In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease ...progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.
We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.
A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.
Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
Objective
Dysbiosis of the infant gut microbiota may have long‐term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut ...microbiota, and to explore whether breastfeeding modifies these effects.
Design
Prospective pregnancy cohort of Canadian infants born in 2010–2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Study.
Setting
General community.
Sample
Representative sub‐sample of 198 healthy term infants from the CHILD Study.
Methods
Maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota was characterised by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months.
Main outcome measures
Infant gut microbiota profiles.
Results
In this cohort, 21% of mothers received IAP for Group B Streptococcus prophylaxis or pre‐labour rupture of membranes; another 23% received IAP for elective or emergency caesarean section (CS). Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon‐specific composition also differed, with the genera Bacteroides and Parabacteroides under‐represented, and Enterococcus and Clostridium over‐represented at 3 months following maternal IAP. Microbiota differences were especially evident following IAP with emergency CS, with some changes (increased Clostridiales and decreased Bacteroidaceae) persisting to 12 months, particularly among non‐breastfed infants.
Conclusions
Intrapartum antibiotics in caesarean and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects. Further research is warranted to explore the health consequences of these associations.
Tweetable
Maternal #antibiotics during childbirth alter the infant gut #microbiome.
Tweetable
Maternal #antibiotics during childbirth alter the infant gut #microbiome.
Structural deformity of the hippocampus is characteristic of individuals with very mild and mild forms of dementia of the Alzheimer type (DAT). The purpose of this study was to determine whether a ...similar deformity of the hippocampus can predict the onset of dementia in nondemented elders. Using high dimensional diffeomorphic transformations of a neuroanatomical template, hippocampal volumes and surfaces were defined in 49 nondemented elders; the hippocampal surface was subsequently partitioned into three zones (i.e., lateral, superior and inferior-medial), which were proximal to the underlying CA1 subfield, CA2–4 subfields plus dentate gyrus, and subiculum, respectively. Annual clinical assessments using the Clinical Dementia Rating scale (CDR), where CDR 0 indicates no dementia and CDR 0.5 indicates very mild dementia, were then performed for a mean of 4.9 years (range 0.9–7.1 years) to monitor subjects who converted from CDR 0 to CDR 0.5. Inward variation of the lateral zone and left hippocampal volume significantly predicted conversion to CDR 0.5 in separate Cox proportional hazards models. When hippocampal surface variation and volume were included in a single model, inward variation of the lateral zone of the left hippocampal surface was selected as the only significant predictor of conversion. The pattern of hippocampal surface deformation observed in nondemented subjects who later converted to CDR 0.5 was similar to the pattern of hippocampal surface deformation previously observed to discriminate subjects with very mild DAT and nondemented subjects. These results suggest that inward deformation of the left hippocampal surface in a zone corresponding to the CA1 subfield is an early predictor of the onset of DAT in nondemented elderly subjects.
The pulsar/massive star binary system PSR B1259−63/LS 2883 is one of the best-studied gamma-ray binaries, a class of systems whose bright gamma-ray flaring can provide important insights into ...high-energy physics. Using the Australian Long Baseline Array, we have conducted very long baseline interferometric observations of PSR B1259−63 over 4.4 years, fully sampling the 3.4-year orbital period. From our measured parallax of 0.38 ± 0.05 mas- we use a Bayesian approach to infer a distance of |$2.6^{+0.4}_{-0.3}$| kpc. We find that the binary orbit is viewed at an angle of 154 ± 3° to the line of sight, implying that the pulsar moves clockwise around its orbit as viewed on the sky. Taking our findings together with previous results from pulsar timing observations, all seven orbital elements for the system are now fully determined. We use our measurement of the inclination angle to constrain the mass of the stellar companion to lie in the range 15–31 M_⊙. Our measured distance and proper motion are consistent with the system having originated in the Cen OB1 association and receiving a modest natal kick, causing it to have moved ∼8 pc from its birthplace over the past ∼3 × 10^5 years. The orientation of the orbit on the plane of the sky matches the direction of motion of the X-ray synchrotron-emitting knot observed by the Chandra X-ray Observatory to be moving away from the system.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurological disorder characterized by death of motoneurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the mechanisms ...whereby they induce disease are not fully understood. Here, we use time-lapse microscopy to monitor for the first time the effect of mutant SOD1 on fast axonal transport (FAT) of bona fide cargoes in living neurons. We analyzed FAT of mitochondria that are a known target for damage by mutant SOD1 and also of membrane-bound organelles (MBOs) using EGFP-tagged amyloid precursor protein as a marker. We studied FAT in motor neurons derived from SOD1G93A transgenic mice that are a model of ALS and also in cortical neurons transfected with SOD1G93A and three further ALS-associated SOD1 mutants. We find that mutant SOD1 damages transport of both mitochondria and MBOs, and that the precise details of this damage are cargo-specific. Thus, mutant SOD1 reduces transport of MBOs in both anterograde and retrograde directions, whereas mitochondrial transport is selectively reduced in the anterograde direction. Analyses of the characteristics of mitochondrial FAT revealed that reduced anterograde movement involved defects in anterograde motor function. The selective inhibition of anterograde mitochondrial FAT enhanced their net retrograde movement to deplete mitochondria in axons. Mitochondria in mutant SOD1 expressing cells also displayed features of damage. Together, such changes to mitochondrial function and distribution are likely to compromise axonal function. These alterations represent some of the earliest pathological features so far reported in neurons of mutant SOD1 transgenic mice.
MAXI J1535−571 is a Galactic black hole candidate X-ray binary that was discovered going into outburst in 2017 September. In this paper, we present comprehensive radio monitoring of this system using ...the Australia Telescope Compact Array, as well as the MeerKAT radio observatory, showing the evolution of the radio jet during its outburst. Our radio observations show the early rise and subsequent quenching of the compact jet as the outburst brightened and then evolved toward the soft state. We constrain the compact jet quenching factor to be more than 3.5 orders of magnitude. We also detected and tracked (for 303 days) a discrete, relativistically moving jet knot that was launched from the system. From the motion of the apparently superluminal knot, we constrain the jet inclination (at the time of ejection) and speed to ≤45° and ≥0.69 c, respectively. Extrapolating its motion back in time, our results suggest that the jet knot was ejected close in time to the transition from the hard intermediate state to soft intermediate state. The launching event also occurred contemporaneously with a short increase in X-ray count rate, a rapid drop in the strength of the X-ray variability, and a change in the type-C quasi-periodic oscillation (QPO) frequency that occurs >2.5 days before the first appearance of a possible type-B QPO.
Systematic improvements in algorithmic design of regional ocean circulation models have led to significant enhancement in simulation ability across a wide range of space/time scales and marine system ...types. As an example, we briefly review the Regional Ocean Modeling System, a member of a general class of three-dimensional, free-surface, terrain-following numerical models. Noteworthy characteristics of the ROMS computational kernel include: consistent temporal averaging of the barotropic mode to guarantee both exact conservation and constancy preservation properties for tracers; redefined barotropic pressure-gradient terms to account for local variations in the density field; vertical interpolation performed using conservative parabolic splines; and higher-order, quasi-monotone advection algorithms. Examples of quantitative skill assessment are shown for a tidally driven estuary, an ice-covered high-latitude sea, a wind- and buoyancy-forced continental shelf, and a mid-latitude ocean basin. The combination of moderate-order spatial approximations, enhanced conservation properties, and quasi-monotone advection produces both more robust and accurate, and less diffusive, solutions than those produced in earlier terrain-following ocean models. Together with advanced methods of data assimilation and novel observing system technologies, these capabilities constitute the necessary ingredients for multi-purpose regional ocean prediction systems.
By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars’ surface the SEIS (
S
eismic
E
xperiment for
I
nternal
S
tructure) instrument; a ...six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking’s Mars seismic monitoring by a factor of
∼
2500
at 1 Hz and
∼
200
000
at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars’ surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of
M
w
∼
3
at
40
∘
epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution.
We investigate the influence of annealing conditions on the physical properties of thin films of poly(3,4‐ethylenedioxythiophene)/poly(styrene sulfonate) (PEDOT/PSS). In particular, we describe how ...annealing temperature, the ambient gas, and choice of dopant affect the conductivity, morphology, and work function of the films. Two specific dopants are considered, sorbitol and glycerol, and broad guidelines are developed for using PEDOT/PSS as a hole‐injection electrode in polymeric light‐emitting devices, solar cells, and photodetectors.
The influence of annealing conditions on the physical properties of thin films of PEDOT/PSS is investigated. In particular, how the ambient gas (see Figure) and choice of dopant affect the conductivity, morphology, and work function of the films is explored.
Abstract Background and aims The positive and negative health effects of dietary carbohydrates are of interest to both researchers and consumers. Methods International experts on carbohydrate ...research held a scientific summit in Stresa, Italy, in June 2013 to discuss controversies surrounding the utility of the glycemic index (GI), glycemic load (GL) and glycemic response (GR). Results The outcome was a scientific consensus statement which recognized the importance of postprandial glycemia in overall health, and the GI as a valid and reproducible method of classifying carbohydrate foods for this purpose. There was consensus that diets low in GI and GL were relevant to the prevention and management of diabetes and coronary heart disease, and probably obesity. Moderate to weak associations were observed for selected cancers. The group affirmed that diets low in GI and GL should always be considered in the context of diets otherwise understood as healthy, complementing additional ways of characterizing carbohydrate foods, such as fiber and whole grain content. Diets of low GI and GL were considered particularly important in individuals with insulin resistance. Conclusions Given the high prevalence of diabetes and pre-diabetes worldwide and the consistency of the scientific evidence reviewed, the expert panel confirmed an urgent need to communicate information on GI and GL to the general public and health professionals, through channels such as national dietary guidelines, food composition tables and food labels.
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