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Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood.
Aims
Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research.
Method
As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant.
Results
We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation.
Conclusions
DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.
Shunt-related adverse events are frequent in infants after modified Blalock–Taussig despite use of acetylsalicylic acid prophylaxis. A higher incidence of acetylsalicylic acid-resistance and sub-therapeutic acetylsalicylic acid levels has been reported in infants. We evaluated whether using high-dose acetylsalicylic acid can decrease shunt-related adverse events in infants after modified Blalock–Taussig.
Methods
In this single-centre retrospective cohort study, we included infants ⩽1-year-old who underwent modified Blalock–Taussig placement and received acetylsalicylic acid in the ICU. We defined acetylsalicylic acid treatment groups as standard dose (⩽7 mg/kg/day) and high dose (⩾8 mg/kg/day) based on the initiating dose.
Results
There were 34 infants in each group. Both groups were similar in age, gender, cardiac defect type, ICU length of stay, and time interval to second stage or definitive repair. Shunt interventions (18 versus 32%, p=0.16), shunt thrombosis (14 versus 17%, p=0.74), and mortality (9 versus 12%, p=0.65) were not significantly different between groups. On multiple logistic regression analysis, single-ventricle morphology (odds ratio 5.2, 95% confidence interval of 1.2–23, p=0.03) and post-operative red blood cells transfusion ⩾24 hours [odds ratio 15, confidence interval of (3–71), p<0.01] were associated with shunt-related adverse events. High-dose acetylsalicylic acid treatment [odds ratio 2.6, confidence interval of (0.7–10), p=0.16] was not associated with decrease in these events.
Conclusions
High-dose acetylsalicylic acid may not be sufficient in reducing shunt-related adverse events in infants after modified Blalock–Taussig. Post-operative red blood cells transfusion may be a modifiable risk factor for these events. A randomised trial is needed to determine appropriate acetylsalicylic acid dosing in infants with modified Blalock–Taussig.
The porcine small intestinal extracellular matrix reportedly has the potential to differentiate into viable myocardial cells. When used in tetralogy of Fallot repair, it may improve right ventricular function. We evaluated right ventricular function after repair of tetralogy of Fallot with extracellular matrix versus bovine pericardium.
Method
Subjects with non-transannular repair of tetralogy of Fallot with at least 1 year of follow-up were selected. The extracellular matrix and bovine pericardium groups were compared. We used three-dimensional right ventricular ejection fraction, right ventricle global longitudinal strain, and tricuspid annular plane systolic excursion to assess right ventricular function.
Results
The extracellular matrix group had 11 patients, whereas the bovine pericardium group had 10 patients. No differences between the groups were found regarding sex ratio, age at surgery, and cardiopulmonary bypass time. The follow-up period was 28±12.6 months in the extracellular matrix group and 50.05±17.6 months in the bovine pericardium group (p=0.001). The mean three-dimensional right ventricular ejection fraction (55.7±5.0% versus 55.3±5.2%, p=0.73), right ventricular global longitudinal strain (−18.5±3.0% versus −18.0±2.2%, p=0.44), and tricuspid annular plane systolic excursions (1.59±0.16 versus 1.59±0.2, p=0.93) were similar in the extracellular matrix group and in the bovine pericardium group, respectively. Right ventricular global longitudinal strain in healthy children is reported at −29±3% in literature.
Conclusion
In a small cohort of the patients undergoing non-transannular repair of tetralogy of Fallot, there was no significant difference in right ventricular function between groups having extracellular matrix versus bovine pericardium patches followed-up for more than 1 year. Lower right ventricular longitudinal strain noted in both the groups compared to healthy children.
Genetically similar nulliparous Polled Hereford heifers from a closed pedigree herd were used to evaluate the effects of dietary protein during the first and second trimester of gestation upon foetal, placental and postnatal growth. Heifers were randomly allocated into two groups at 35 days after artificial insemination (35 days post conception (dpc)) to a single bull and fed high (15.7% CP) or low (5.9% CP) protein in the first trimester (T1). At 90 dpc, half of each nutritional treatment group changed to a high- or low-protein diet for the second trimester until 180 dpc (T2). High protein intake in the second trimester increased birth weight in females (P=0.05), but there was no effect of treatment upon birth weight when taken over both sexes. Biparietal diameter was significantly increased by high protein in the second trimester with the effect being greater in the female (P=0.02), but also significant overall (P=0.05). Placental weight was positively correlated with birth weight, fibroblast volume and relative blood vessel volume (P<0.05). Placental fibroblast density was increased and trophoblast volume decreased in the high-protein first trimester treatment group (P<0.05). There was a trend for placental weight to be increased by high protein in the second trimester (P=0.06). Calves from heifers fed the high-protein treatment in the second trimester weighed significantly more on all occasions preweaning (at 1 month (P=0.0004), 2 months (P=0.006), 3 months (P=0.002), 4 months (P=0.01), 5 months (P=0.03), 6 months (P=0.001)), and grew at a faster rate over the 6-month period. By 6 months of age, the calves from heifers fed high nutrition in the second trimester weighed 33 kg heavier than those fed the low diet in the second trimester. These results suggest that dietary protein in early pregnancy alters the development of the bovine placenta and calf growth to weaning.
Left thoracic sympathectomy has been shown to be an effective treatment for adults with long QT syndrome who are refractory to medical therapy. We report the successful use of left thoracic sympathectomy for the management of a 10-week-old premature baby with long QT syndrome and heart failure from a large ventricular septal defect and patent ductus arteriosus.
To determine the independent association between diabetes and surgical site infection (SSI) across multiple surgical procedures.
DESIGN
Systematic review and meta-analysis.
METHODS
Studies indexed in PubMed published between December 1985 and through July 2015 were identified through the search terms “risk factors” or “glucose” and “surgical site infection.” A total of 3,631 abstracts were identified through the initial search terms. Full texts were reviewed for 522 articles. Of these, 94 articles met the criteria for inclusion. Standardized data collection forms were used to extract study-specific estimates for diabetes, blood glucose levels, and body mass index (BMI). A random-effects meta-analysis was used to generate pooled estimates, and meta-regression was used to evaluate specific hypothesized sources of heterogeneity.
RESULTS
The primary outcome was SSI, as defined by the Centers for Disease Control and Prevention surveillance criteria. The overall effect size for the association between diabetes and SSI was odds ratio (OR)=1.53 (95% predictive interval [PI], 1.11–2.12; I2, 57.2%). SSI class, study design, or patient BMI did not significantly impact study results in a meta-regression model. The association was higher for cardiac surgery 2.03 (95% PI, 1.13–4.05) compared with surgeries of other types (P=.001).
CONCLUSIONS
These results support the consideration of diabetes as an independent risk factor for SSIs for multiple surgical procedure types. Continued efforts are needed to improve surgical outcomes for diabetic patients.
In September 2014 an unusual mixture of ctenophores was recorded at Arboretet, south-western Norway and at Flødevigen, near Arendal on the south coast of Norway. In addition to the invasive American lobate ctenophore, Mnemiopsis leidyi, the common northern lobate ctenophore Bolinopsis infundibulum and the cydippid Pleurobrachia pileus, two beroid ctenophores, were noted – Beroe cucumis and Beroe gracilis. The latter species had not been documented before in Norwegian waters.
Given the growth of international studies (IS) programs and the reciprocal relationship between political science and IS, this article explores perceptions of IS among political science department chairs. We found that the relationship between political science departments and IS programs is largely positive—that is, a majority of chairs supports the existence of IS at their institution, believes the job prospects for political science and IS majors are about equal, and perceives a low level of financial competition between programs. However, we discovered two points of contention: (1) the perception of lower academic rigor of IS programs, and (2) a high level of competition for majors and the “best students.” Perceptions of IS programs are related to a host of factors, including whether a program is housed within the political science department. Finally, we provide suggestions for improving the relationship between political science and IS.
This study compared the effectiveness of prompts (signs) and posted feedback as litter control strategies in two university cafeterias. Patronage and litter rates were monitored daily throughout the second term of the academic year. Prompts, prompts and posted feedback, and posted feedback were presented sequentially within a multiple baseline across settings experimental design. While litter rates initially declined in the presence of prompts, the addition of posted feedback did not have an additive effect; however, subsequent removal of prompts produced further reductions in litter rates, which were still evident during follow-up 5 weeks later. Results suggest that posted feedback is an effective and inexpensive method of Utter control.
Parasite burden varies widely between individuals within a population, and can covary with multiple aspects of individual phenotype. Here we investigate the sources of variation in faecal strongyle eggs counts, and its association with body weight and a suite of haematological measures, in a cohort of indigenous zebu calves in Western Kenya, using relatedness matrices reconstructed from single nucleotide polymorphism (SNP) genotypes. Strongyle egg count was heritable (h2 = 23·9%, s.e. = 11·8%) and we also found heritability of white blood cell counts (WBC) (h2 = 27·6%, s.e. = 10·6%). All the traits investigated showed negative phenotypic covariances with strongyle egg count throughout the first year: high worm counts were associated with low values of WBC, red blood cell count, total serum protein and absolute eosinophil count. Furthermore, calf body weight at 1 week old was a significant predictor of strongyle EPG at 16–51 weeks, with smaller calves having a higher strongyle egg count later in life. Our results indicate a genetic basis to strongyle EPG in this population, and also reveal consistently strong negative associations between strongyle infection and other important aspects of the multivariate phenotype.
Objective: Symptomatic neonates with Ebstein’s anomaly pose significant challenge. Within this cohort, neonates with associated anatomical pulmonary atresia have higher mortality. We review our experience with this difficult subset. Methods: A total of 32 consecutive symptomatic neonates with Ebstein’s anomaly underwent surgical intervention between 1994 and 2013. Of them, 20 neonates (62%, 20/32) had associated pulmonary atresia. Patients’ weights ranged from 1.9 to 3.4 kg. All patients without pulmonary atresia had two-ventricle repair. Of the 20 neonates, 16 (80%, 16/20) with Ebstein’s anomaly and pulmonary atresia had two-ventricle repair and 4 had single-ventricle palliation, of which 2 underwent Starnes’ palliation and 2 Blalock–Taussig shunts. Six recent patients with Ebstein’s anomaly and pulmonary atresia had right ventricle to pulmonary artery valved conduit as part of their two-ventricle repair. Results: Overall early mortality was 28% (9/32). For those without pulmonary atresia, mortality was 8.3% (1/12). For the entire cohort of neonates with Ebstein’s anomaly and pulmonary atresia, mortality was 40% (8/20; p=0.05). Mortality for neonates with Ebstein’s anomaly and pulmonary atresia having two-ventricle repair was 44% (7/16). Mortality for neonates with Ebstein’s anomaly and pulmonary atresia having two-ventricle repair utilising right ventricle to pulmonary artery conduit was 16% (1/6). For those having one-ventricle repair, the mortality was 25% (1/4). Conclusions: Surgical management of neonates with Ebstein’s anomaly remains challenging. For neonates with Ebstein’s anomaly and anatomical pulmonary atresia, single-ventricle palliation is associated with lower early mortality compared with two-ventricle repair. This outcome advantage is negated by inclusion of right ventricle to pulmonary artery conduit as part of the two-ventricle repair.
The CentriMag ventricular assist device is an extracorporeal, third-generation, continuous flow device. The rapidity and simplicity of operation along with low priming volume make it attractive for use in children with refractory heart failure. We report the successful use of CentriMag as a bridge to recovery in a child and discuss issues that are unique to its use in children.
Nine european national metrology institutes (NMIs) are collaborating in a new project funded by the european metrology research programme (EMRP) to establish traceable dynamic measurement of the mechanical quantities force, pressure, and torque. The aim of this joint research project (JRP) is to develop appropriate calibration methods, mathematical models, and uncertainty evaluation. The duration of the project is 3 years for a global amount of €3.6 million. It began in September 2011.
Maximum likelihood methods for the mapping of quantitative trait loci (QTL) have been investigated in an F2 population using simulated data. The use of adjacent (flanking) marker pairs gave improved power for the detection of QTL over the use of single markers when markers were widely spaced and the QTL effect large. The use of flanking marker loci also always gave moreaccurate and less biassed estimates for the effect and position of the QTL and made the method less sensitive to violations of assumptions, for example non-normality of the distribution. Testing the hypothesis of a linked QTL against that of no QTL is not biassed by the presence of unlinked QTL. This test is more robust and easier to obtain than the comparison of a linked with an unlinked QTL. Fixing the recombination fraction between the markers at an incorrect value in the analyses with flanking markers does not generally bias the test for QTL or estimates of their effect. The presence of multiple linked QTL bias both tests and estimates of effect with interval mapping, leading to inflated values when QTL are in association in the lines crossed and deflated values when they are in dispersion.
Mapping quantitative trait loci (QTLs) for binary traits in backcross and F2 populations was investigated using stochastic stimulation. Data were analysed using either linear regression or a generalized linear model. Parameters which were varied in the simulations were the population size (200 and 500), heritability in the backcross or F2 population (0·01, 0·05, 0·10), marker spacing (10 and 20 cM) and the incidence of the trait (0·50, 0·25, 0·10). The methods gave very similar results in terms of estimates of the QTL location and QTL effects and power of QTL detection, and it was concluded that in practice treating the zero-one data as continuous and using standard linear regression was efficient.
Gene action underlying selection responses has been studied using crossbreeding. Maximum likelihood based segregation analysis has been presented for analysing backcross data for the presence of genes with a large effect. Two sets of divergently selected lines (P-lines for body weight and F-lines for fat content) were reciprocally crossed and the F1s were crossed to the high and low lines to produce all possible backcrosses. Earlier analysis had shown that the difference in body weight at 10 weeks (n = 595) between the high and low P-lines was largely (75–80%) explained by autosomal, additive genes with the remainder explained by additive genes on the X chromosome. Maximum likelihood segregation analysis suggested the presence of a major effect on the X chromosome, but as there was only one round of recombination between the X chromosomes in the forming of the backcrosses, linked genes on the X chromosome could have acted together to give the appearance of a single major gene. The difference in fat content between the F-lines (n = 578) could be explained by autosomal genes of largely additive effect. Segregation analysis suggested the presence of a major gene with complete dominance, but this was attributed to a relationship between the mean and the variance: transformation of the data resulted in only polygenic additive genes being of importance. This study concluded that maximum likelihood based analysis and crosses between selected lines provide a powerful means for studying the gene action underlying responses to selection.
Nippostrongylus brasiliensis larvae are particularly susceptible to immunological attack during the pre-lung stage of primary and secondary infections in mice. Whilst most of the common laboratory strains of mice are permissive hosts for the parasite, in this study we report for the first time, the strong resistance of naïve FVB/N mice to N. brasiliensis. Damage to larvae is evident within the first 24 h of infection and this may be critical to later larval development and reproductive success. Inflammatory responses in the skin, and larval escape from this tissue were comparable in susceptible CBA/Ca and resistant FVB/N mice, with most larvae exiting within 4 h of a primary infection. Lung larval burdens were also similar between strains, but larvae recovered from FVB/N mice were smaller and less motile. In FVB/N mice, larval colonization of the gut was impaired and worms produced very few eggs. However FVB/N mice did not show enhanced resistance to Heligmosomoides bakeri (also known as Heligmosomoides polygyrus), a nematode largely restricted to the gut. Damage done in the pre-lung or lung stages of infection with N. brasiliensis is likely to contribute to ongoing developmental and functional abnormalities, which are profoundly evident in the gut phase of infection.
Dominance is an important source of variation in complex traits. Here, we have carried out the first thorough investigation of quantitative trait locus (QTL) detection using variance component (VC) models extended to incorporate both additive and dominant QTL effects. Simulation results showed that the empirical distribution of the test statistic when testing for dominant QTL effects did not behave in accordance with existing theoretical expectations and varied with pedigree structure. Extensive simulations were carried out to assess accuracy of estimates, type 1 error and statistical power in two-generation human-, poultry- and pig-type pedigrees each with 1900 progeny in small-, medium- and large-sized families, respectively. The distribution of the likelihood-ratio test statistic was heavily dependent on family structure, with empirical thresholds lower for human pedigrees. Power to detect QTL was high (0·84–1·0) in pig and poultry scenarios for dominance effects accounting for >7% of phenotypic variance but much lower (0·42) in human-type pedigrees. Maternal or common environment effects can be partially confounded with dominance and must be fitted in the QTL model. Including dominance in the QTL model did not affect power to detect additive QTL effects. Also, detection of spurious dominance QTL effects only occurred when maternal effects were not included in the QTL model. When dominance effects were present in the data but not in the analysis model, this resulted in spurious detection of additive QTL or inflated estimates of additive QTL effects. The study demonstrates that dominance can be included routinely in QTL analysis of general pedigrees; however, optimal power is dependent on selection of the appropriate thresholds for pedigree structure.
In 1990, Fontan, Kirklin, and colleagues published equations for survival after the so-called “Perfect Fontan” operation. After 1988, we evolved a protocol using an internal or external polytetraflouroethylene tube of 16 to 19 millimetres diameter placed from the inferior caval vein to either the right or left pulmonary artery along with a bidirectional cava-pulmonary connection. The objective of this study was to test the hypothesis that a “perfect” outcome is routinely achievable in the current era when using a standardized surgical procedure.
Methods
Between 1 January, 1988, and 12 December, 2005, 112 patients underwent the Fontan procedure using an internal or external polytetraflouroethylene tube plus a bidirectional cava-pulmonary connection, the latter usually having been constructed as a previous procedure. This constituted 45% of our overall experience in constructing the Fontan circulation between 1988 and 1996, and 96% of the experience between 1996 and 2005. Among all surviving patients, the median follow-up was 7.3 years. We calculated the expected survival for an optimal candidate, given from the initial equations, and compared this to our entire experience in constructing the Fontan circulation.
Results
An internal tube was utilized in 61 patients, 97% of whom were operated prior to 1998, and an external tube in 51 patients, the latter accounting for 95% of all operations since 1999. At 1, 5, 10 and 15 years, survival of the entire cohort receiving polytetraflouroethylene tubes is superimposable on the curve calculated for a “perfect” outcome. Freedom from replacement or revision of the tube was 97% at 10 years.
Conclusion
Using a standardized operative procedure, combining a bidirectional cavopulmonary connection with a polytetraflouroethylene tube placed from the inferior caval vein to the pulmonary arteries for nearly all patients with functionally univentricular hearts, early and late survival within the “perfect” outcome as predicted by the initial equations of Fontan and Kirklin is routinely achievable in the current era. The need for late revision or replacement of the tube is rare.
Methods that detect QTL within commercial populations circumvent the need for expensive experimental populations and facilitate direct application of results through marker assisted selection. Variance component analysis (VCA) uses phenotypic, pedigree and marker information within a mixed linear model to simultaneously detect QTL and estimate breeding values. The inclusion of non-additive effects has potential for greater accuracy of selection and understanding of underlying mechanisms. The linear model can be extended to include higher order effects such as dominance, however, there is little information on empirical power. Here VCA was applied to real and simulated commercial broiler data to detect additive and dominant QTL effects.