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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.
Cucumber powdery mildew is a destructive foliar disease caused by Podosphaera xanthii (formerly known as Sphaerotheca fuliginea) that substantially damages the yield and quality of crops. The control of this disease primarily involves the use of chemical pesticides that cause serious environmental problems. Currently, numerous studies have indicated that some plant extracts or products potentially have the ability to act as natural pesticides to control plant diseases. It has been reported that turmeric (Curcuma longa L.) and its extract can be used in agriculture due to their insecticidal and fungicidal properties. However, the most effective fungicidal component of this plant is still unknown. In the current study, the crude extract of C. longa L. was found to have a fungicidal effect against P. xanthii. Afterwards, eight fractions (Fr.1–Fr.8) were gradually separated from the crude extract by column chromatography. Fraction 1 had the highest fungicidal effect against this pathogen among the eight fractions. The active compound, (+)-(S)-ar-turmerone, was separated from Fr 1 by semi-preparative high-performance liquid chromatography and identified based on its 1H nuclear magnetic resonance (NMR) and 13C NMR spectrum data. The EC50 value of (+)-(S)-ar-turmerone was found to be 28.7 µg/ml. The compound also proved to have a curative effect. This is the first study to report that the compound (+)-(S)-ar-turmerone has an effect on controlling this disease. These results provide a basis for developing a new phytochemical fungicide from C. longa L. extract.
The aims of this study were to investigate risk factors for the development of postoperative chylothorax following paediatric congenital heart surgery and to investigate the impact of a management guideline on management strategies and patient outcome.
All patients with chylothorax following cardiac surgery at the Royal Children’s Hospital, Melbourne, over a 48-month period beginning in January 2008 were identified. A control group, matched for age, date of surgery, and sex, was identified. To investigate potential risk factors, univariable and multivariable logistic regression models were constructed with paired analysis. To examine the effect of a standardised management protocol, data before and after the implementation of the guideline were compared.
In total, 121 cases of chylothorax were identified, with 121 controls, matched for age at surgery, date of surgery, and sex. The incidence of chylothorax was 5.23%. Increasing surgical complexity (univariable OR 0.17 for the least complex versus the most complex group, p=0.02), closed-heart surgeries (OR 0.07 for open versus closed, p<0.001), and redo chest incisions (OR 10.0 for redo versus virgin, p<0.001) were significantly associated with chylothorax. The standardised management protocol had no significant impact on either drainage duration or management strategy.
We have replicated the previously reported association between surgical complexity and chylothorax risk, and have shown, for the first time, that redo chest openings are also associated with a significantly increased risk. The implementation of a standardised management protocol in our institution did not result in a significant change in either chylothorax drainage duration or management strategy.
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.
Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women’s Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child’s primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity.
The model diatom Thalassiosira pseudonana is believed to be a single species with a global distribution, but it has not been confirmed previously whether isolates from different environmental and geographic origins are genotypically and phenotypically identical. In the present study, a polyphasic approach was employed to characterize nine clonal isolates, plus an additional replicate of one of the isolates, of the diatom T. pseudonana from culture collections to investigate whether there was any cryptic speciation in the publicly available strains of this species. Morphological analysis using scanning electron microscopy concluded that the strains were indistinguishable. Furthermore, conventional DNA barcoding genes (SSU rDNA, ITS1 and ITS2 rDNA and rbcL), revealed no nucleotide variation among the strains tested. On employing a whole genome fingerprinting technique, Amplified Fragment Length Polymorphism (AFLP), three clusters were revealed, although the level of variation between the clusters was surprisingly low. These findings indicate a low level of diversity among these cultured T. pseudonana strains, despite their wide spatial and temporal distribution and the salinity range of their original habitats. Based on the limited number of available strains, this suggests that T. pseudonana is a highly conserved diatom that nevertheless has an ability to tolerate wide ranges of salinity and populate varied geographic locations.
To determine risk factors for sporadic Vibrio parahaemolyticus gastroenteritis, we conducted a population-based case-control study in sentinel hospital surveillance areas of Shanghai and Jiangsu province, China. Seventy-one patients with diarrhoea and confirmed V. parahaemolyticus infections were enrolled, and they were matched with 142 controls for gender, age and residential area. From the multivariable analysis, V. parahaemolyticus infections were associated with antibiotics taken during the 4 weeks prior to illness [odds ratio (OR) 8·1, 95% confidence interval (CI) 1·2–56·4)], frequent eating out (OR 3·3, 95% CI 1·1–10·1), and shellfish consumption (OR 3·2, 95% CI 1·0–9·9), with population-attributable fractions of 0·09, 0·25, and 0·14, respectively. Protective factors included keeping the aquatic products refrigerated (OR 0·4, 95% CI 0·1–0·9) and pork consumption (OR 0·2, 95% CI 0·1–0·8). Further study of the association of V. parahaemolyticus gastroenteritis with prior antibiotic use and shellfish consumption is needed.
To determine the burden and distribution of acute gastrointestinal illness (AGI) in the population, a cross-sectional, monthly face-to-face survey of 10 959 residents was conducted in Jiangsu province between July 2010 and June 2011. The adjusted monthly prevalence was 4·7% with 0·63 AGI episodes/person per year. The prevalence was the highest in children aged <5 years and lowest in persons aged ⩾65 years. A bimodal seasonal distribution was observed with peaks in summer and winter. Regional difference of AGI prevalence was substantial [lowest 0·5% in Taicang, highest 15·1% in Xinqu (Wuxi prefecture)]. Healthcare was sought by 38·4% of the ill respondents. The use of antibiotics was reported by 65·2% of the ill respondents and 38·9% took antidiarrhoeals. In the multivariable model, gender, education, season, sentinel site and travel were significant risk factors of being a case of AGI. These results highlight the substantial burden of AGI and the risk factors associated with AGI in Jiangsu province, China.
We report the first observation of ultraviolet lasing in ZnO powder and ZnO polycrystalline films grown on amorphous fused silica substrates. In the absence of any fabricated mirrors, laser action occurs in the closed loops formed by multiple optical scattering of light.
We report an interesting property of carbon dots: they emit light under charge injection. We synthesized carbon dots in diameter about 20 nm using wet chemistry methods. The photoluminescence quantum efficiency of the carbon dots dissolved in water was about 11%. We observed strong electrogenerated chemiluminescence (ECL) from the sample. This observation of ECL from carbon dots indicates that they could be a good candidate material for carbon-based electroluminescent devices.
High-Tc superconducting epitaxial thin films of gadolinium barium copper oxide,grown in situ by dc-magnetron sputtering onto substrates of single crystal (001) orientated LaAIO3 , SrTiO3 and yttrium stabilisedZrO2 have been studied by high resolution double axis difffactometry, X-ray white beam-Laue topography and double crystal topography. Rocking curve halfwidths were found to vary from about 1000 to 3000 arc seconds, very good in thecontext of these complex materials. The topographs showed that the orientations of the small crystallites was randomly distributed across the sample.
The equilibrium phase diagrams of monolayers of many substances adsorbed on graphite have long been studied as examples of 2-dimensional (2D) matter. One typically observes 2D gas and liquid phases, and solid phases that may be commensurate or incommensurate with the substrate lattice. Many experimental techniques have been used, but thermodynamic measurements are generally the most useful for tracing out phase boundaries.
Recent advances in technique have made it possible to use thermodynamic measurements to study the phase diagrams of the second and higher layers, up to the fifth or sixth. These advances include ultra high resolution scanning calorimetry, and a detailed understanding of the role of capillary condensation in corners and pores of the graphite foam substrate. We find a rich array of phases and phase transitions in multilayer methane, argon and krypton. The second and third layers typically have distinct 2D gas, liquid and solid phases evidenced by 2D triple points and critical points. We observe phase transitions between solid phases that are commensurate and incommensurate with the layer below. We also observe melting of the first layer at higher temperatures, even when one to five additional layers are adsorbed on top of it.
In argon and krypton, but not in methane, a strange new phenomenon is observed at temperatures above the gas-liquid critical point of the nth layer for n> 3. Below that temperature, nthlayer gas coexists with a condensed nth layer. At some temperature above it, a new coexistence region is observed in which a partial nth layer coexists with a partial n + 1st layer. This behavior is thought to be evidence for a theoretically predicted phase transition of the bulk interface, called the preroughening transition.
The natural weathering process of fly ashes was studied in artificial fly ash beds. The ashes were previously classified according to their total alkali content into acid, neutral and alkaline. After 4 years the effects of weathering are minor. The formation of concretions due to local cementation by calcite is observed in alkaline fly ash. Small brown pellets, highly enriched in some heavy metals, are present in the acid fly ash beds. Under natural conditions leaching is mainly confined to the alkaline fly ash. Elements which are leached most are sulphur and some alkalis as well as minor amounts of some trace elements.
Shake- and column experiments of the weathered fly ashes with acids of pH 1 and 4, the latter also in combination with complexing agents, were carried out in order to check if the natural leaching process may be accelerated artificially. Strong acids (pH= 1) were most effective, but relatively large quantities of major elements were also leached. Experiments with the weak acids, combined with complexing agents, resulted in leaching percentages which did not significantly differ from experiments without these agents. This indicates that a major part of the elements are present in an immobile form; because of the use of sulphuric acid, it is likely that they are in some cases precipitated as sulphates (e.g. barium, calcium).
Ion-implantation can increase the electrical conductivity of the polymer poly (p-phenylene sulfide) (PPS) by ~ 14 orders of magnitude. This conductivity increase, which is stable under ambient conditions, is studied as a function of temperature, ion energy, fluence and species, using a novel technique, based on microelectronics processing, capable of accurately measuring conductivities as low as 10−10 (Ω-cm)−1. Mechanisms for the enhanced conductivity of PPS are discussed in relation to our measurements.