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Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.
Landraces (including heritage varieties) are an important agrobiodiversity resource offering considerable value as a buffer against crop failures, as a crop for niche markets, and as a source of diversity for crop genetic improvement activities underpinning future food security. Home gardens are reservoirs of landrace diversity, but some of the accessions held in them are vulnerable or threatened with extinction. Those associated with seed saving networks have added security, for example, ca. 800 varieties are stored in the Heritage Seed Library (HSL) of Garden Organic, UK. In this study, Amplified Fragment Length Polymorphisms-based genetic analysis of accessions held in the HSL was used to (a) demonstrate the range of diversity in the collection, (b) characterize accessions to aid collection management and (c) promote broader use of the collection. In total, 171 accessions were included from six crops: Vicia faba L., Pisum sativum L., Daucus carota L., Cucumis sativus L., Lactuca sativa L. and Brassica oleracea L. var. acephala (DC.) Metzq. Average expected heterozygosity ranged from 0.18 to 0.28 in D. carota; 0.02–0.18 in P. sativum; 0.05–0.18 in L. sativa; 0.15–0.26 in B. oleracea var. acephala; 0.15–0.37 in C. sativus and 0.07–0.36 in V. faba. Genetic diversity and Fst values generally reflected the breeding system and cultivation history of the different crops. Comparisons of the diversity found in heritage varieties with that found in commercial varieties did not show a consistent pattern. Principal coordinates analysis and Unweighted Pair Group Method with Arithmetic Mean cluster analysis were used to identify four potential duplicate accession pairs.
During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds. Previously, we found attenuated vocalization-related auditory cortical suppression in psychosis and a similar trend in the psychosis risk syndrome. Here, we report data from the final sample of early illness schizophrenia patients (ESZ), individuals at clinical high risk for psychosis (CHR), and healthy controls (HC).
Event-related potentials (ERP) were recorded from ESZ (n = 84), CHR (n = 71), and HC (n = 103) participants during a vocalization paradigm. The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Age effects on N1 suppression (Talk–Listen), Talk N1, and Listen N1 were compared across groups. N1 measures were adjusted for normal aging before testing for group differences.
Both ESZ and CHR groups showed reduced Talk–Listen N1 suppression relative to HC, but did not differ from each other. Listen N1 was reduced in ESZ, but not in CHR, relative to HC. Deficient Talk–Listen N1 suppression was associated with greater unusual thought content in CHR individuals. N1 suppression increased with age in HC (12–36 years), and while CHR individuals showed a similar age-related increase, no such relationship was evident in ESZ.
Putative efference copy/corollary discharge-mediated auditory cortical suppression during vocalization is deficient in ESZ and precedes psychosis onset, particularly in CHR individuals with greater unusual thought content. Furthermore, this suppression increases from adolescence through early adulthood, likely reflecting the effects of normal brain maturation. This maturation effect is disrupted in ESZ, presumably due to countervailing illness effects.
Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities.
Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined.
HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior.
Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.
Background: Lung cancer screening and tobacco treatment for patients at high-risk for lung cancer may greatly reduce mortality from smoking, and there is an urgent need to improve smoking cessation therapies for this population.
Aims: The purpose of this study is to test the efficacy of two separate, sequential interventions to promote tobacco cessation/reduction compared to standard care in smokers considered high-risk for lung cancer.
Methods: The study will recruit 276 current smokers attending a lung cancer screening clinic or considered high-risk for lung cancer based on age and smoking history across two sites. Patients first will be randomized to either standard tobacco treatment (8 weeks of nicotine patch and five individual counselling sessions) or standard tobacco treatment plus personalized gain-framed messaging. At the 8-week visit, all patients will be re-randomized to receive biomarker feedback or no biomarker feedback. Repeated assessments during treatment will be used to evaluate changes in novel biomarkers: skin carotenoids, lung function, and plasma bilirubin that will be used for biomarker feedback. We hypothesize that personalized gain-framed messages and receiving biomarker feedback related to tobacco cessation/reduction will improve quit rates and prevent relapse compared to standard care. Primary outcomes include 7-day point-prevalence abstinence verified with expired carbon monoxide at 8 weeks and mean cigarettes per day in the past week at 6 months.
Conclusions: Study findings will inform the development of novel interventions for patients at risk for lung cancer to improve smoking cessation rates.
Phased Array Feed (PAF) technology is the next major advancement in radio astronomy in terms of combining high sensitivity and large field of view. The Focal L-band Array for the Green Bank Telescope (FLAG) is one of the most sensitive PAFs developed so far. It consists of 19 dual-polarization elements mounted on a prime focus dewar resulting in seven beams on the sky. Its unprecedented system temperature of ~17 K will lead to a 3 fold increase in pulsar survey speeds as compared to contemporary single pixel feeds. Early science observations were conducted in a recently concluded commissioning phase of the FLAG where we clearly demonstrated its science capabilities. We observed a selection of normal and millisecond pulsars and detected giant pulses from PSR B1937+21.
Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the ‘rich-club’, represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses.
We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks.
Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus.
This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD.
Introduction: The addition of computerized physician order entry (CPOE) to Emergency Departments in recent years has led to speculation over potential benefits and pitfalls. Recent studies have shown benefits to CPOE, though there lacks sufficient evidence on how it could change physician behaviour. Physician practices are known to be difficult to change, with getting evidence into daily practice being the main challenge of knowledge translation. Our study aims were to determine if well-designed electronic order sets for CPOE improved MD practices. Methods: The Calgary Zone Pain Management in the Emergency Department Working Group relied on a GRADE-based literature review for identifying best practices for analgesia and antiemetics, resulting in soft changes to the dedicated analgesia and antiemetic electronic order set noting working group preference, and emphasizing hydromorphone over morphine, as well as 4 mg ondansetron over 8 mg. The new electronic order set was started in the only Calgary Region order entry system on December 11th, 2014. Data was collected from July 2014 - May 2015. A Yates chi-squared analysis was completed on all orders in a category, as well as the subgroups of ED staff and residents, and orders placed using the new order set. Results: A total of 100460 orders were analyzed. The use of hydromorphone increased significantly across all 4 EDs. IV hydromorphone use increased (5.82% of all opioid orders up to 26.93%, P<0.0001) with a reciprocal decline in IV morphine (67.81% of all opioid orders down to 46.56%, P<0.0001). Similar effects were observed with ondansetron 4 mg IV orders increasing (1.37% of all ondansetron orders to 18.64%, P<0.0001) with a decrease in 8 mg dosing (15.75% of all ondansetron orders to 7.23%, P<0.0001). These results were replicated to a lesser degree in the non-ED staff and non-order set subgroups. Implementation of the new order set resulted in an increase of its use (37.64% of all opioid orders up to 49.29%, P<0.0001). Finally, a cost-savings analysis was completed showing a projected annual savings of $185,676.52 on medications alone. Conclusion: This data supports the manipulation of electronic order sets to help shape physician behaviour towards best practices. This provides another strong argument towards the benefits of CPOE, and can help maintain best practices in Emergency Medicine.
With the increasing use of complex quantitative models in applications throughout the financial world, model risk has become a major concern. Such risk is generated by the potential inaccuracy and inappropriate use of models in business applications, which can lead to substantial financial losses and reputational damage. In this paper, we deal with the management and measurement of model risk. First, a model risk framework is developed, adapting concepts such as risk appetite, monitoring, and mitigation to the particular case of model risk. The usefulness of such a framework for preventing losses associated with model risk is demonstrated through case studies. Second, we investigate the ways in which different ways of using and perceiving models within an organisation both lead to different model risks. We identify four distinct model cultures and argue that in conditions of deep model uncertainty, each of those cultures makes a valuable contribution to model risk governance. Thus, the space of legitimate challenges to models is expanded, such that, in addition to a technical critique, operational and commercial concerns are also addressed. Third, we discuss through the examples of proxy modelling, longevity risk, and investment advice, common methods and challenges for quantifying model risk. Difficulties arise in mapping model errors to actual financial impact. In the case of irreducible model uncertainty, it is necessary to employ a variety of measurement approaches, based on statistical inference, fitting multiple models, and stress and scenario analysis.
The ITRACK study explored the process and predictors of transition between Child and Adolescent Mental Health Services (CAMHS) and Adult Mental Health Services (AMHS) in the Republic of Ireland.
Following ethical approval, clinicians in each of Ireland’s four Health Service Executive (HSE) areas were contacted, informed about the study and were invited to participate. Clinicians identified all cases who had reached the transition boundary (i.e. upper age limit for that CAMHS team) between January and December 2010. Data were collected on clinical and socio-demographic details and factors that informed the decision to refer or not refer to the AMHS, and case notes were scrutinised to ascertain the extent of information exchanged between services during transition.
A total of 62 service users were identified as having crossed the transition boundary from nine CAMHS [HSE Dublin Mid-Leinster (n=40, 66%), HSE South (n=18, 30%), HSE West (n=2, 3%), HSE Dublin North (n=1, 2%)]. The most common diagnoses were attention deficit hyperactivity disorder (ADHD; n=19, 32%), mood disorders (n=16, 27%), psychosis (n=6, 10%) and eating disorders (n=5, 8%). Forty-seven (76%) of those identified were perceived by the CAMHS clinician to have an ‘on-going mental health service need’, and of these 15 (32%) were referred, 11 (23%) young people refused and 21 (45%) were not referred, with the majority (12, 57%) continuing with the CAMHS for more than a year beyond the transition boundary. Young people with psychosis were more likely to be referred [χ2 (2, 46)=8.96, p=0.02], and those with ADHD were less likely to be referred [χ2 (2, 45)=8.89, p=0.01]. Being prescribed medication was not associated with referral [χ2 (2, 45)=4.515, p=0.11]. In referred cases (n=15), there was documented evidence of consent in two cases (13.3%), inferred in another four (26.7%) and documented preparation for transition in eight (53.3%). Excellent written communication (100%) was not supported by face-to-face planning meetings (n=2, 13.3%), joint appointments (n=1, 6.7%) or telephone conversations (n=1, 6.7%) between corresponding clinicians.
Despite perceived on-going mental health (MH) service need, many young people are not being referred or are refusing referral to the AMHS, with those with ADHD being the most affected. CAMHS continue to offer on-going care past the transition boundary, which has resource implications. Further qualitative research is warranted to understand, in spite of perceived MH service need, the reason for non-referral by the CAMHS clinicians and refusal by the young person.
To compare the behaviour of sows and the physiological indices of their offspring in stall and group-housing systems, 28 sows were randomly distributed into two systems with 16 sows in stalls, and the other 12 sows were divided into three groups with four sows per pen. The area per sow in stalls and groups was 1.2 and 2.5 m2, respectively. Back fat depth of the sow was measured. Salivary cortisol concentration of the sows, colostrum composition and piglets’ serum biochemical indicators were evaluated. The behaviour of the sows, including agonistic behaviour, non-agonistic social behaviour, stereotypical behaviour and other behaviours at weeks 2, 9 and 14 of pregnancy were analysed. The results showed no differences in the back fat depth of sows. Colostrum protein, triglyceride, triiodothyronine, thyroxine and prolactin concentrations in the whey also demonstrated no significant differences between the two housing systems. Salivary cortisol concentration was significantly higher in the sows housed in groups than the sows in stalls. The concentrations of serum total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly higher in the offspring of sows housed in groups (P=0.006 and 0.005, respectively). The GLM procedure for repeated measures analysis showed the frequency of drinking, and non-agonistic social behaviour was significantly higher in the sows housed in groups than the sows in stalls; yet the frequency of agonistic and sham chewing demonstrated the opposite direction. The duration of standing was significantly longer in the sows housed in groups, but the sitting and stereotypical behaviour duration were significantly shorter compared with the sows in stalls. These results indicated that group housing has no obvious influence on the colostrum composition of sows; however, it was better for sows to express their non-agonistic social behaviour and reduce the frequency of agonistic behaviour and stereotypical behaviour. Meanwhile, group housing during gestation significantly increased serum total cholesterol and LDL cholesterol of offspring.
A survey of the Milky Way disk and the Magellanic System at the wavelengths of the 21-cm atomic hydrogen (H i) line and three 18-cm lines of the OH molecule will be carried out with the Australian Square Kilometre Array Pathfinder telescope. The survey will study the distribution of H i emission and absorption with unprecedented angular and velocity resolution, as well as molecular line thermal emission, absorption, and maser lines. The area to be covered includes the Galactic plane (|b| < 10°) at all declinations south of δ = +40°, spanning longitudes 167° through 360°to 79° at b = 0°, plus the entire area of the Magellanic Stream and Clouds, a total of 13 020 deg2. The brightness temperature sensitivity will be very good, typically σT≃ 1 K at resolution 30 arcsec and 1 km s−1. The survey has a wide spectrum of scientific goals, from studies of galaxy evolution to star formation, with particular contributions to understanding stellar wind kinematics, the thermal phases of the interstellar medium, the interaction between gas in the disk and halo, and the dynamical and thermal states of gas at various positions along the Magellanic Stream.
Under- and over-nutrition during gestation may influence fetal hypothalamic development resulting in individuals predisposed to adverse health effects. This study examined fetuses from obese and control ewes to determine whether dam obesity alters hypothalamic expression of fetal appetite regulatory genes. A second objective was to contrast the expression of appetite regulatory genes in ewes that become the most obese to those that remained in moderate body condition on the same energy-rich diet. Multiparous, western white-faced ewes were weighed and individually fed 100% (control) or 150% (obese) of National Research Council requirements from day 60 before mating until day 75 of gestation. At day 75 of gestation, fetuses were collected and weighed. Hypothalamic tissue from fetal lambs and dams was collected and frozen for mRNA extraction. Dam obesity (P ⩾ 0.16), fetal sex (P ⩾ 0.44) or their interaction (P ⩾ 0.42) did not affect the relative expression of fetal hypothalamic regulators of appetite, including neuropeptide Y, agouti-related protein, pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript and receptors for leptin. Maternal obesity at day 75 of gestation in ewes did not affect developmental mechanisms responsible for the expression of fetal appetite regulatory genes and would not be expected to predispose offspring to adult-onset obesity through disrupted appetite regulation at this developmental time point. In the ewe, appetite regulatory genes did not differ (P > 0.20) with ewe adiposity; however, expression of estrogen receptor α, but not β (P = 0.37), in the medial basal hypothalamus was greater (P = 0.04) in obese than in control ewes.