
with a larger proportion of the ligand surface protected in the interior
of the assembly. In agreement with this, <sup>1</sup>H NMR spectra
in a nonaqueous solvent (MeNO<sub>2</sub>) show formation of only
[Co<sub>2</sub>(L<sup>18w</sup>)<sub>3</sub>]X<sub>4</sub> because
the driving force for reorganization into larger assemblies is now
absent. Thus, we can identify the contributions of temperature, concentration,
and solvent on the result of the metal/ligand self-assembly process
and have determined the speciation behavior of the <b>Co</b><sub><b>2</b></sub>/<b>Co</b><sub><b>4</b></sub>/<b>Co</b><sub><b>12</b></sub> system in aqueous solution
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