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Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.
Using both a theoretical and an empirical approach, we have investigated the frequency of low redshift galaxy-galaxy lensing systems in which the signature of 3D weak lensing might be directly detectable. We find good agreement between these two approaches. Using data from the Galaxy and Mass Assembly redshift survey we estimate the frequency of detectable weak lensing at low redshift. We find that below a redshift of z ~ 0.6, the probability of a galaxy being weakly lensed by γ ⩾ 0.02 is ~ 0.01. We have also investigated the feasibility of measuring the scatter in the M* − Mh relation using shear statistics. We estimate that for a shear measurement error of Δγ = 0.02 (consistent with the sensitivity of the Direct Shear Mapping technique), with a sample of ~$50,000 spatially and spectrally resolved galaxies, the scatter in the M* − Mh relation could be measured. While there are currently no existing IFU surveys of this size, there are upcoming surveys that will provide this data (e.g The Hobby-Eberly Telescope Dark Energy Experiment (HETDEX), surveys with Hector, and the Square Kilometre Array (SKA)).
Both maternal 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and
placental amino acid transporter gene expression have been associated with
development of the offspring in terms of body composition and bone structure.
Several amino acid transporter genes have vitamin D response elements in their
promoters suggesting the possible linkage of these two mechanisms. We aimed to
establish whether maternal 25(OH)D and vitamin D-binding protein (VDBP) levels
relate to expression of placental amino acid transporters. RNA was extracted
from 102 placental samples collected in the Southampton Women's Survey,
and gene expression was analysed using quantitative real-time PCR. Gene
expression data were normalised to the geometric mean of three housekeeping
genes, and related to maternal factors and childhood body composition. Maternal
serum 25(OH)D and VDBP levels were measured by radioimmunoassay. Maternal
25(OH)D and VDBP levels were positively associated with placental expression of
specific genes involved in amino acid transport. Maternal 25(OH)D and VDBP
concentrations were correlated with the expression of specific placental amino
acid transporters, and thus may be involved in the regulation of amino acid
transfer to the fetus. The positive correlation of VDBP levels and placental
transporter expression suggests that delivery of vitamin D to the placenta may
be important. This exploratory study identifies placental amino acid
transporters which may be altered in response to modifiable maternal factors and
provides a basis for further studies.
To investigate the association between fruit and vegetable consumption and self-reported physical and mental functional health measured by an anglicised short-form 36-item questionnaire (UK SF-36).
Population-based cross-sectional study.
General community in Norfolk, UK.
A total of 16 792 men and women aged 40–79 years recruited from general practice population registers as part of the European Prospective Investigation into Cancer (EPIC)–Norfolk study, who completed food-frequency questionnaires in 1993–1997 and Health and Life Experiences Questionnaires 18 months later, were enrolled in the study.
Mean SF-36 physical component summary scores increased significantly with increasing total fruit and vegetable consumption in both men and women (P < 0.0001 for trend). Men and women in the top quartile of consumption compared with the bottom quartile had a significantly higher likelihood of reporting good physical health (defined as a score ≥ 55); odds ratio (OR) 1.30, 95% confidence interval (CI) 1.11–1.53 for men and OR 1.28, 95% CI 1.11–1.48 for women, after controlling for age, body mass index, smoking, education, social class, prevalent illness and total energy intake. Exclusion of current smokers and people with prevalent illness did not alter the associations.
Higher fruit and vegetable consumption is associated with better self-reported physical functional health within a general population. Increasing daily intake by two portions of fruit and vegetables was associated with an 11% higher likelihood of good functional health. Since the current average consumption of fruit and vegetables in the UK is about three portions, the recommended ‘five a day’ strategy may have additional benefit for functional as well as other health outcomes in the population.
To examine the association between fish consumption and stroke risk.
Prospective population cohort study.
Norfolk, UK cohort of the European Prospective Investigation into Cancer (EPIC–Norfolk).
Subjects were 24 312 men and women aged 40–79 years who had no previous history of stroke at baseline.
Fish consumption was assessed using a food-frequency questionnaire at baseline in 1993–1997 and stroke incidence ascertained to 2004.
A total of 421 incident strokes were identified (mean follow-up=8.5 years, total person-years=209 238). There were no significant relationships between total fish, shellfish or fish roe consumption and risk of stroke in men and women after adjusting for age, systolic blood pressure, body mass index, smoking, cholesterol, diabetes, physical activity, alcohol consumption, fish oil supplement use and total energy intake using Cox regression analyses. Oily fish consumption was significantly lower in women who subsequently had a stroke (odds ratio (OR) for consumers vs. non-consumers=0.69, 95% confidence interval (CI) 0.51–0.94, P=0.02). The trend in men was similar but not significant (OR for consumers vs. non-consumers=0.88, 95% CI 0.65–1.19, P=0.41).
There was no consistent relationship between fish consumption and stroke in this British population. Inconsistencies in the observed health effects of fish consumption in different populations may reflect different patterns and type of fish consumed and preparation methods.
The passive film stability of several Fe-based amorphous metal formulations have been found to be comparable to that of high-performance Ni-based alloys, and superior to that of stainless steels, based on electrochemical measurements of the passive film breakdown potential and general corrosion rates. Chromium (Cr), molybdenum (Mo) and tungsten (W) provide corrosion resistance; boron (B) enables glass formation; and rare earths such as yttrium (Y) lower critical cooling rate (CCR). The high boron content of this particular amorphous metal also makes it an effective neutron absorber, and suitable for criticality control applications, as discussed in companion publications. Corrosion data for SAM2X5 (Fe49.7Cr17.7Mn1.9Mo7.4W1.6B15.2C3.8Si2.4) is discussed here.
Data assimilation techniques are one method by which to improve the quality of model Simulations of Sea ice. The availability of daily gridded fields of Sea-ice motion makes this field one that can be readily assimilated. These fields are generally of higher resolution than forcing values Such as atmospheric wind which are used to drive the model, and on any given day may depict ice circulation that is dramatically different than what the model Solution represents. Typically, a blending method Such as optimal interpolation (OI) is used and corrections are applied to the initial modeled velocity field Such that the new Solution corresponds better with actual observations. However, care must be taken in Such a technique, as the corrections are not applied directly to the model physics, and the underlying physical assumptions in the ice dynamics may be violated. Previous Studies have Shown that improvements in the ice-motion Solution come at the cost of the quality of other modeled fields. The Strength parameterization in Sea-ice models controls the ice velocity in the model, and is obtained in part by comparison with observed motions. Here we investigate the Sensitivity of the Sea-ice model to variations in the Strength parameterization, and determine the effect of using data assimilation to impose observed velocities. We find that the alternation of the frictional loss parameter has limited effect on model performance. Rather, it is the assimilated data that overwhelm and degrade the Solution, bringing into question whether underlying physical assumptions in the model may be compromised.
The optical and electrical properties of InN films with different levels of carrier concentrations have been investigated. Hall effect measurements at room temperature show that the InN films are n-type with carrier concentration, ne, ranging from ∼ 7 ×1017 cm-3 to ∼ 3 × 1020 cm-3 and corresponding mobility, //, of ∼ 1300 to 50 cm2V-1S-1. Optical absorption spectra of these films show a bandgap absorption edge ∼ 0.6 eV for the InN sample with the lowest ne, and 1.5 eV for the InN sample with the highest ne. However, after corrections for the degeneracy effects, all samples show an intrinsic Eg ∼ (0.60 ± 0.05) eV. Temperature dependent (5 – 600 K) electrical measurements show that ne is nearly independent of temperature below 300 K, perhaps due to the presence of donor energy levels resonating with the InN conduction band. However, all the samples show an exponential increase in ne above 300 K due to excitation of other shallow donor like sources. Mobility versus temperature graph shows a maximum ∼ 200 K for InN film with ne = 7 × 1017 cm-3 and moves towards lower temperature with increasing ne.
The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35–70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrolment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case–control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.
The relative quantity of cyclin B1 was determined during the development of in vitro and in vivo derived porcine 4-cell embryos by western blotting and immunolocalised during the 4-cell stage. After cleavage to the 4-cell stage cyclin B1 localised to the cytoplasm at the 5, 10, 18 and 25 time points and localised to the nucleus 33 h post 4-cell cleavage (P4CC). The relative abundance of cyclin B1 was not significantly different in in vivo or in vitro derived 4-cell stage embryos cultured in the absence of the RNA polymerase inhibitor α-amanitin. Cyclin B1 protein was not detectable in embryos cultured in medium without α-amanitin for 5, 10, 18 or 25 h P4CC followed by culture in medium with α-amanitin to 33 P4CC. These results suggest that the maternal to zygotic transition of mRNA production that occurs at the 4-cell stage of the pig embryo does not result in an increase in cyclin B1 production. In addition, cyclin B1 protein levels remained constant in the absence of embryonic genome activation at the 4-cell stage.
Long PCR followed by nested PCR has previously been used to determine CYP2A6 160H alleles,
but the method proved unreliable. We have optimized this approach in a DNA bank of 1032 subjects
(age range 59–74 years) to give reliable results, yielding indirect molecular evidence and very strong
statistical evidence of hitherto unrecognized common alleles (designated O) recalcitrant to the long
PCR. Coding three alleles (160L, 160H and O) and an approach to association analysis originally
developed to deal with null alleles implicit in ABO blood group phenotyping, the contribution of
160H (functionally null) to reduced smoking habit has been clearly measured for the first time,
unconfounded by alleles null to the long PCR. The most significant findings (p < 0.01) are that the
possession of a 160H allele, compared with not possessing a 160H allele, is associated with a mean
age of starting regular smoking 3 years later (95% CI±1.93 years, average start age 20–21 years
rather than 17–18 years); and that the average likelihood of quitting smoking at any time is 1.75 fold
(95% CI. 1.17–2.61) for those possessing an 160H allele compared with those who have no 160H
allele. This suggests that a smoking subject with a genotype predicted to confer 50% of the ability
to eliminate nicotine via the CYP2A6 pathway has almost twice the likelihood of quitting smoking.
Previous research into free-farrowing systems for pigs has found that although sow welfare is better than in crated systems, piglet mortality levels are often unacceptably high. Whilst on-going research programmes are investigating methods to address this problem, the effect of alternative farrowing systems on piglet behaviour and welfare post-weaning is largely unknown. A recent study found that the increased social contact between piglets reared outdoors prior to weaning resulted in welfare benefits post-weaning (Cox and Cooper, 1999). The aim of this experiment was to investigate whether offering different degrees of social contact in an indoor community-lactation system would confer similar enhancements to piglet welfare post-weaning.
Fe K-edge x-ray absorption fine-structure (XAFS) measurements were performed on glass samples of (Fe3O4)0.3(P2O5)0.7 with various amounts of Na2O or UO2. Near-edge and extended XAFS regions are studied and comparisons are made to several reference compounds. We find that iron in the base glass is ∼25% divalent and that the Fe2+ coordination is predominantly octahedral, while Fe3+ sites are roughly split between tetrahedral and octahedral coordinations. Also, we measure roughly one Fe–O–P link per iron. Substitution of Na2O or UO2 up to 15 mol% primarily affects the first Fe–O shell. The results are compared to data from the related material Fe3(P2O7)2.
A 36C1 peak has been found at about 37 ka BP in the Guliya ice core, drilled from the Qinghai-Tibetan Plateau. This peak is indicative of enhanced cosmogenic isotope production in the atmosphere, rather than a change in accumulation rate. Comparison with the records of 10Be and 36C1 in ice cores from Antarctica and Greenland indicates that peaks of the cosmogenic isotopes are global, and that they can be used as time markers for dating ice cores. Interestingly, the 37 ka BP global event coincided with a cold period.
Microploughing experiments were used as a method for better understanding the ploughing mechanism in gold and iridium single crystals. The plough depths ranged from 20 nm in iridium to 1600 nm in gold. Yield stress profiles and TEM analyses indicate that both materials strain harden even when very small volumes of material are involved. Strain hardening theory, as applied to bulk material, is useful in analyzing the results.