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Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer’s disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4−).
Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51–60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy.
In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory.
Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.
Analysis of food webs is important for defining functional components of ecosystems, but dietary data are often difficult to obtain and coarsely characterised. We compared three methods of rainbow trout (Oncorhynchus mykiss (Walbaum); Salmoniformes: Salmonidae) and prickly sculpin (Cottus asper Richardson; Scorpaeniformes: Cottidae) gut content analysis: traditional morphological taxonomy of prey items, genetic sequencing of individual prey items, and next-generation sequencing of homogenised gut contents. Prey analysis of invertebrates by morphological identification allowed order-level classifications and produced ecologically important count and mass data. Sequencing individual specimens provided greater taxonomic resolution, while next-generation sequencing of stomach contents revealed more prey diversity in the diets of both fish species as it was possible to detect prey that were degraded beyond visual recognition. Both fish species exhibited generalist feeding characteristics; however, terrestrial Insecta were a large diet component for rainbow trout. This study demonstrates an efficient approach for prey analysis using molecular techniques that complement traditional taxonomy.
Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
Maternal undernutrition decreases sperm production in male offspring, possibly through insulin-like growth factor (IGF-I). To test this hypothesis, we fed pregnant Wistar rats ad libitum with a standard diet (CONTROL) or fed 50% of CONTROL intake, either throughout pregnancy (UNP), lactation (UNL, or both (UNPL). After weaning, male offspring (n = 10 per treatment) were fed a standard diet until postnatal day 160, when testes process for histological and molecular analyses. IGF-I immunostaining area and intensity in the testis were greater (P = 0.003) in the UNPL group compared to CONTROL, but lower in the UNP group (P < 0.0001). Levels of IGF-I receptor transcript were lower in the UNPL and UNL groups, compared to CONTROL. There were more Ki-67-positive germ and Sertoli cells, in all underfed groups than in CONTROL. Compared to CONTROL, frequency of spermatogenic cycle stage VII was lower in all underfed groups, and seminiferous tubule diameter was smaller in UNP and UNPL. Plasma FSH concentrations were greater in UNP male offspring compared to all groups (P = 0.05), whereas inhibin B concentrations were greater in UNP (P = 0.01) and UNL (P = 0.003) than in CONTROL or UNPL. Thus, prenatal undernutrition leads to a decrease in testicular IGF-I levels, whereas of pre- and postnatal undernutrition increased testicular IGF-I levels and decreased amounts of IGF-I receptor mRNA in adult offspring. We conclude that maternal undernutrition during pregnancy and lactation leads to long-lasting effects on adult male offspring testicular morphology, spermatogenesis, and IGF-I testicular system.
Dimensional models of psychopathology are increasingly common and there is evidence for the existence of a general dimension of psychopathology (‘p’). The existing literature presents two ways to model p: as a bifactor or as a higher-order dimension. Bifactor models typically fit sample data better than higher-order models, and are often selected as better fitting alternatives but there are reasons to be cautious of such an approach to model selection. In this study the bifactor and higher-order models of p were compared in relation to associations with established risk variables for mental illness.
A trauma exposed community sample from the United Kingdom (N = 1051) completed self-report measures of 49 symptoms of psychopathology.
A higher-order model with four first-order dimensions (Fear, Distress, Externalising and Thought Disorder) and a higher-order p dimension provided satisfactory model fit, and a bifactor representation provided superior model fit. Bifactor p and higher-order p were highly correlated (r = 0.97) indicating that both parametrisations produce near equivalent general dimensions of psychopathology. Latent variable models including predictor variables showed that the risk variables explained more variance in higher-order p than bifactor p. The higher-order model produced more interpretable associations for the first-order/specific dimensions compared to the bifactor model.
The higher-order representation of p, as described in the Hierarchical Taxonomy of Psychopathology, appears to be a more appropriate way to conceptualise the general dimension of psychopathology than the bifactor approach. The research and clinical implications of these discrepant ways of modelling p are discussed.
We describe an ultra-wide-bandwidth, low-frequency receiver recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (
), the system temperature is approximately 22 K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver, including its astronomical objectives, as well as the feed, receiver, digitiser, and signal processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified, including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration, and timing stability.
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the hyperkinetic movements of motor and phonic tics manifested in young age. Currently approved treatments in the United States are antipsychotics: haloperidol, pimozide, and aripiprazole, which are associated with serious side effects, including tardive dyskinesia (TD). Deutetrabenazine, a vesicular monoamine transporter type 2 (VMAT2) inhibitor, was approved in 2017 by the US FDA for the treatment of chorea associated with Huntington’s disease and TD. Three ongoing studies (Alternatives for Reducing Tics in TS [ARTISTS]) are evaluating the efficacy, safety, and tolerability of deutetrabenazine in reducing tics in TS in children and adolescents (age 6-16 years).
ARTISTS 1, a phase 2/3, response-driven, dose-titration, placebo-controlled study, randomizes patients (N=116) 1:1 to deutetrabenazine or placebo for 12 weeks. ARTISTS 2, a phase 3, fixed-dose study, randomizes patients (N=150) 1:1:1 to deutetrabenazine high or low dose, or placebo for 8 weeks. The primary efficacy outcome in these pivotal studies is change from baseline to end of treatment in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Additional efficacy endpoints and safety/tolerability are also evaluated. ARTISTS is a 56-week, open-label, single-arm, long-term safety/tolerability study in patients who have successfully completed either ARTISTS 1 or ARTISTS 2.
Not available yet.
TS can have potentially long-term life impact, and there remains unmet medical need for effective and well-tolerated treatments. Three ARTISTS studies will evaluate the efficacy, safety, and tolerability of deutetrabenazine in patients with tics in TS.
The studies are sponsored by Teva Pharmaceuticals and operationalized by Teva’s development partner, Nuvelution TS Pharma INC.
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Cultures around the world are converging as populations become more connected. On the one hand this increased connectedness can promote the recombination of existing cultural practices to generate new ones, but on the other it may lead to the replacement of traditional practices and global WEIRDing. Here we examine the process and causes of changes in cultural traits concerning wild plant knowledge in Mbendjele BaYaka hunter–gatherers from Congo. Our results show that the BaYaka who were born in town reported knowing and using fewer plants than the BaYaka who were born in forest camps. Plant uses lost in the town-born BaYaka related to medicine. Unlike the forest-born participants, the town-born BaYaka preferred Western medicine over traditional practices, suggesting that the observed decline of plant knowledge and use is the result of replacement of cultural practices with the new products of cumulative culture.
Crack initiation in zirconium alloys is an important issue for the safety of water-cooled fission reactors. Zirconium hydrides that precipitate in service are potential crack nucleation sites. In this work, the deformation and cracking of zirconium hydrides was studied during room temperature deformation of a Zircaloy-4 tensile sample up to fracture. The sample contained a hydrogen concentration of 100 ± 20 ppm. The main aims of this study were to better understand the mechanisms behind the hydride fracture in a polycrystalline matrix, and to identify at which point in the deformation of the Zr matrix the first hydrides break. Cracks thus nucleated may coalesce and propagate through the hydrided Zr-alloy. Scanning electron microscopy (SEM) images of a number of hydrides, both intergranular and intragranular, were taken at discrete increments of deformation during an interrupted tensile test. The results show that cracks in hydrides tend to always occur normal to the applied load, signalling the importance of the external stress. However, evidence is also provided to support the hypothesis that internal stresses generated by microstructural constraints may lead to the fracture of some intergranular hydrides.
The influence of a horizontal wall on the evolution of the long-wave instability in equal strength counter-rotating vortex pairs is studied with direct numerical simulation. The two vortices descend under mutual induction and interact with a ground plane, as would aircraft trailing vortices in ground effect. Both the linear and nonlinear development of the pair is studied for three initial heights above the wall, representative of three modes of interaction identified by experiment. A study of two vortex core sizes over a range of Reynolds numbers (
$1000\leqslant Re\leqslant 2500$
) is used to verify parameter independence. The vortex system undergoes complex topological changes in the presence of a wall, with the separation of wall generated vorticity into hairpin-like vortex tongues and axial flow development in the primary pair. The secondary structures are rotated and stretched around the primary vortices, strongly influencing the resultant flow evolution and are comparable with those observed for oblique ring–wall interaction. Of the three modes, the small-amplitude mode shows the formation of four principal tongues per long wavelength of the Crow instability, with the secondary vortex remaining connected. The large-amplitude mode undergoes a re-connective process to form two non-planar secondary vortex structures per wavelength, and a simulation of the large ring mode in its first formation develops six tongues per wavelength. These secondary structures ‘rebound’ from the wall and interact at the symmetry plane prior to dissipation, governing the bending, stretching and trajectory of the primary vortex pair.
The SDG14 targets cover more than 70 per cent of the planet, including the coastal zone, where a range of forest resources are located. In this chapter we investigate the potential negative consequences of SDG14 on forest resources, using the example of coastal mangrove forests. SDG14 is likely to have negative impacts on forest resources because it focuses primarily on fisheries, potentially excluding other coastal natural resources. Many SDG14 targets are also more appropriate for oceanic areas, rather than the complex governance arrangements found in the coastal zone. This means that coastal forests such as mangroves may be forgotten, inadvertently impacted or fall through the ‘policy gap’ between terrestrial and marine legislation or between different levels of governance. This also has impacts on the human populations that rely on the ecosystem services provided by mangrove forests, and has implications for environmental justice. To minimise the impacts of SDG14 on mangrove forests and associated coastal communities, we recommend that SDG14 indicators should be broadened to encompass other coastal and oceanic natural resources, decentralisation of coastal zone governance should continue to be encouraged, and management regimes should include coastal communities and enshrine principles of environmental justice.
This paper examines the misalignment between modern human society and certain male phenotypes, a misalignment that has been highlighted and explored in great detail in the work of Tom Dishion. We begin by briefly enumerating the ongoing developmental difficulties of many boys and young men and how these difficulties affect them and those around them. We then suggest that the qualities that have been advantageous for men and their families in our earlier evolution but that are often no longer functional in modern society are a source of these problems. Finally, we provide a brief review of prevention programs that can contribute to preventing this type of problematic development and eliciting more prosocial behavior from at-risk boys and men. We conclude with an overview of research and policy priorities that could contribute to reducing the proportion of boys and young men who experience developmental difficulties in making their way in the world.
To promote good governance, citizens can inform governments directly and routinely about the implementation of policies and the delivery of public services. Yet citizens lack incentives to provide information when they do not expect governments to be responsive, and citizen disengagement in turn often prevents governments from providing public goods effectively. In two field experiments, we studied potential remedies to this dilemma related to solid waste services in Uganda. We randomly assigned reporters to be recruited by community nomination and to be recognized by community leaders in an attempt to select for and motivate information sharing. We also randomly assigned reporters to hear from the government about how their reports were used to make real improvements to waste services. Community nominations and public announcements did not increase reporting. However, responsiveness boosted participation over several months for reporters who had been recruited earliest and had been reporting longest, highlighting the critical role of timely government responsiveness in sustaining information flows from citizens.
Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.
We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.
We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.
Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.