To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
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.
The aim of the study was to investigate any association between extrauterine growth restriction (EUGR) and intestinal flora of <30-week-old preterm infants. A total of 59 preterm infants were assigned to EUGR (n=23) and non-EUGR (n=36) groups. Intestinal bacteria were compared by using high-throughput sequencing of bacterial rRNA. The total abundance of bacteria in 344 genera (7568 v. 13,760; P<0.0001) and 456 species (10,032 v. 18,240; P<0.0001) was significantly decreased in the EUGR group compared with the non-EUGR group. After application of a multivariate logistic model and adjusting for potential confounding factors, as well as false-discovery rate corrections, we found four bacterial genera with higher and one bacterial genus with lower abundance in the EUGR group compared with the control group. In addition, the EUGR group showed significantly increased abundances of six species (Streptococcus parasanguinis, Bacterium RB5FF6, two Klebsiella species and Microbacterium), but decreased frequencies of three species (one Acinetobacter species, Endosymbiont_of_Sphenophorus_lev and one Enterobacter_species) compared with the non-EUGR group. Taken together, there were significant changes in the intestinal microflora of preterm infants with EUGR compared to preterm infants without EUGR.
Obesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status.
We analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses.
Third National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults.
Nationally representative sample of US adults in NHANES (n 13 489).
After adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers.
The study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings.
In vivo and in vitro trials were conducted to assess the effects of tributyrin (TB) supplementation on short-chain fatty acid (SFCA) concentrations, fibrolytic enzyme activity, nutrient digestibility and methanogenesis in adult sheep. Nine 12-month-old ruminally cannulated Small Tail ewes (initial body weight 55 ± 5.0 kg) without pregnancy were used for the in vitro trial. In vitro substrate made to offer TB at 0, 2, 4, 6 and 8 g/kg on a dry matter (DM) basis was incubated by ruminal microbes for 72 h at 39°C. Forty-five adult Small Tail ewes used for the in vivo trial were randomly assigned to five treatments with nine animals each for an 18-d period according to body weight (55 ± 5.0 kg). Total mixed ration fed to ewes was also used to offer TB at 0, 2, 4, 6 and 8 g/kg on a DM basis. The in vitro trial showed that TB supplementation linearly increased apparent digestibility of DM, crude protein, neutral detergent fibre and acid detergent fibre, and enhanced gas production and methane emissions. The in vivo trial showed that TB supplementation decreased DM intake, but enhanced ruminal fermentation efficiency. Both in vitro and in vivo trials showed that TB supplementation enhanced total SFCA concentrations and carboxymethyl cellulase activity. The results indicate that TB supplementation might exert advantage effects on rumen microbial metabolism, despite having an enhancing effect on methanogenesis.
Multiple human immunodeficiency virus (HIV)-1 genotypes in China were first discovered in Yunnan Province before disseminating throughout the country. As the HIV-1 epidemic continues to expand in Yunnan, genetic characteristics and transmitted drug resistance (TDR) should be further investigated among the recently infected population. Among 2828 HIV-positive samples newly reported in the first quarter of 2014, 347 were identified as recent infections with BED-captured enzyme immunoassay (CEIA). Of them, 291 were successfully genotyped and identified as circulating recombinant form (CRF)08_BC (47.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (15.8%), CRF07_BC (14.4%), subtype C (2.7%), CRF55_01B (0.7%), subtype B (0.3%) and CRF64_BC (0.3%). CRF08_BC and CRF01_AE were the predominant genotypes among heterosexual and homosexual infections, respectively. CRF08_BC, URFs, CRF01_AE and CRF07_BC expanded with higher prevalence in central and eastern Yunnan. The recent common ancestor of CRF01_AE, CRF07_BC and CRF08_BC dated back to 1983.1, 1992.1 and 1989.5, respectively. The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially during 1991–1999 and 1994–1999, respectively. The EPS for CRF08_BC underwent two exponential growth phases in 1994–1998 and 2001–2002. Lastly, TDR-associated mutations were identified in 1.8% of individuals. These findings not only enhance our understanding of HIV-1 evolution in Yunnan but also have implications for vaccine design and patient management strategies.
A range of hormonal therapies has been evaluated to potentially improve the reproductive performance of lactating dairy cows. Early lactation treatments with gonadotrophin releasing hormone (GnRH) or prostaglandin F2∝ (PGF) may reduce the interval to first insemination or increase the conception rate to first insemination, but mainly in cows which have had a difficult pueperium or which are in herds with low conception rates. These two hormones, as well as progesterone and oestradiol benzoate (ODB) are commonly used either singly, or in combination (GnRH + PGF; progesterone + ODB + PGF) to synchronise the oestrus preceding first inseminations. None of these synchrony treatments is associated with increased conception rates. Extensive series of trials have been completed to identify post-oestrous or post-insemination hormonal therapies which could increase conception rates to the preceding insemination. The wide variation in results has precluded any being commonly regarded as sufficiently reliable for routine use. Nonetheless, meta-analyses have shown that GnRH treatment at insemination or in late dioestrus (11 to 13 day post-first insemination) can significantly increase “the risk of pregnancy”. Insemination treatments have been most effective with repeat breeders (+22.5%), whereas late dioestrous treatments (10%) may be dose and analogue specific (10 μg buserelin). Although metoestrous supplementation with progesterone can stimulate early embryonic development, the associated reduction in oestrous cycle length also reduces conception rates in heifers. Late dioestrous use of GnRH can prevent both of these negative effects. Early dioestrous supplementation with progesterone may enhance production of interferon tau, but this potentially beneficial effect has not been able to be reliably translated into increased conception rates. Many of these hormonal therapies are associated with altered patterns of ovarian follicle development which are similar to those in some synchrony treatments preceding first insemination. Recent studies have indicated that OBD and progesterone can be used to synchronise returns to service and increase the submission rate for second inseminations made about 3 weeks after first inseminations. This can make the non-return rate a more accurate measure of the response to a hormonal treatment and potentially overcome confusing impressions created when oestrous detection rates may be around 50%. Even if effective hormonal therapies are successfully developed, the results may be compromised by environmental factors such as heat stress, energy balance or energy partitioning for lactation. These factors may reduce oocyte quality, fertilization rates or normal uterine secretion patterns. Reduced conception rates associated with high daily milk yields in early lactation may not be able to be remedied simply with hormonal supplementation or by altering patterns of ovarian follicle development. Under these circumstances, controlling the inter-service interval could reduce the impact of the lowered conception rates.
The development of adverse behaviour in group–housed growing/ finishing pigs with intact tails was studied in a straw–flow housing system and in a part–slatted system with a commercial enrichment object. Food intake, body weight and behaviour were monitored over the finishing period, with tail biting outbreaks defined as an occasion where three or more pigs within a group had freshly damaged tails and tail biting behaviour was ongoing. Data from the two systems were analysed to identify tail–biting outbreaks and behavioural changes over time. Levels of pig manipulation were higher in the part–slatted system. Over time, pigs in both systems showed reduced interest in the enrichment provided, but not in each other. Despite the presence of the enrichment device, tail biting occurred in all groups in the part–slatted system, but only 1/12 groups in the straw–flow system. The amount of time occupied by manipulation of the enrichment provided was very significantly higher for straw than for the commercial object. Better design of enrichment strategies is therefore needed and should be based on species–relevant requirements.
In order to reduce ammonia emissions from pig housing systems, the Council of Europe proposes the use of part slatted flooring in preference to fully slatted flooring, but the effects of such changes on the health and welfare of pigs in the UK has not been defined. The aim of this experiment was to investigate the effects of different floor types on the emission of ammonia, behaviour and welfare, physical performance and respiratory and enteric health of growing/finishing pigs. This involved three replications of five treatments: 1) UK fully-slatted, 2) UK fully–slatted with rubber matting over 50% of the slats, 3) UK fully–slatted with “structural” modifications which involved “paving” over 50% of the floor and partitioning off the slurry channel beneath the solid floor, 4) UK part–slatted, and 5) novel Dutch partslatted with UK pig stocking density. Groups of 10 pigs (balanced for gender) weighing approximately 40kg were on–test for 10 weeks.
The Chinese Solar and Geophysical Data (CSGD) was first issued at the Beijing Astronomical Observatory, Chinese Academy of Sciences (now the headquarter of the National Astronomical Observatories, Chinese Academy of Sciences) in 1971, when China’s satellite-industry was booming. CSGD covers the observational data (observations of the sunspots, solar flares, solar radio bursts, ionospheric storm and geomagnetic storm) from a couple of domestic observatories and the forecast data. The compiler of CSGD still keeps the data exchange with other institutes worldwide. The type of the dataset includes texts, tables, figures and so on. Up to now, we have electronized all the historic archives, making them easily accessible to people who are interested in them.
We analyse ruin probabilities for an insurance risk process with a more generalised dependence structure compared to the one introduced in Constantinescu et al. (2016). In this paper, we assume that a random threshold window is generated every time after a claim occurs. By comparing the previous inter-claim time with the threshold window, the distributions of the current threshold window and the inter-arrival time are determined. Furthermore, the statuses for the previous and current inter-arrival times give rise to the current claim size distribution as well. Like Constantinescu et al. (2016), we first identify the embedded Markov additive process where all the randomness takes a general form. Inspired by the Erlangisation technique, the key message of this paper is to analyse such risk process using a Markov fluid flow model where the underlying random variables follow phase-type distributions. This would further allow us to approximate the fixed observation windows by Erlang random variables. Then ruin probabilities under the process with Erlang(n) observation windows are proved to be Erlangian approximations for those related to the process with fixed threshold windows at the limit. An exact form of the limit can be obtained whose application will be illustrated further by a numerical example.
The WAIS (West Antarctic Ice Sheet) Divide deep ice core was recently completed to a total depth of 3405 m, ending 50 m above the bed. Investigation of the visual stratigraphy and grain characteristics indicates that the ice column at the drilling location is undisturbed by any large-scale overturning or discontinuity. The climate record developed from this core is therefore likely to be continuous and robust. Measured grain-growth rates, recrystallization characteristics, and grain-size response at climate transitions fit within current understanding. Significant impurity control on grain size is indicated from correlation analysis between impurity loading and grain size. Bubble-number densities and bubble sizes and shapes are presented through the full extent of the bubbly ice. Where bubble elongation is observed, the direction of elongation is preferentially parallel to the trace of the basal (0001) plane. Preferred crystallographic orientation of grains is present in the shallowest samples measured, and increases with depth, progressing to a vertical-girdle pattern that tightens to a vertical single-maximum fabric. This single-maximum fabric switches into multiple maxima as the grain size increases rapidly in the deepest, warmest ice. A strong dependence of the fabric on the impurity-mediated grain size is apparent in the deepest samples.
In this paper, the dynamical behavior and stability of hanging micropipes conveying fluid with pinned-free boundary conditions are investigated. For a pinned-free rigid micropipe, the dynamical system is found to be stable for various flow velocities. Particular emphasis is placed on the effects of flow velocity, mass ratio and gravity on the dynamics and flutter instability of flexible micropipe system with pinned-free boundary conditions. The governing equations for flexible micropipes are discretized using the differential quadrature method (DQM), yielding a generalized eigenvalue problem which is then solved for various flow velocities, mass ratios and gravity parameters. It is shown that, with increasing flow velocity, the flexible micropipe with pinned-free boundary conditions is stable until it becomes unstable via a Hopf bifurcation leading to flutter. The system may lose stability first in the second or third mode, mainly depending on the selected value of mass ratio. The existence of mode exchange between the second and third modes is possible. The gravity parameter of positive values causes additional restoring force and hence enhances the stability of the micropipe system; however, it can generate the complexity of stability diagrams.
Correlative microscopy approaches offer synergistic solutions to many research problems. One such combination, that has been studied in limited detail, is the use of atom probe tomography (APT) and transmission Kikuchi diffraction (TKD) on the same tip specimen. By combining these two powerful microscopy techniques, the microstructure of important engineering alloys can be studied in greater detail. For the first time, the accuracy of crystallographic measurements made using APT will be independently verified using TKD. Experimental data from two atom probe tips, one a nanocrystalline Al–0.5Ag alloy specimen collected on a straight flight-path atom probe and the other a high purity Mo specimen collected on a reflectron-fitted instrument, will be compared. We find that the average minimum misorientation angle, calculated from calibrated atom probe reconstructions with two different pole combinations, deviate 0.7° and 1.4°, respectively, from the TKD results. The type of atom probe and experimental conditions appear to have some impact on this accuracy and the reconstruction and measurement procedures are likely to contribute further to degradation in angular resolution. The challenges and implications of this correlative approach will also be discussed.
The quality and utility of the records of oxygen-isotopic abundances, dust concentrations and anionic concentrations preserved in the ice at Siple Station (75°55′ S, 84° 15′ W) are assessed from four shallow (20 m) cores. The combination of high accumulation (0.56 m a−1 w.e.) and low mean annual temperature (—24°C) preserves the prominent seasonal variations in δ18Ο which are very spatially coherent. Sulfate concentrations vary seasonally and, in conjunction with δ18Ο, will allow accurate dating of deeper cores from Siple Station. The concentrations of insoluble dust are the lowest measured in Antarctica, making Siple Station an excellent location to examine large increases in atmospheric tubidity.
The seasonal variations and annual fluxes of the anions are examined for the last two decades (AD 1966–85) with regard to probable sources. An unusually high sulfate flux in 1976 may reflect the February 1975 eruption of Mount Ngauruhoe, New Zealand. No annual signal in nitrate concentration is confirmed and no unusually high nitrate fluxes support the suggestion of nitrate production by large solar flares. However, nitrate flux is higher for the latter half of the 1970s and early 1980s, possibly reflecting the recent loss of stratospheric ozone.
Finally, comparison of the δ18O record with available surface-temperature data (AD 1957–85) reveals that multi-year trends along the western coast of the Antarctic Peninsula are recorded at Siple. More importantly, comparison with areally weighted temperature reconstructions suggests that the δ18Ο record may reflect larger-scale, persistent trends in the high southern latitudes. The strong spatial coherence of the preserved records, the potential for accurate dating, and possible relevance to larger-scale processes make Siple Station an excellent site for paleoenvironmental reconstruction from ice cores.
Rural-to-urban migrant workers are a large marginalised population in urban China. Prevalence estimates of common mental health problems (CMHPs) in previous studies varied widely and very few studies have investigated migration-related factors of CMHPs in migrant workers. The objective of this study was to determine the prevalence and risk factors of CMHPs among Chinese migrant workers.
A random sample of 3031 migrant workers of ten manufacturing factories in Shenzhen, China, completed a standardised questionnaire containing socio-demographic and migration-related variables and the Chinese 12-item General Health Questionnaire (GHQ-12). A GHQ-12 score of three or higher was used to denote the presence of CMHPs.
The prevalence of CMHPs was 34.4% in Chinese migrant workers. In multiple logistic regression, risk factors for CMHPs included being 16–25 years old (odd ratio [OR] 1.65, 95% confidence interval [CI] 1.28, 2.12), being 26–35 years old (OR 1.36, 95% CI: 1.05, 1.75), low monthly income (OR 1.42, 95% CI 1.04, 1.92), poor living condition (OR: 1.76, 95% CI: 1.22, 2.54), physical illness in the past 2 weeks (OR 1.72, 95% CI 1.43, 2.05), having worked in many cities (OR 1.34, 95% CI 1.03, 1.74), infrequently visiting hometown (OR 1.56, 95% CI 1.22, 1.99), poor Mandarin proficiency (OR 1.51, 95%CI 1.13, 2.01), a low level of perceived benefits of migration (OR 1.33, 95% CI 1.14, 1.55) and working more than 8 h/day (OR 1.39, 95% CI 1.14, 1.70).
CMHPs are very prevalent among Chinese migrant workers. Given the large number of Chinese migrant workers, there is an urgent need to address the mental health burden of China's migrant worker population.
Preterm birth and exposure to childhood sexual abuse (CSA) are early physiological and psychological adversities that have been linked to reduced social functioning across the lifespan. However, the joint effects of being born preterm and being exposed to CSA on adult social outcomes remains unclear. We sought to determine the impact of exposure to both preterm birth and CSA on adult social functioning in a group of 179 extremely low birth weight (ELBW; <1000 g) survivors and 145 matched normal birth weight (>2500 g) participants in the fourth decade of life. Social outcome data from a prospective, longitudinal, population-based Canadian birth cohort initiated between the years of 1977 and 1982 were examined. At age 29–36 years, ELBW survivors who experienced CSA reported poorer relationships with their partner, worse family functioning, greater loneliness, lower self-esteem and had higher rates of avoidant personality problems than those who had not experienced CSA. Birth weight status was also found to moderate associations between CSA and self-esteem (P=0.032), loneliness (P=0.021) and family functioning (P=0.060), such that the adverse effects of CSA were amplified in ELBW survivors. Exposure to CSA appears to augment the adult social risks associated with perinatal adversity. Individuals born preterm and exposed to CSA appear to be a group at particularly high risk for adverse social outcomes in adulthood.
Eleven radiocarbon dates and tree-ring analyses of 3 juniper logs demonstrate the potential for 14C analysis of buried logs in the American Midwest. Three junipers (cf. Juniperus virginiana) were recovered from 9.20, 10.50, and 10.60 m in the fill of Carnegie Canyon, west-central Oklahoma. Their 14C ages are calibrated between 3300 and 2800 yr ago. A negative correlation of tree rings and ∆14C (p = 0.013) supports the findings of Schmidt and Gruhle (1988), who demonstrate the association of global cooling with reduced solar activity.
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.