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5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion.
Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity.
Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks.
These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.
An ongoing challenge in understanding and treating personality disorders (PDs) is a significant heterogeneity in disorder expression, stemming from variability in underlying dynamic processes. These processes are commonly discussed in clinical settings, but are rarely empirically studied due to their personalized, temporal nature. The goal of the current study was to combine intensive longitudinal data collection with person-specific temporal network models to produce individualized symptom-level structures of personality pathology. These structures were then linked to traditional PD diagnoses and stress (to index daily functioning).
Using about 100 daily assessments of internalizing and externalizing domains underlying PDs (i.e. negative affect, detachment, impulsivity, hostility), a temporal network mapping approach (i.e. group iterative multiple model estimation) was used to create person-specific networks of the temporal relations among domains for 91 individuals (62.6% female) with a PD. Network characteristics were then associated with traditional PD symptomatology (controlling for mean domain levels) and with daily variation in clinically-relevant phenomena (i.e. stress).
Features of the person-specific networks predicted paranoid, borderline, narcissistic, and obsessive-PD symptom counts above average levels of the domains, in ways that align with clinical conceptualizations. They also predicted between-person variation in stress across days.
Relations among behavioral domains thought to underlie heterogeneity in PDs were indeed associated with traditional diagnostic constructs and with daily functioning (i.e. stress) in person-specific networks. Findings highlight the importance of leveraging data and models that capture person-specific, dynamic processes, and suggest that person-specific networks may have implications for precision medicine.
This paper presents a review of the current status of photodiode array systems adapted for Energy Dispersive EXAFS (EDE) using a synchrotron radiation source. The performance of a conventional Reticon PDA is compared with that of a hybrid CCD. The specification of a new detector system for EDE is discussed in the light of experience gained with current linear detectors.
The last 12 years have seen the evolution of a new funding regime under the supervision of the Pensions Regulator. Over this period, there has been significant turbulence in financial markets, including record low interest rates. This paper takes a critical look at the development of funding approaches and methodologies over this period. It analyses the Pensions Regulator guidance and how scheme specific actuarial methods have emerged since the move away from the Minimum Funding Requirement in 2001 and the introduction of the Scheme Specific Funding Requirements in 2005. It asks whether these new methodologies have been successful from the perspective of members, trustees, employers and shareholders. At a time when actuarial valuation methodologies have faced considerable criticism, this paper aims to propose a pension funding methodology which is fit for purpose and also reflects the latest guidance from the Pensions Regulator on integrated risk management.
We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent’s non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children’s attainment with their own PRS increased substantially with the standardized effect size, moving from β = 0.134, 95% CI = 0.079, 0.188 for EA2, to β = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent’s PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from β = 0.201, 95% CI = 0.147, 0.256 to β = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring — therefore acting via the parenting environment — was increased in effect size from β = 0.058, 95% CI = 0.003, 0.114 to β = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual’s own genetic inheritance and are mediated by parental socioeconomic competence.
Birth weight and early growth have been associated with later blood pressure. However, not all studies consistently find a significant reduction in blood pressure with an increase in birth weight. In addition, the relative importance of birth weight and of other lifestyle and environmental factors is often overlooked and the association is rarely studied in adolescents. We investigated early life predictors, including birth weight, of adolescent blood pressure in the Gateshead Millennium Study (GMS). The GMS is a cohort of 1029 individuals born in 1999–2000 in Gateshead in Northern England. Throughout infancy and early childhood, detailed information were collected, including birth weight and measures of height and weight. Assessments of 491 returning participants at age 12 years included measures of body mass and blood pressure. Linear regression and path analysis were used to determine predictors and their relative importance on blood pressure. Birth weight was not directly associated with blood pressure at the age of 12. However, after adjustment for contemporaneous body mass index (BMI), an inverse association of standardized birth weight on systolic blood pressure was significant. The relative importance of birth weight on later systolic blood pressure was smaller than other contemporaneous body measures (height and BMI). There was no independent association of birth weight on blood pressure seen in this adolescent population. Contemporaneous body measures have an important role to play. Lifestyle factors that influence body mass or size, such as diet and physical activity, where interventions are directed at early prevention of hypertension should be targeted.
Trait impulsivity is thought to play a key role in predicting behaviors on the externalizing spectrum, such as drug and alcohol use and aggression. Research suggests that impulsivity may not be a unitary construct, but rather multidimensional in nature with dimensions varying across self-report assessments and laboratory behavioral tasks. Few studies with large samples have included a range of impulsivity-related measures and assessed several externalizing behaviors to clarify the predictive validity of these assessments on important life outcomes.
Community adults (N = 1295) between the ages of 30 and 54 completed a multidimensional assessment of impulsivity-related traits (including 54 self-report scales of personality traits implicated in impulsive behaviors, and four behavioral tasks purporting to assess a construct similar to impulsivity) and reported on five externalizing behavioral outcomes (i.e. drug, alcohol, and cigarette use, and physical and verbal aggression). We ran an exploratory factor analysis on the trait scales, and then a structural equation model predicting the externalizing behaviors from the three higher-order personality factors (i.e. Disinhibition v. Constraint/Conscientiousness, Neuroticism/Negative Emotionality, and Extraversion/Positive Emotionality) and the four behavioral tasks.
Relations between the self-report factors and behavioral tasks were small or nonexistent. Associations between the self-report factors and the externalizing outcomes were generally medium to large, but relationships between the behavioral tasks and externalizing outcomes were either nonexistent or small.
These results partially replicate and extend recent meta-analytic findings reported by Sharma et al. (2014) to further clarify the predictive validity of impulsivity-related trait scales and laboratory behavioral tasks on externalizing behaviors.
Introduction: For patients with chest pain, the target time from first medical contact to obtaining an electrocardiogram (ECG) is 10 minutes, as reperfusion within 120 minutes can reduce the risk of death and adverse outcomes in patients with ST elevation myocardial infarction (STEMI). In 2007, Vancouver Coastal Health (VCH) began tracking key indicators including time to first ECG. The Vancouver General Hospital (VGH) Emergency Department (ED) has been troubled with the longest door to ECG times in the region since 2014. In 2016, the VGH ED Quality Council developed a strategy to address this issue, with an aim of obtaining ECGs on 95% of patients presenting to the VGH ED with active chest pain within 10 minutes of presentation within a 6 month period. Methods: The VGH ED Quality Council brought together frontline clinicians, ECG technicians, and other stakeholders and completed a process map. We obtained baseline data regarding the median time to ECG in both patients with STEMI and all patients presenting with chest pain. Root cause analysis determined two main barriers: access to designated space to obtain ECGs, and the need for patients to be registered in the computer system before an ECG could be ordered. The team identified strategies to eliminate these barriers, identifying a dedicated space and undergoing multiple PDSA cycles to change the workflow to stream patients to this space before registration. Results: Our median times in patients with STEMI have gone from 33 minutes to 8 minutes as of June 2017. In all patients presenting with chest pain, we improved from a median of 36 to 17 minutes. As of April 2017 we are obtaining an ECG within 10 minutes in 27% of our patients, compared to 3% in 2016. Given the limitations in our data extraction process, we were not able to differentiate between patients with active chest pain versus those whose chest pain had resolved. Conclusion: By involving frontline staff, and having frontline champions providing real time support, we were able to make significant changes to the culture at triage. We cultivated sustainability by changing the workflow and physical space, and not relying on education only. While we have improved the times for our walk-in patients, we have not perfected the process when a patient moves immediately to a bed or presents via ambulance. Implementing small changes and incorporating feedback has allowed us to identify these new challenges early.
Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.
Concerns have been raised about the potential adverse effects on reproductive health in farm animals, humans, and wildlife species from a range of environmental chemicals that disrupt normal hormonal actions. The alkylphenol polyethoxylates are non-ionic surfactants used in the manufacture of detergents, paints and herbicides. During sewage treatment, these compounds are broken down to short chain alkylphenol polyethoxylates, alkylphenol carboxylic acids and alkylphenols which bioaccumulate in the lipid of living organisms. The estrogenic nature of one of these compounds - octylphenol has been clearly demonstrated in cell culture, in a recombinant yeast screen with human estrogen receptor?and in animal studies. It is proposed that these endocrine disrupting compounds influence male adult reproductive potential by disrupting the development of the hypothalamic-pituitary-testicular axis during fetal life. We have recently identified that exposure to octylphenol for the second half of gestation decreases circulating concentrations of FSH during fetal life and the number of Sertoli cells of the testis and testis size at birth in comparison to control animals (Sweeney et al., 2000). However, the testes size, % interstitial space, semen volume, semen concentration and % live semen was similar in both treatment groups in the adult. In contrast animals exposed to octylphenol from birth to weaning (16 weeks of age) had a significantly greater number of primary and secondary abnormalities in comparison to controls and animals exposed to octylphenol for the second half of gestation. A number of the animals exposed to octylphenol from birth to weaning exhibited augmented sexual behaviour, while those exposed to octylphenol for the second half of pregnancy showed a suppression of sexual behaviour. The current data suggests the physiological effect of exposure to octylphenol is dependant on the time and duration of exposure. This has major implications for the determination of universal end-point measurements to assess exposure to endocrine disrupting compounds.
We have mapped the nearby (z=0.018), active galaxy NGC 1275 (3C84) at 6 different epochs from 1981 to 1986 at 1.3 cm (22.3 GHz) with a global VLBI array of seven telescopes. We find a long-lived knot of emission separating from the brightest radio component with a projected velocity = 0.4 6±0.12 h−1 c. This knot moves through diffuse emission that also moves away from the main component with a slower projected velocity of 0.33±0.12 h−1 c. We show that the knot and diffuse emission result from two separate events that occurred around 1959 and 1968.
Early in the history of schistosomiasis research, children under 5 years of age were known to be infected. Although this problem was recognized over 100 years ago, insufficient action has been taken to address this issue. Under current policy, such infected children only receive their first antiparasitic treatment (praziquantel – PZQ) upon entry into primary school as current mass drug administration programmes typically target school-aged children. For many infected children, they will wait up to 6 years before receiving their first medication and significant schistosomiasis-related morbidity may have already established. This inequity would not be accepted for other diseases. To unveil some of the reasons behind this neglect, it is paramount to understand the intricate historical relationship between schistosomiasis and British Imperial medicine, to underline its lasting influence on today's public health priorities. This review presents a perspective on the historical neglect of paediatric schistosomiasis, focusing on important gaps that persist from the early days after discovery of this parasite. Looking to end this inequity, we address several issues that need to be overcome to move forward towards the lasting success of schistosomiasis control and elimination efforts.
Open-water swimming is increasingly popular, often in water not considered safe for bathing. Limited evidence exists on the associated health risks. We investigated gastrointestinal illness in 1100 swimmers in a River Thames event in London, UK, to describe the outbreak and identify risk factors. We conducted a retrospective cohort study. Our case definition was swimmers with any: diarrhoea, vomiting, abdominal cramps lasting ⩾48 h, nausea lasting ⩾48 h, with onset within 9 days after the event. We used an online survey to collect information on symptoms, demographics, pre- and post-swim behaviours and open-water experience. We tested associations using robust Poisson regression. We followed up case microbiological results. Survey response was 61%, and attack rate 53% (338 cases). Median incubation period was 34 h and median symptom duration 4 days. Five cases had confirmed microbiological diagnoses (four Giardia, one Cryptosporidium). Wearing a wetsuit [adjusted relative risk (aRR) 6·96, 95% confidence interval (CI) 1·04–46·72] and swallowing water (aRR 1·42, 95% CI 1·03–1·97) were risk factors. Recent river-swimming (aRR 0·78, 95% CI 0·67–0·92) and age >40 years (aRR 0·83, 95% CI 0·70–0·98) were protective. Action to reduce risk of illness in future events is recommended, including clarification of oversight arrangements for future swims to ensure appropriate risk assessment and advice is provided.
We report aperture synthesis observations of the HCO+ and HCN J=1–0 molecular lines towards the Galactic center. These data complement existing HCN data and trace a dense molecular ring surrounding the ionized central 2 pc of the Galaxy. The new data are consistent with the model of a clumpy, almost complete ring which is inclined to the line of sight at 50 to 75 degrees. The same structure is seen in HCO+ and in HCN with the exception of an HCN feature at 60 to 100 km/s in the western part of the ring, which is not detected in HCO+ emission. The HCN and HCO+ are collisionally excited in clumps with densities around 10 cm and volume filling factor 1/3 to 1/30. H13 CN emission from the ring was detected at about 1/7 of the intensity of the HCN; the latter is optically thick and is mapping a combination of surface density and excitation temperature. The HCO+ emission shows deep absorption features associated with galactic structure along the line of sight. Absorption features corresponding to the 3 kpc arm, the inner disk and an expanding ring at −195 km/s can be seen in absorption against the Sgr A radio continuum.
During 1990 we surveyed the southern sky using a multi-beam receiver at frequencies of 4850 and 843 MHz. The half-power beamwidths were 4 and 25 arcmin respectively. The finished surveys cover the declination range between +10 and −90 degrees declination, essentially complete in right ascension, an area of 7.30 steradians. Preliminary analysis of the 4850 MHz data indicates that we will achieve a five sigma flux density limit of about 30 mJy. We estimate that we will find between 80 000 and 90 000 new sources above this limit. This is a revised version of the paper presented at the Regional Meeting by the first four authors; the surveys now have been completed.
We present preliminary results from a programme designed to produce deep images of radio source fields drawn from the Parkes 2700 MHz and Molongolo 408 MHz catalogues using the charge-coupled-device (CCD) camera system built at the Institute of Astronomy, Cambridge. The programme is directed at a search both for faint extensions and nebulosity around radio QSOs and BL Lac objects and for faint objects in otherwise empty radio source fields; a detailed examination of the morphology of selected radio galaxies is also included.
We question Newton’s inverse square law of universal gravitation in the light of recent, alternative formulations. In addition, we present numerical simulations of galaxy interactions which were used in an attempt to distinguish between an inverse square law and an inverse linear law. We conclude that an inverse linear relation is as compatible with the observational data on interacting galaxy systems as the inverse square law.
Several extragalactic HI surveys using a λ21 cm 13-beam focal plane array will begin in early 1997 using the Parkes 64 m telescope. These surveys are designed to detect efficiently nearby galaxies that have failed to be identified optically because of low optical surface brightness or high optical extinction. We discuss scientific and technical aspects of the multibeam receiver, including astronomical objectives, feed, receiver and correlator design and data acquisition. A comparison with other telescopes shows that the Parkes multibeam receiver has significant speed advantages for any large-area λ21 cm galaxy survey in the velocity range range 0–14000 km s−1.