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Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.
To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.
We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.
Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015–0.017), with carriers being 7.5–7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.
This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.
Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings.
To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank.
We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups.
Carrier status was associated with reduced surface area (β = −0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance).
Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.
Iron deficiency is common in pregnant and lactating women and is associated with reduced cognitive development of the offspring. Since iron affects lipid metabolism, the availability of fatty acids, particularly the polyunsaturated fatty acids required for early neural development, was investigated in the offspring of female rats fed iron-deficient diets during gestation and lactation. Subsequent to the dams giving birth, one group of iron-deficient dams was recuperated by feeding an iron-replete diet. Dams and neonates were killed on postnatal days 1, 3 and 10, and the fatty acid composition of brain and stomach contents was assessed by gas chromatography. Changes in the fatty acid profile on day 3 became more pronounced on day 10 with a decrease in the proportion of saturated fatty acids and a compensatory increase in monounsaturated fatty acids. Long-chain polyunsaturated fatty acids in the n-6 family were reduced, but there was no change in the n-3 family. The fatty acid profiles of neonatal brain and stomach contents were similar, suggesting that the change in milk composition may be related to the changes in the neonatal brain. When the dams were fed an iron-sufficient diet at birth, the effects of iron deficiency on the fatty acid composition of lipids in both dam’s milk and neonates’ brains were reduced. This study showed an interaction between maternal iron status and fatty acid composition of the offspring’s brain and suggests that these effects can be reduced by iron repletion of the dam’s diet at birth.
Xpert MTB/RIF (Xpert) is the preferred first-line test for all persons with tuberculosis (TB) symptoms in South Africa in line with a diagnostic algorithm. This study evaluates pre- and post-implementation trends in diagnostic practices for drug-sensitive, pulmonary TB in adults in an operational setting, following the introduction of the Xpert-based algorithm. We retrospectively analysed data from the national TB database for Greater Tzaneen sub-district, Limpopo Province. Trends in a number of cases, diagnosis and outcome and characteristics associated with death are reported. A total of 8407 cases were treated from 2008 until 2015, with annual cases registered decreasing by 31·7% over that time period (from 1251 to 855 per year). After implementation of Xpert, 69·9% of cases were diagnosed by Xpert, 29·4% clinically, 0·6% by smear microscopy and 0·1% by culture. Cases with a recorded microbiological test increased from 76·2% to 96·4%. Cases started on treatment without confirmation, but with a negative microbiological test increased from 7·1% to 25·7%. Case fatality decreased from 15·0% to 9·8%, remaining consistently higher in empirically treated groups, regardless of HIV status. Implementation of the algorithm coincided with a reduced number of TB cases treated and improved coverage of microbiological testing; however, a substantial proportion of cases continued to start treatment empirically.
Mitochondrial dysfunction and resulting changes in adiposity have been observed in the offspring of animals fed a high fat (HF) diet. As iron is an important component of the mitochondria, we have studied the offspring of female rats fed complete (Con) or iron-deficient (FeD) rations for the duration of gestation to test for similar effects. The FeD offspring were ~12% smaller at weaning and remained so because of a persistent reduction in lean tissue mass. The offspring were fed a complete (stock) diet until 52 weeks of age after which some animals from each litter were fed a HF diet for a further 12 weeks. The HF diet increased body fat when compared with animals fed the stock diet, however, prenatal iron deficiency did not change the ratio of fat:lean in either the stock or HF diet groups. The HF diet caused triglyceride to accumulate in the liver, however, there was no effect of prenatal iron deficiency. The activity of the mitochondrial electron transport complexes was similar in all groups including those challenged with a HF diet. HF feeding increased the number of copies of mitochondrial DNA and the prevalence of the D-loop mutation, however, neither parameter was affected by prenatal iron deficiency. This study shows that the effects of prenatal iron deficiency differ from other models in that there is no persistent effect on hepatic mitochondria in aged animals exposed to an increased metabolic load.
Motorcycle helmet laws are perceived to infringe upon individual rights even though they reduce mortality and health care costs. We describe proposed helmet legislation that protects individual rights and provides incentives for helmet use through a differential motorcycle registration fee that requires higher fees for those who wish to ride without a helmet.
Euclid is a Europe-led cosmology space mission dedicated to a visible and near infrared survey of the entire extra-galactic sky. Its purpose is to deepen our knowledge of the dark content of our Universe. After an overview of the Euclid mission and science, this contribution describes how the community is getting organized to face the data analysis challenges, both in software development and in operational data processing matters. It ends with a more specific account of some of the main contributions of the Swiss Science Data Center (SDC-CH).
Increasing recognition of the extent to which nitrous oxide (N2O) contributes to climate change has resulted in greater demand to improve quantification of N2O emissions, identify emission sources and suggest mitigation options. Agriculture is by far the largest source and grasslands, occupying c. 0·22 of European agricultural land, are a major land-use within this sector. The application of mineral fertilizers to optimize pasture yields is a major source of N2O and with increasing pressure to increase agricultural productivity, options to quantify and reduce emissions whilst maintaining sufficient grassland for a given intensity of production are required. Identification of the source and extent of emissions will help to improve reporting in national inventories, with the most common approach using the IPCC emission factor (EF) default, where 0·01 of added nitrogen fertilizer is assumed to be emitted directly as N2O. The current experiment aimed to establish the suitability of applying this EF to fertilized Scottish grasslands and to identify variation in the EF depending on the application rate of ammonium nitrate (AN). Mitigation options to reduce N2O emissions were also investigated, including the use of urea fertilizer in place of AN, addition of a nitrification inhibitor dicyandiamide (DCD) and application of AN in smaller, more frequent doses. Nitrous oxide emissions were measured from a cut grassland in south-west Scotland from March 2011 to March 2012. Grass yield was also measured to establish the impact of mitigation options on grass production, along with soil and environmental variables to improve understanding of the controls on N2O emissions. A monotonic increase in annual cumulative N2O emissions was observed with increasing AN application rate. Emission factors ranging from 1·06–1·34% were measured for AN application rates between 80 and 320 kg N/ha, with a mean of 1·19%. A lack of any significant difference between these EFs indicates that use of a uniform EF is suitable over these application rates. The mean EF of 1·19% exceeds the IPCC default 1%, suggesting that use of the default value may underestimate emissions of AN-fertilizer-induced N2O loss from Scottish grasslands. The increase in emissions beyond an application rate of 320 kg N/ha produced an EF of 1·74%, significantly different to that from lower application rates and much greater than the 1% default. An EF of 0·89% for urea fertilizer and 0·59% for urea with DCD suggests that N2O quantification using the IPCC default EF will overestimate emissions for grasslands where these fertilizers are applied. Large rainfall shortly after fertilizer application appears to be the main trigger for N2O emissions, thus applicability of the 1% EF could vary and depend on the weather conditions at the time of fertilizer application.
Depressive symptoms are prominent psychopathological features of Huntington's disease (HD), making a negative impact on social functioning and well-being.
We compared the frequencies of a history of depression, previous suicide attempts and current subthreshold depression between 61 early-stage HD participants and 40 matched controls. The HD group was then split based on the overall HD group's median Hospital Anxiety and Depression Scale-depression score into a group of 30 non-depressed participants (mean 0.8, s.d. = 0.7) and a group of 31 participants with subthreshold depressive symptoms (mean 7.3, s.d. = 3.5) to explore the neuroanatomy underlying subthreshold depressive symptoms in HD using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI).
Frequencies of history of depression, previous suicide attempts or current subthreshold depressive symptoms were higher in HD than in controls. The severity of current depressive symptoms was also higher in HD, but not associated with the severity of HD motor signs or disease burden. Compared with the non-depressed HD group DTI revealed lower fractional anisotropy (FA) values in the frontal cortex, anterior cingulate cortex, insula and cerebellum of the HD group with subthreshold depressive symptoms. In contrast, VBM measures were similar in both HD groups. A history of depression, the severity of HD motor signs or disease burden did not correlate with FA values of these regions.
Current subthreshold depressive symptoms in early HD are associated with microstructural changes – without concomitant brain volume loss – in brain regions known to be involved in major depressive disorder, but not those typically associated with HD pathology.
This paper describes a preliminary investigation of the extent to which the normalised difference vegetation index (NDVI), derived from satellite optical imagery, can indicate the extent of damage to upland tundra (fruticose lichen and dwarf shrub) vegetation. We combine the results of a previously reported classification of Landsat multispectral scanner imagery from Kol'skiy Poluostrov, Russia, with field measurements of the biomass and spectral reflectance of tundra vegetation. The results show that the NDVI is not strongly influenced by biomass, but that differences in species composition and ground cover are significant. Other workers have concluded that vegetation indices are not useful for boreal forests. It is therefore suggested that the use of the NDVI by itself as an indicator of the state of disturbed vegetation in Arctic regions is not recommended.
Cognitive behaviour therapy (CBT) is widely used to treat depression. However, CBT is not always available to patients because of a shortage of therapists and long waiting times. Computerized CBT (CCBT) is one of several alternatives currently available to treat patients with depression. Evidence of its clinical effectiveness has led to programs being used increasingly within the UK and elsewhere. However, little information is available regarding the acceptability of CCBT to patients.
A systematic review of sources of information on acceptability to patients of CCBT for depression.
Sources of information on acceptability included: recruitment rates, patient drop-outs and patient-completed questionnaires. We identified 16 studies of CCBT for the treatment of depression that provided at least some information on these sources. Limited information was provided on patient take-up rates and recruitment methods. Drop-out rates were comparable to other forms of treatment. Take-up rates, when reported, were much lower. Six of the 16 studies included specific questions on patient acceptability or satisfaction although information was only provided for those who had completed treatment. Several studies have reported positive expectancies and high satisfaction in routine care CCBT services for those completing treatment.
Trials of CCBT should include more detailed information on patient recruitment methods, drop-out rates and reasons for dropping out. It is important that well-designed surveys and qualitative studies are included alongside trials to determine levels and determinants of patient acceptability.
The main purpose is to characterise continuous maps that are n-branched coverings in terms of induced maps on the rings of functions. The special properties of Frobenius n-homomorphisms between two function spaces that correspond to n-branched coverings are determined completely. Several equivalent definitions of a Frobenius n-homomorphism are compared and some of their properties are proved. An axiomatic treatment of n-transfers is given in general and properties of n-branched coverings are studied and compared with those of regular coverings.
Hubertus J. E. Beaumont, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand,
Stefanie M. Gehrig, Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK,
Rees Kassen, Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, 150 Louis Pasteur, Ottawa, ON, K1N 6N5, Canada,
Christopher G. Knight, School of Chemistry, University of Manchester, Faraday Building, Box 88, Sackville St, Manchester M60 1QD, UK,
Jacob Malone, Division of Molecular Microbiology, Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland,
Andrew J. Spiers, Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK,
Paul B. Rainey, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand; Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK
The majority of phenotypic and ecological diversity on the planet has arisen during successive adaptive radiations, that is, periods in which a single lineage diverges rapidly to generate multiple niche-specialist types. Microbiologists tend not to think of bacteria as undergoing adaptive radiation, but there is no reason to exclude them from this general statement – in fact, rapid generation times and large population sizes suggest that bacteria may be particularly prone to bouts of rapid ecological diversification. Indeed, there is evidence from both experimental bacterial populations (Korona et al., 1994; Rainey & Travisano, 1998) and natural populations (Stahl et al., 2002). This being so, insight into the evolutionary emergence of diversity requires an understanding of the causes of adaptive radiation.
The causes of adaptive radiation are many and complex, but at a fundamental level there are just two: one genetic and the other ecological. Put simply, heritable phenotypic variation arises primarily by mutation, while selection working via various ecological processes shapes this variation into the patterns of phenotypic diversity evident in the world around us.
The ecological causes of adaptive radiation are embodied in theory that stems largely from Darwin's insights into the workings of evolutionary change (Darwin, 1890), but owes much to developments in the 1940s and 1950s attributable to Lack (1947), Dobzhansky (1951) and Simpson (1953). Recent work has seen a reformulation of the primary concepts (Schluter, 2000).
The class of co-context-free groups is studied. A co-context-free group is defined as one whose co-word problem (the complement of its word problem) is context-free. This class is larger than the subclass of context-free groups, being closed under the taking of finite direct products, restricted standard wreath products with context-free top groups, and passing to finitely generated subgroups and finite index overgroups. No other examples of co-context-free groups are known. It is proved that the only examples amongst polycyclic groups or the Baumslag–Solitar groups are virtually abelian. This is done by proving that languages with certain purely arithmetical properties cannot be context-free; this result may be of independent interest.
Background and objective: To investigate the clinical application of a mathematical model of pulmonary gas exchange, which ascribes hypoxaemia to shunt and ventilation/perfusion mismatch. Ventilation/perfusion mismatch is quantified by ΔPO2, which is the drop in oxygen pressure from alveoli to lung capillaries. Shunt and ΔPO2 were used to describe changes in oxygenation after coronary artery bypass grafting.
Methods: Fourteen patients were studied 2–4 h after surgery and on postoperative days 2, 3 and 7. On each occasion inspired oxygen fraction was changed in four to six steps to obtain arterial oxygen saturation (SaO2) in the range of 90–100%, enabling construction of FeO2/SaO2 curves. Measurements of ventilation, circulation and oxygenation were entered in a previously described mathematical model of pulmonary gas exchange.
Results: We found that oxygenation was most impaired 3 days after surgery. By fitting the mathematical model to the FeO2/SaO2 curve, we found that shunt remained constant throughout the study period. However, ΔPO2 increased from 0.5 kPa (median, range 0–3.8) 2–4 h after surgery, to 3.2 kPa (range 1.2–6.4, P < 0.05) on day 2, and to 4.0 kPa (range 1.2–8.3) on day 3. On day 7, ΔPO2 decreased to 2.2 kPa (range 0–3.5, P < 0.05).
Conclusions: Ventilation/perfusion mismatch (ΔPO2), rather than shunt, explains the changes in postoperative oxygenation. The model of pulmonary gas exchange may serve as a useful and potentially non-invasive clinical tool for monitoring patients at risk of postoperative hypoxaemia.
Background. The long-term use of methamphetamine (MAMP) can result in psychosis but it is not clear why some individuals develop psychotic symptoms, while others use MAMP regularly over long periods and remain unscathed. We set out to characterize MAMP users and to examine the relationship of pre-morbid personality, pre-morbid social function and other psychiatric disorders to MAMP psychosis.
Method. Four hundred and forty-five amphetamine users were recruited from a psychiatric hospital and a detention centre in Taipei, and were assessed with the Diagnostic Interview for Genetic Studies (DIGS). Their parents were interviewed with the Premorbid Schizoid and Schizotypal Traits (PSST) and the Premorbid Social Adjustment (PSA) schedules. Pre-morbid characteristics and psychiatric co-morbidity were compared between the MAMP users with a lifetime diagnosis of MAMP psychosis and those without.
Results. The MAMP users with psychosis presented a clinical picture which mimicked the positive symptoms of schizophrenia: 85% had auditory hallucinations; 71% persecutory delusions; 63% delusions of reference. Compared with their non-psychotic counterparts, these MAMP users were younger at first MAMP use, used larger amounts of MAMP, had a significantly higher mean PSST score, and higher rates of major depressive disorder, alcohol dependence and antisocial personality disorder.
Conclusions. Earlier and larger use of MAMP was associated with increased risk of psychosis. Our data are also compatible with the view that pre-morbid schizoid/schizotypal personality predisposes MAMP users to develop psychosis, and that the greater the personality vulnerability, the longer the psychosis will persist.