Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.

Abstract Background Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. Methods Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. Results A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8–47.8 months) and untreated controls (n = 7; age, 12.6–45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. Conclusion rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. Trial registration ClinicalTrials.gov NCT02060526 ; EudraCT 2013-003450-24

First light of the VLT planet finder SPHERE. I. Detection and characterization of the sub-stellar companion GJ 758 B

GJ758 B is a brown dwarf companion to a nearby (15.76 pc) solar-type, metal-rich (M/H = +0.2 dex) main-sequence star (G9V) that was discovered with Subaru/HiCIAO in 2009. From previous studies, it has drawn attention as being the coldest (~600K) companion ever directly imaged around a neighboring star. We present new high-contrast data obtained during the commissioning of the SPHERE instrument at the VLT. The data was obtained in Y-, J-, H-, and Ks-bands with the dual-band imaging (DBI) mode of IRDIS, providing a broad coverage of the full near-infrared (near-IR) range at higher contrast and better spectral sampling than previously reported. In this new set of high-quality data, we report the re-detection of the companion, as well as the first detection of a new candidate closer-in to the star. We use the new 8 photometric points for an extended comparison of GJ758 B with empirical objects and 4 families of atmospheric models. From comparison to empirical object, we estimate a T8 spectral type, but none of the comparison object can accurately represent the observed near-IR fluxes of GJ758 B. From comparison to atmospheric models, we attribute a Teff = 600K $\pm$ 100K, but we find that no atmospheric model can adequately fit all the fluxes of GJ758 B. The photometry of the new candidate companion is broadly consistent with L-type objects, but a second epoch with improved photometry is necessary to clarify its status. The new astrometry of GJ758 B shows a significant proper motion since the last epoch. We use this result to improve the determination of the orbital characteristics using two fitting approaches, Least-Square Monte Carlo and Markov Chain Monte Carlo. Finally, we analyze the sensitivity of our data to additional closer-in companions and reject the possibility of other massive brown dwarf companions down to 4-5 AU. [abridged]Comment: 20 pages, 15 figures. Accepted for publication in A&

SPHERE: the exoplanet imager for the Very Large Telescope

Observations of circumstellar environments to look for the direct signal of exoplanets and the scattered light from disks has significant instrumental implications. In the past 15 years, major developments in adaptive optics, coronagraphy, optical manufacturing, wavefront sensing and data processing, together with a consistent global system analysis have enabled a new generation of high-contrast imagers and spectrographs on large ground-based telescopes with much better performance. One of the most productive is the Spectro-Polarimetic High contrast imager for Exoplanets REsearch (SPHERE) designed and built for the ESO Very Large Telescope (VLT) in Chile. SPHERE includes an extreme adaptive optics system, a highly stable common path interface, several types of coronagraphs and three science instruments. Two of them, the Integral Field Spectrograph (IFS) and the Infra-Red Dual-band Imager and Spectrograph (IRDIS), are designed to efficiently cover the near-infrared (NIR) range in a single observation for efficient young planet search. The third one, ZIMPOL, is designed for visible (VIR) polarimetric observation to look for the reflected light of exoplanets and the light scattered by debris disks. This suite of three science instruments enables to study circumstellar environments at unprecedented angular resolution both in the visible and the near-infrared. In this work, we present the complete instrument and its on-sky performance after 4 years of operations at the VLT.Comment: Final version accepted for publication in A&

Exclusive Leptoproduction of rho^0 Mesons from Hydrogen at Intermediate Virtual Photon Energies

Measurements of the cross section for exclusive virtual-photoproduction of rho^0 mesons from hydrogen are reported. The data were collected by the HERMES experiment using 27.5 GeV positrons incident on a hydrogen gas target in the HERA storage ring. The invariant mass W of the photon-nucleon system ranges from 4.0 to 6.0 GeV, while the negative squared four-momentum Q^2 of the virtual photon varies from 0.7 to 5.0 GeV^2. The present data together with most of the previous data at W > 4 GeV are well described by a model that infers the W-dependence of the cross section from the dependence on the Bjorken scaling variable x of the unpolarized structure function for deep-inelastic scattering. In addition, a model calculation based on Off-Forward Parton Distributions gives a fairly good account of the longitudinal component of the rho^0 production cross section for Q^2 > 2 GeV^2.Comment: 10 pages, 6 embedded figures, LaTeX for SVJour(epj) document class. Revisions: curves added to Fig. 1, several clarifications added to tex

Cross-validated stepwise regression for identification of novel non-nucleoside reverse transcriptase inhibitor resistance associated mutations

<p>Abstract</p> <p>Background</p> <p>Linear regression models are used to quantitatively predict drug resistance, the phenotype, from the HIV-1 viral genotype. As new antiretroviral drugs become available, new resistance pathways emerge and the number of resistance associated mutations continues to increase. To accurately identify which drug options are left, the main goal of the modeling has been to maximize predictivity and not interpretability. However, we originally selected linear regression as the preferred method for its transparency as opposed to other techniques such as neural networks. Here, we apply a method to lower the complexity of these phenotype prediction models using a 3-fold cross-validated selection of mutations.</p> <p>Results</p> <p>Compared to standard stepwise regression we were able to reduce the number of mutations in the reverse transcriptase (RT) inhibitor models as well as the number of interaction terms accounting for synergistic and antagonistic effects. This reduction in complexity was most significant for the non-nucleoside reverse transcriptase inhibitor (NNRTI) models, while maintaining prediction accuracy and retaining virtually all known resistance associated mutations as first order terms in the models. Furthermore, for etravirine (ETR) a better performance was seen on two years of unseen data. By analyzing the phenotype prediction models we identified a list of forty novel NNRTI mutations, putatively associated with resistance. The resistance association of novel variants at known NNRTI resistance positions: 100, 101, 181, 190, 221 and of mutations at positions not previously linked with NNRTI resistance: 102, 139, 219, 241, 376 and 382 was confirmed by phenotyping site-directed mutants.</p> <p>Conclusions</p> <p>We successfully identified and validated novel NNRTI resistance associated mutations by developing parsimonious resistance prediction models in which repeated cross-validation within the stepwise regression was applied. Our model selection technique is computationally feasible for large data sets and provides an approach to the continued identification of resistance-causing mutations.</p

Models of peer support to remediate post-intensive care syndrome: A report developed by the SCCM Thrive International Peer Support Collaborative

Objective: Patients and caregivers can experience a range of physical, psychological, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. Design: We sought to identify technical, safety and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. Subjects: 17 Thrive sites from the USA, UK, and Australia were represented by a range of healthcare professionals. Interventions: Via an iterative process of in-person and email/conference calls, members of the Collaborative, defined the key areas on which peer support models could be defined and compared; collected detailed self-reports from all sites; reviewed the information and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Results: Within the Thrive Collaborative, six general models of peer support were identified: Community based, Psychologist-led outpatient, Models based within ICU follow-up clinics, Online, Groups based within ICU and Peer mentor models. The most common barriers to implementation were: recruitment to groups, personnel input and training: sustainability and funding, risk management and measuring success. Conclusion: A number of different models of peer support are currently being developed to help patients and families recover and grow in the post-critical care setting

SPHERE view of Wolf-Rayet 104. Direct detection of the Pinwheel and the link with the nearby star

Context. WR104 is an emblematic dusty Wolf-Rayet star and the prototypical member of a sub-group hosting spirals that are mainly observable with high-angular resolution techniques. Previous aperture masking observations showed that WR104 is likely to be an interacting binary star at the end of its life. However, several aspects of the system are still unknown. This includes the opening angle of the spiral, the dust formation locus, and the link between the central binary star and a candidate companion star detected with the Hubble Space Telescope (HST) at 1′′. Aims. Our aim was to directly image the dusty spiral or “pinwheel” structure around WR104 for the first time and determine its physical properties at large spatial scales. We also wanted to address the characteristics of the candidate companion detected by the HST. Methods. For this purpose, we used SPHERE and VISIR at the Very Large Telescope to image the system in the near- and mid-infrared, respectively. Both instruments furnished an excellent view of the system at the highest angular resolution a single, ground-based telescope can provide. Based on these direct images, we then used analytical and radiative transfer models to determine several physical properties of the system. Results. Employing a different technique than previously used, our new images have allowed us to confirm the presence of the dust pinwheel around the central star. We have also detected up to five revolutions of the spiral pattern of WR104 in the K band for the first time. The circumstellar dust extends up to 2 arcsec from the central binary star in the N band, corresponding to the past 20 yr of mass loss. Moreover, we found no clear evidence of a shadow of the first spiral coil onto the subsequent ones, which likely points to a dusty environment less massive than inferred in previous studies. We have also confirmed that the stellar candidate companion previously detected by the HST is gravitationally bound to WR104 and herein provide information about its nature and orbital elements

Niemann-Pick disease type C

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations