Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA

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Effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes in low risk pregnancy (the IRIS study): nationwide, pragmatic, multicentre, stepped wedge cluster randomised trial

Objectives To investigate the effectiveness of routine ultrasonography in the third trimester in reducing adverse perinatal outcomes in low risk pregnancies compared with usual care and the effect of this policy on maternal outcomes and obstetric interventions. Design Pragmatic, multicentre, stepped wedge cluster randomised trial. Setting 60 midwifery practices in the Netherlands. Participants 13 046 women aged 16 years or older with a low risk singleton pregnancy. Interventions 60 midwifery practices offered usual care (serial fundal height measurements with clinically indicated ultrasonography). After 3, 7, and 10 months, a third of the practices were randomised to the intervention strategy. As well as receiving usual care, women in the intervention strategy were offered two routine biometry scans at 28-30 and 34-36 weeks’ gestation. The same multidisciplinary protocol for detecting and managing fetal growth restriction was used in both strategies. Main outcome measures The primary outcome measure was a composite of severe adverse perinatal outcomes: perinatal death, Apgar score <4, impaired consciousness, asphyxia, seizures, assisted ventilation, septicaemia, meningitis, bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leucomalacia, or necrotising enterocolitis. Secondary outcomes were two composite measures of severe maternal morbidity, and spontaneous labour and birth. Results Between 1 February 2015 and 29 February 2016, 60 midwifery practices enrolled 13 520 women in mid-pregnancy (mean 22.8 (SD 2.4) weeks’ gestation). 13 046 women (intervention n=7067, usual care n=5979) with data based on the national Dutch perinatal registry or hospital records were included in the analyses. Small for gestational age at birth was significantly more often detected in the intervention group than in the usual care group (179 of 556 (32%) v 78 of 407 (19%), P<0.001). The incidence of severe adverse perinatal outcomes was 1.7% (n=118) for the intervention strategy and 1.8% (n=106) for usual care. After adjustment for confounders, the difference between the groups was not significant (odds ratio 0.88, 95% confidence interval 0.70 to 1.20). The intervention strategy showed a higher incidence of induction of labour (1.16, 1.04 to 1.30) and a lower incidence of augmentation of labour (0.78, 0.71 to 0.85). Maternal outcomes and other obstetric interventions did not differ between the strategies. Conclusion In low risk pregnancies, routine ultrasonography in the third trimester along with clinically indicated ultrasonography was associated with higher antenatal detection of small for gestational age fetuses but not with a reduced incidence of severe adverse perinatal outcomes compared with usual care alone. The findings do not support routine ultrasonography in the third trimester for low risk pregnancies. Trial registration Netherlands Trial Register NTR4367

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts

Purpose: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the68Ga-labelled bombesin analogue AMBA with metabolism-based tar

Global warming and Bergmann’s rule: do central European passerines adjust their body size to rising temperatures?

Recent climate change has caused diverse ecological responses in plants and animals. However, relatively little is known about homeothermic animals’ ability to adapt to changing temperature regimes through changes in body size, in accordance with Bergmann’s rule. We used fluctuations in mean annual temperatures in south-west Germany since 1972 in order to look for direct links between temperature and two aspects of body size: body mass and flight feather length. Data from regionally born juveniles of 12 passerine bird species were analysed. Body mass and feather length varied significantly among years in eight and nine species, respectively. Typically the inter-annual changes in morphology were complexly non-linear, as was inter-annual variation in temperature. For six (body mass) and seven species (feather length), these inter-annual fluctuations were significantly correlated with temperature fluctuations. However, negative correlations consistent with Bergmann’s rule were only found for five species, either for body mass or feather length. In several of the species for which body mass and feather length was significantly associated with temperature, morphological responses were better predicted by temperature data that were smoothed across multiple years than by the actual mean breeding season temperatures of the year of birth. This was found in five species for body mass and three species for feather length. These results suggest that changes in body size may not merely be the result of phenotypic plasticity but may hint at genetically based microevolutionary adaptations

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression

Neural circuits in the medial entorhinal cortex (MEC) encode an animal's position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations

The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial

BackgroundBreast cancer diagnosis may be a teachable moment for lifestyle behaviour change and to prevent adjuvant therapy associated weight gain. We assessed the acceptability and effectiveness of two weight control programmes initiated soon after breast cancer diagnosis to reduce weight amongst overweight or obese women and prevent gains in normal-weight women.MethodsOverweight or obese (n?=?243) and normal weight (n?=?166) women were randomised to a three-month unsupervised home (home), a supervised community weight control programme (community) or to standard written advice (control). Primary end points were change in weight and body fat at 12 months. Secondary end points included change in insulin, cardiovascular risk markers, quality of life and cost-effectiveness of the programmes.ResultsForty-three percent of eligible women were recruited. Both programmes reduced weight and body fat: home vs. control mean (95% CI); weight ?2.3 (?3.5, ?1.0) kg, body fat ?1.6 (?2.6, ?0.7) kg, community vs. control; weight ?2.4 (?3.6, ?1.1) kg, body fat ?1.4 (?2.4, ?0.5) kg (all p?&#x3c;?0.001). The community group increased physical activity, reduced insulin, cardiovascular disease risk markers, increased QOL and was cost-effective.ConclusionsThe programmes were equally effective for weight control, but the community programme had additional benefits.Clinical trial registrationISRCTN6857614