GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Infectious disease modelling to inform policy.

With modelling becoming increasingly important in helping to inform decisions about animal diseases, it is essential that the process be optimised to gain the maximum benefit for the decision-maker. Here, the authors set out ten steps that can improve this process for all concerned. Four steps describe initialisation to ensure that the question, answer and timescale are defined; two steps describe the modelling process and quality assurance; and four steps describe the reporting stage. The authors believe that this greater emphasis at the beginning and end of a modelling project will increase the relevance of the work and understanding of the results, and thus contribute towards better decision-making.

Compte tenu de l'importance croissante de la modélisation pour documenter les décisions sur les maladies animales, il est essentiel d'optimiser le processus afin de le rendre le plus profitable possible pour les personnes décisionnaires. Les auteurs définissent dix étapes permettant d'améliorer le processus pour tous les intervenants. Quatre étapes concernent la phase de démarrage et visent à s'assurer que les questions posées, les réponses obtenues et le calendrier sont bien définis ; les deux étapes suivantes portent sur le processus de modélisation et sur l'assurance qualité ; les quatre dernières décrivent la phase d'élaboration des rapports. Les auteurs estiment que cette attention particulière accordée aux phases de démarrage et d'achèvement d'un projet de modélisation rend l'exercice plus pertinent et améliore la compréhension des résultats, ce qui contribue à une meilleure prise de décisions.

Dada la creciente importancia que está cobrando la modelización como herramienta para ayudar a fundamentar las decisiones relativas a enfermedades animales, es esencial optimizar el proceso para que las instancias decisorias puedan aprovecharlo al máximo. Los autores exponen diez pasos que pueden mejorar el proceso para cuantos trabajan en este ámbito. En cuatro pasos se describe la inicialización, que sirve para definir debidamente la pregunta, la respuesta y la escala temporal de que se trate. En otros dos pasos se describe el proceso de modelización y de garantía de calidad, mientras que en los últimos cuatro pasos se describe la fase de producción de informes. Los autores consideran que el hecho de otorgar mayor peso a las fases iniciales y finales de un proyecto de modelización hará que el trabajo gane en pertinencia y que se entiendan mejor sus resultados, lo que a su vez contribuye a un proceso más eficaz de adopción de decisiones.

External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

OBJECTIVE: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. METHODS: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. RESULTS: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. CONCLUSIONS: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

UK stillbirth trends in over 11 million births provide no evidence to support effectiveness of Growth Assessment Protocol program.

OBJECTIVE: Use of the Growth Assessment Protocol (GAP) has increased internationally under the assumption that it reduces the stillbirth rate. The evidence for this is limited and based largely on an ecological time-trend study. Discordance in the uptake of the GAP program between Scotland and England/Wales enabled us to assess the assertion that implementation of GAP leads to a reduced stillbirth rate. METHODS: We analyzed data from the National Records for Scotland and the Office for National Statistics on the number of singleton maternities and stillbirths in Scotland and in England and Wales, respectively, from 1 January 2000 to 31 December 2015. National uptake of the GAP program over time in each of the regions was recorded. Stillbirth rate per 1000 maternities was calculated, according to year of delivery, and compared between Scotland and England/Wales. RESULTS: During the study period, there were 870 632 singleton maternities in Scotland, of which 4243 were stillbirths, and there were 10 469 120 singleton maternities in England and Wales, of which 51 562 were stillbirths. There was a marked difference in uptake of the GAP program between the two regions, with substantially fewer maternity units in Scotland implementing the program. Stillbirth rates were static up to 2010, with a decline thereafter in both regions, to 3.75 (95% CI, 3.25-4.30) per 1000 maternities in Scotland and 4.30 (95% CI, 4.15-4.46) per 1000 maternities in England and Wales in 2015. From 2010 onwards, the decline in Scotland was faster, equating to 48 (95% CI, 47.9-48.1) fewer stillbirths per 100 000 maternities in Scotland than in England and Wales from 2010 to 2015 compared with 2000 to 2009. CONCLUSIONS: We observed a decline in stillbirth rate in England and Wales, which coincided with implementation of the GAP program. However, a concurrent decline in stillbirth rate was observed in Scotland in the absence of increased implementation of GAP. The secular rates of change in stillbirth rate in England and Wales cannot be used to infer efficacy of the GAP program. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Blinded ultrasound fetal biometry at 36 weeks and risk of emergency Cesarean delivery in a prospective cohort study of low-risk nulliparous women.

OBJECTIVES: To compare the association between risk of emergency Cesarean delivery (CD) and non-customized vs customized ultrasound estimated fetal weight (EFW) at 36 weeks' gestation, determine whether addition of ultrasound EFW to a model based on maternal characteristics alone improved prediction of emergency CD, assess the screening performance of a multivariable model using both EFW and maternal characteristics to predict emergency CD, and determine whether women at high predicted risk of emergency CD based on this model had higher risk of maternal and perinatal morbidity compared with screen-negative women. METHODS: We studied 3047 low-risk (no pre-existing medical conditions or acquired complications of pregnancy) nulliparous women from the prospective Pregnancy Outcome Prediction study (Cambridge, UK) cohort, who underwent ultrasound EFW at ∼36 weeks' gestation. Both the women and their clinicians were blinded to fetal biometry results. Emergency CD was defined as delivery by Cesarean section in pregnancies in which the date of delivery had not been prearranged. Additional candidate predictors of emergency CD evaluated were maternal age, height, body mass index (BMI), weight gain, fetal abdominal circumference growth velocity and fetal sex. External validation of the predictive model was performed using routinely collected data from 55 337 births in Scotland between 2003 and 2008. Women with an estimated risk of emergency CD ≥ 40% were defined as screen positive. RESULTS: Blinded EFW was associated strongly with the risk of emergency CD (coefficient for increase of 1 SD in EFW, 0.39 (95% CI, 0.30-0.48); odds ratio (OR), 1.48 (95% CI, 1.35-1.62)). The coefficient for customized EFW was similar (0.42 (95% CI, 0.33-0.51); OR, 1.53 (95% CI, 1.39-1.67)); hence, for simplicity, non-customized EFW was employed subsequently. A multivariable logistic regression model combining maternal characteristics (age, height, BMI and weight gain between 12 and 36 weeks) was moderately predictive of emergency CD (area under the receiver-operating characteristics curve (AUC) = 0.68). Addition of blinded EFW to the model increased the AUC to 0.71 and improved prediction (likelihood-ratio test P < 0.0001). Based on this model, 189 (6.2%) women were screen positive and 48% of these delivered by CD. Screen-positive women had elevated risks of severe postpartum hemorrhage (relative risk (RR), 2.49; 95% CI, 1.83-3.38), any adverse neonatal outcome (RR, 1.86; 95% CI, 1.22-2.82) and severe adverse neonatal outcome (RR, 4.03; 95% CI, 1.35-12.03) compared with screen-negative women. The risks of these events were also higher compared with women who had a term CD for breech presentation. The model was similarly predictive of the risk of emergency CD and perinatal morbidity when evaluated using the dataset from Scotland. CONCLUSIONS: Ultrasound EFW at 36 weeks, combined with maternal characteristics, can identify women who are at increased risk of subsequent emergency CD. These women are at increased risk of maternal and perinatal morbidity compared with women at low risk of emergency CD and those having CD for breech presentation at term. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Universal vs selective ultrasonography to screen for large-for-gestational-age infants and associated morbidity.

OBJECTIVES: To compare the diagnostic effectiveness of selective vs universal ultrasonography as a screening test for large-for-gestational-age (LGA) infants, and to determine whether previously described ultrasound markers of excessive fetal growth could identify suspected LGA fetuses that are at increased risk of adverse neonatal outcome. METHODS: Data from the Pregnancy Outcome Prediction study, a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan, were analyzed. Women were selected for clinically indicated ultrasound assessment in the third trimester as per routine clinical care, and the results of these scans were reported ('selective ultrasonography'). In addition, all participants underwent research ultrasound scans, including estimated fetal weight (EFW) assessment, at around 36 weeks' gestation, in which both the women and their clinicians were blinded to the results ('universal ultrasonography'). Participants who attended the 36-week research scan and had a live birth at the Rosie Hospital were included in the study. Screen positive for LGA was defined as EFW > 90th percentile at ≥ 34 weeks. RESULTS: The current analysis included 3866 eligible women, of whom 1354 (35%) had a clinically indicated ultrasound scan at or after 34 weeks' gestation. A total of 177 (4.6%) infants had a birth weight > 90th percentile. The sensitivity for detection of LGA infants was 27% for selective ultrasonography and 38% for universal ultrasonography. The specificity of both approaches was high (99% and 97%, respectively). Using universal ultrasonography, neonatal outcome differed (P for interaction) by abdominal circumference growth velocity (ACGV) for both any neonatal morbidity (P = 0.08) and severe adverse neonatal outcome (P = 0.03). LGA fetuses with increased ACGV had a relative risk of any neonatal morbidity of 2.0 (95% CI, 1.1-3.6; P = 0.04) and of severe adverse neonatal outcome of 6.5 (95% CI, 2.0-21.1; P = 0.01), whereas LGA fetuses with normal ACGV were not at increased risk. CONCLUSIONS: Third-trimester screening of nulliparous women by universal ultrasound fetal biometry increases the detection rate of LGA infants and, combined with ACGV, identifies those at increased risk of adverse neonatal outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

The role of modelling in predicting rabies and understanding the impact of control measures.

Rabies is probably the most commonly modelled disease as both its epidemiology and host dynamics are well understood. Models are simplifications of reality and there are different approaches to achieving these representations. Over time, modelling has moved from simple mathematical methods towards more realistic biological models that incorporate spatial and individual variation. In this article, the author reviews models that have increased our understanding of actions taken to manage disease. The most developed of these focus on fox (Vulpes vulpes) rabies in Europe, where a suite of models has helped researchers to explore fox management options and the complications caused by other potential hosts, such as raccoon dogs (Nyctereutes procyonoides). Models of dog (Canis familiaris) rabies support the idea of a 70% vaccine threshold for disease elimination and are now being used to explore and optimise management methods, combining vaccination with either surgical sterilisation or the use of chemical sterilisation. Future challenges are also identified, such as the need to develop practical management models in other hosts, and to explore different Lyssavirus strains in bats.

La rage est probablement la maladie pour laquelle on recourt le plus souvent à des modèles, son épidémiologie et sa dynamique chez ses hôtes étant désormais bien connues. Les modèles sont des représentations simplifiées de la réalité que l'on peut obtenir de différentes manières. Au fil du temps, la modélisation a évolué depuis les premières méthodes mathématiques simples jusqu'aux modèles biologiques actuels, plus réalistes et capables d'intégrer des variations spatiales et individuelles. L'auteur passe en revue les modèles qui ont permis de mieux comprendre les mesures à adopter pour maîtriser la maladie. Les plus sophistiqués de ces modèles portent sur la rage chez le renard (Vulpes vulpes) en Europe, où une suite de modèles a permis aux chercheurs d'étudier diverses options en matière de gestion des renards, ainsi que les complications induites par la présence d'autres hôtes potentiels, en particulier le chien viverrin (Nyctereutes procyonoides). Les modèles portant sur la rage chez le chien (Canis familiaris) confortent l'idée d'un seuil de 70 % de couverture vaccinale pour l'élimination de la maladie et sont utilisés actuellement pour étudier et optimiser les méthodes de gestion qui associent à la vaccination canine une stérilisation chirurgicale ou chimique. Les défis à venir sont également mis en lumière, par exemple la nécessité de mettre au point des modèles de gestion applicables chez d'autres hôtes et d'étudier les différentes souches de Lyssavirus chez les chauves-souris.

La rabia es probablemente la enfermedad de la que más a menudo se elaboran modelos, pues se conocen bien tanto su epidemiología como su dinámica en los anfitriones. Para construir modelos, que son simplificaciones de la realidad, cabe aplicar distintas lógicas. Con el transcurrir del tiempo, los primeros modelos, que eran sencillos métodos matemáticos, han dado paso a modelos biológicos más cercanos a la realidad, que incorporan las variaciones espaciales e individuales. El autor pasa revista a los modelos que nos han aportado un mejor conocimiento de las medidas adecuadas para combatir la enfermedad. De ellos, los más perfeccionados se refieren a la rabia del zorro (Vulpes vulpes) en Europa, donde los investigadores se han servido de un conjunto de modelos para estudiar distintas opciones de lucha en el zorro, así como las complicaciones ocasionadas por otros posibles anfitriones, como el perro mapache (Nyctereutes procyonoides). Los modelos de la rabia del perro (Canis familiaris) avalan la idea de que el umbral de vacunaciones para poder eliminar la enfermedad se sitúa en un 70%. Estos modelos se utilizan ahora para estudiar y optimizar los métodos de lucha, combinando la práctica de vacunaciones con procedimientos de esterilización quirúrgica o química. El autor también expone las dificultades que nos aguardan de cara el futuro, como la elaboración de modelos prácticos para combatir la enfermedad en otros anfitriones o el estudio de diferentes cepas de Lyssavirus en los murciélagos.

Passive surveillance of United Kingdom bats for lyssaviruses (2005-2015).

Passive surveillance for lyssaviruses in UK bats has been ongoing since 1987 and has identified 13 cases of EBLV-2 from a single species; Myotis daubentonii. No other lyssavirus species has been detected. Between 2005 and 2015, 10 656 bats were submitted, representing 18 species, creating a spatially and temporally uneven sample of British bat fauna. Uniquely, three UK cases originate from a roost at Stokesay Castle in Shropshire, England, where daily checks for grounded and dead bats are undertaken and bat carcasses have been submitted for testing since 2007. Twenty per cent of Daubenton's bats submitted from Stokesay Castle since surveillance began, have tested positive for EBLV-2. Phylogenetic analysis reveals geographical clustering of UK viruses. Isolates from Stokesay Castle are more closely related to one another than to viruses from other regions. Daubenton's bats from Stokesay Castle represent a unique opportunity to study a natural population that appears to maintain EBLV-2 infection and may represent endemic infection at this site. Although the risk to public health from EBLV-2 is low, consequences of infection are severe and effective communication on the need for prompt post-exposure prophylaxis for anyone that has been bitten by a bat is essential.

Population genetic structure of serotine bats (Eptesicus serotinus) across Europe and implications for the potential spread of bat rabies (European bat lyssavirus EBLV-1).

Understanding of the movements of species at multiple scales is essential to appreciate patterns of population connectivity and in some cases, the potential for pathogen transmission. The serotine bat (Eptesicus serotinus) is a common and widely distributed species in Europe where it frequently harbours European bat lyssavirus type 1 (EBLV-1), a virus causing rabies and transmissible to humans. In the United Kingdom, it is rare, with a distribution restricted to south of the country and so far the virus has never been found there. We investigated the genetic structure and gene flow of E. serotinus across the England and continental Europe. Greater genetic structuring was found in England compared with continental Europe. Nuclear data suggest a single population on the continent, although further work with more intensive sampling is required to confirm this, while mitochondrial sequences indicate an east-west substructure. In contrast, three distinct populations were found in England using microsatellite markers, and mitochondrial diversity was very low. Evidence of nuclear admixture indicated strong male-mediated gene flow among populations. Differences in connectivity could contribute to the high viral prevalence on the continent in contrast with the United Kingdom. Although the English Channel was previously thought to restrict gene flow, our data indicate relatively frequent movement from the continent to England highlighting the potential for movement of EBLV-1 into the United Kingdom.

The utility of whole-genome sequencing to identify likely transmission pairs for pathogens with slow and variable evolution.

Pathogen whole-genome sequencing (WGS) has been used to track the transmission of infectious diseases in extraordinary detail, especially for pathogens that undergo fast and steady evolution, as is the case with many RNA viruses. However, for other pathogens evolution is less predictable, making interpretation of these data to inform our understanding of their epidemiology more challenging and the value of densely collected pathogen genome data uncertain. Here, we assess the utility of WGS for one such pathogen, in the "who-infected-whom" identification problem. We study samples from hosts (130 cattle, 111 badgers) with confirmed infection of M. bovis (causing bovine Tuberculosis), which has an estimated clock rate as slow as ∼0.1-1 variations per year. For each potential pathway between hosts, we calculate the relative likelihood that such a transmission event occurred. This is informed by an epidemiological model of transmission, and host life history data. By including WGS data, we shrink the number of plausible pathways significantly, relative to those deemed likely on the basis of life history data alone. Despite our uncertainty relating to the evolution of M. bovis, the WGS data are therefore a valuable adjunct to epidemiological investigations, especially for wildlife species whose life history data are sparse.

Multi-state modelling reveals sex-dependent transmission, progression and severity of tuberculosis in wild badgers.

Statistical models of epidemiology in wildlife populations usually consider diseased individuals as a single class, despite knowledge that infections progress through states of severity. Bovine tuberculosis (bTB) is a serious zoonotic disease threatening the UK livestock industry, but we have limited understanding of key epidemiological processes in its wildlife reservoirs. We estimated differential survival, force of infection and progression in disease states in a population of Eurasian badgers (Meles meles), naturally infected with bTB. Our state-dependent models overturn prevailing categorizations of badger disease states, and find novel evidence for early onset of disease-induced mortality in male but not female badgers. Males also have higher risk of infection and more rapid disease progression which, coupled with state-dependent increases in mortality, could promote sex biases in the risk of transmission to cattle. Our results reveal hidden complexities in wildlife disease epidemiology, with implications for the management of TB and other zoonotic diseases.

Heterogeneity in the risk of Mycobacterium bovis infection in European badger (Meles meles) cubs.

The behaviour of certain infected individuals within socially structured populations can have a disproportionately large effect on the spatio-temporal distribution of infection. Endemic infection with Mycobacterium bovis in European badgers (Meles meles) in Great Britain and Ireland is an important source of bovine tuberculosis in cattle. Here we quantify the risk of infection in badger cubs in a high-density wild badger population, in relation to the infection status of resident adults. Over a 24-year period, we observed variation in the risk of cub infection, with those born into groups with resident infectious breeding females being over four times as likely to be detected excreting M. bovis than cubs from groups where there was no evidence of infection in adults. We discuss how our findings relate to the persistence of infection at both social group and population level, and the potential implications for disease control strategies.

Long-term temporal trends and estimated transmission rates for Mycobacterium bovis infection in an undisturbed high-density badger (Meles meles) population.

We describe epidemiological trends in Mycobacterium bovis infection in an undisturbed wild badger (Meles meles) population. Data were derived from the capture, clinical sampling and serological testing of 1803 badgers over 9945 capture events spanning 24 years. Incidence and prevalence increased over time, exhibiting no simple relationship with host density. Potential explanations are presented for a marked increase in the frequency of positive serological test results. Transmission rates (R0) estimated from empirical data were consistent with modelled estimates and robust to changes in test sensitivity and the spatial extent of the population at risk. The risk of a positive culture or serological test result increased with badger age, and varied seasonally. Evidence consistent with progressive disease was found in cubs. This study demonstrates the value of long-term data and the repeated application of imperfect diagnostic tests as indices of infection to reveal epidemiological trends in M. bovis infection in badgers.

Obstetric factors and different causes of special educational need: retrospective cohort study of 407,503 schoolchildren.

OBJECTIVE: To determine whether relationships with gestational age and birthweight centile vary between specific causes of special educational need (SEN). DESIGN: Retrospective cohort study. SETTING: Scotland. POPULATION: A cohort of 407,503 schoolchildren. METHODS: Polytomous logistic regression was used to examine the risk of each cause of SEN across the spectrum of gestation at delivery and birthweight centile, adjusting for potential confounding factors. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios and confidence intervals. RESULTS: Of the 19,821 children with SEN, 557 (2.8%) had sensory impairments, 812 (4.1%) had physical or motor disabilities, 876 (4.4%) had language impairments, 2823 (14.2%) had social, emotional, or behavioural problems, 7018 (35.4%) had intellectual disabilities, 4404 (22.2%) had specific learning difficulties, and 1684 (8.5%) autistic spectrum disorder (ASD). Extreme preterm delivery (at 24-27 weeks of gestation) was a strong predictor of sensory (adjusted OR 23.64, 95% CI 12.03-46.45), physical or motor (adjusted OR 29.69, 95% CI 17.49-50.40), and intellectual (adjusted OR 11.67, 95% CI 8.46-16.10) impairments, with dose relationships across the range of gestation. Similarly, birthweight below the third centile was associated with sensory (adjusted OR 2.85, 95% CI 2.04-3.99), physical or motor (adjusted OR 2.47, 95% CI 1.82-3.37), and intellectual (adjusted OR 2.67, 95% CI 2.41-2.96) impairments. Together, gestation and birthweight centile accounted for 24.0% of SEN arising from sensory impairment, 34.3% arising from physical or motor disabilities, and 26.6% arising from intellectual disabilities. Obstetric factors were less strongly associated with specific learning difficulties and social or emotional problems, and there were no significant associations with ASD. CONCLUSIONS: The association between gestation and birthweight centile and overall risk of SEN is largely driven by very strong associations with sensory, physical or motor impairments, and intellectual impairments.

Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis.

Poly(ADP-ribose) polymerase (PARP) and DNA-dependent protein kinase (DNA-PK) are DNA break-activated molecules, Although mice that lack PARP display no gross phenotype and normal DNA excision repair, they exhibit high levels of sister chromatid exchange, indicative of elevated recombination rates. Mutation of the gene for DNA-PK catalytic subunit (Prkdc) cases defective antigen receptor V(D)J recombination and arrests B- and T-lymphocyte development in severe combined immune-deficiency (SCID) mice. SCID V(D)J recombination can be partly rescued in T-lymphocytes by either DNA-damaging agents (gamma-irradiation and bieomycin) or a null mutation of the p53 gene, possibly because of transiently elevated DNA repair activity in response to DNA damage or to delayed apoptosis in the absence of p53. To determine whether the increased chromosomal recombination observed in PARP-deficient cells affects SCID V(D)J recombination, we generated mice lacking both PARP and DNA-PK. Here, we show that thymocytes of SCID mice express both CD4 and CD8 co-receptors, bypassing the SCID block. Double-mutant T-cells in the periphery express TCR beta, which is attributable to productive TCR beta joints. Double-mutant mice develop a high frequency of T-cell lymphoma. These results demonstrate that increased recombination activity after the loss of PARP anti-recombinogenic function can rescue V(D)J recombination in SCID mice and indicate that PARP and DNA-PK cooperate to minimize genomic damage caused by DNA strand breaks.

Farm-scale risk factors for bovine tuberculosis incidence in cattle herds during the Randomized Badger Culling Trial.

We analysed the incidence of cattle herd breakdowns due to bovine tuberculosis (Mycobacterium bovis) in relation to experimental badger culling, badger populations and farm characteristics during the Randomized Badger Culling Trial (RBCT). Mixed modelling and event history analysis were used to examine the individual risk factors. The interdependencies of covariates were examined using structural equation modelling. There were consistent findings among the different analyses demonstrating that during a badger culling programme farms experiencing: reactive culling, larger herd sizes, larger holdings and holdings with multiple parcels of land were all at greater risk of a herd breakdown. Proactive culling reduced risks within the culling area, but we did not assess any potential effects in the periphery of the treatment area. Badger-related variables measured prior to the start of culling (number of social groups and length of badger territorial boundaries) did not consistently point to an increase in risk, when set against a background of ongoing badger culling. This could be because (1) the collected variables were not important to risk in cattle, or (2) there were insufficient data to demonstrate their importance. Our findings highlight the difficulty in identifying simple predictors of spatial variation in transmission risks from badger populations and the consequent challenge of tailoring management actions to any such field data.

Maternal waist to hip ratio is a risk factor for macrosomia.

OBJECTIVE: Fetal growth during pregnancy may be affected by the metabolic activity and distribution of fat stores in women. This study investigates the association between waist to hip ratio (WHR) as a measure of the distribution of adiposity in primiparous mothers living in Avon, England, and macrosomia in their offspring. DESIGN: Prospective historical cohort study. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study in Avon, UK. POPULATION: A cohort of 3083 primiparous women with a term singleton delivery with expected dates of delivery from 1 April 1991 to 31 December 1992. METHODS: The distribution of WHR was categorised into quartiles. We compared the second, third and fourth quartiles against the first (reference) quartile with respect to whether the mother delivered a macrosomic newborn. We controlled for maternal age, gestational age, body mass index (BMI), marital status and racial group using multivariate logistic regression. MAIN OUTCOME MEASURES: Macrosomia defined in three ways: birthweight ≥ 4000 g; birthweight ≥ 4500 g; large for gestational age (LGA: ≥ 95th percentile of birth weight adjusted for sex and gestational age). RESULTS: Waist to hip ratios in the third and fourth quartiles were associated with a higher odds of delivering a macrosomic infant, defined as a birthweight ≥ 4000 g (third quartile, OR 1.59, 95% CI 1.12-2.26; fourth quartile, OR 1.69, 95% CI 1.18-2.42) or as LGA (≥95th percentile of the cohort; third quartile, OR 1.77, 95% CI 1.10-2.85; fourth quartile, OR 1.78, 95% CI 1.09-2.91). When defined as a birthweight ≥ 4500 g, the fourth quartile was associated with increased odds of macrosomia (OR 2.74, 95% CI 1.05-7.16). Odds ratios after adjustment for confounding factors followed a similar pattern. CONCLUSION: Independent of confounding factors, women with increased WHRs were significantly more likely to give birth to macrosomic newborns.

Meta-analysis of the association between preterm delivery and intelligence.

BACKGROUND: An increasing proportion of infants are born preterm, and their survival has improved. Therefore, their long-term sequelae are of increasing public health importance. METHODS: We conducted a systematic review covering a 30 year period (1980-2009). A random effects meta-analysis provided a pooled estimate of the difference in IQ score between individuals born preterm and term. Small-study bias was examined using a funnel plot and Egger's test, and meta-regression was used to investigate possible causes of heterogeneity. Cumulative meta-analysis was used to determine if the magnitude of the association had changed over time. RESULTS: The 27 eligible studies covered 7044 individuals; 3504 (50%) delivered preterm and 3540 (50%) at term. They provided 37 estimates of difference in IQ. All demonstrated a reduced IQ among those delivered preterm and all but four reached statistical significance. Overall, IQ score was 11.94 (95% CI: 10.47-13.42, P < 0.001) points lower among children born preterm. There was moderate heterogeneity (overall I(2) 74.2%, P < 0.001), but no significant small-study bias (P = 0.524). The association between preterm delivery and IQ did not change significantly over time. There was a statistically significant, linear association across the gestational age range (adjusted coefficient: -0.91, 95% CI: -1.64, -0.17, P = 0.018). CONCLUSIONS: There is a strong and consistent body of evidence suggesting an association between preterm delivery and reduced IQ, with evidence of a dose-response relationship with gestational age.