Association of Co-Exposure of Antenatal Steroid and Prophylactic Indomethacin with Spontaneous Intestinal Perforation

Objective: To evaluate the association of a combined exposure to antenatal steroids and prophylactic indomethacin with the outcome of spontaneous intestinal perforation (SIP) among neonates born at \u3c26 weeks of gestation or \u3c750 g birth weight. Study design: We conducted a retrospective study of preterm infants admitted to Canadian Neonatal Network units between 2010 and 2018. Infants were classified into 2 groups based on receipt of antenatal steroids; the latter subgrouped as recent (≤7 days before birth) or latent (\u3e7 days before birth) exposures. The co-exposure was prophylactic indomethacin. The primary outcome was SIP. Multivariable logistic regression analysis was used to calculate aORs. Results: Among 4720 eligible infants, 4121 (87%) received antenatal steroids and 1045 (22.1%) received prophylactic indomethacin. Among infants exposed to antenatal steroids, those who received prophylactic indomethacin had higher odds of SIP (aOR 1.61, 95% CI 1.14-2.28) compared with no prophylactic indomethacin. Subgroup analyses revealed recent antenatal steroids exposure with prophylactic indomethacin had higher odds of SIP (aOR 1.67, 95% CI 1.15-2.43), but latent antenatal steroids exposure with prophylactic indomethacin did not (aOR 1.24, 95% CI 0.48-3.21), compared with the respective groups with no prophylactic indomethacin. Among those not exposed to antenatal steroids, mortality was lower among those who received prophylactic indomethacin (aOR 0.45, 95% CI 0.28-0.73) compared with no prophylactic indomethacin. Conclusions: In preterm neonates of \u3c26 weeks of gestation or birth weight \u3c750 g, co-exposure of antenatal steroids and prophylactic indomethacin was associated with SIP, especially if antenatal steroids was received within 7 days before birth. Among those unexposed to antenatal steroids, prophylactic indomethacin was associated with lower odds of mortality

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2015

The RCM NS&EA met 31st August - 4th September 2015 at den Haag, Netherlands with 27 participants form 11 member states and autonomous regions attending, including representatives of ICES and the Commission. National correspondents from Spain, UK, Denmark, Lithuania, Germany, Sweden and the Netherlands were present. The meeting was co-chaired by Katja Ringdahl (Sweden) and Alastair Pout (Scotland). The RCM N&SEA considered the recommendations from the 11th Liasion meeting and summaries were presented of the work of expert groups and end users for the 2014-15 period to the plenary session of the meeting. The expert groups included WGCATCH, PGDATA, WKISCON2, WKRDB 2014-01, RDB–SC, STECF and the Zagreb meeting on transversal variables. ICES, as a main end user, provided feedback. A summary was presented of the progress in the regional coordination project (fishPi). This project involves over 40 participants from 12 members states from NS&EA, NA and Baltic regions, two external statistical experts, and ICES. The project has a wide scope of regional cooperation issues including sampling designs, data formats, code lists, PETS, stomach sampling, small scale and recreational sampling, and data quality software production. It has a budget of €400,000, and a one year time line and with a planned completion date of April 2016. A project with identical aims is running in paralleled in the Mediterranean and Black Sea regions The majority of the ToRs of the RCM NS&EA were addressed by three subgroups: one concerned with data analysis, one with the landing obligation, and one with issues particularly related to role and work of national correspondents

Culture Adaptation Alters Transcriptional Hierarchies among Single Human Embryonic Stem Cells Reflecting Altered Patterns of Differentiation

We have used single cell transcriptome analysis to re-examine the substates of early passage, karyotypically Normal, and late passage, karyotypically Abnormal (‘Culture Adapted’) human embryonic stem cells characterized by differential expression of the cell surface marker antigen, SSEA3. The results confirmed that culture adaptation is associated with alterations to the dynamics of the SSEA3(+) and SSEA3(-) substates of these cells, with SSEA3(-) Adapted cells remaining within the stem cell compartment whereas the SSEA3(-) Normal cells appear to have differentiated. However, the single cell data reveal that these substates are characterized by further heterogeneity that changes on culture adaptation. Notably the Adapted population includes cells with a transcriptome substate suggestive of a shift to a more naïve-like phenotype in contrast to the cells of the Normal population. Further, a subset of the Normal SSEA3(+) cells expresses genes typical of endoderm differentiation, despite also expressing the undifferentiated stem cell genes, POU5F1 (OCT4) and NANOG, whereas such apparently lineage-primed cells are absent from the Adapted population. These results suggest that the selective growth advantage gained by genetically variant, culture adapted human embryonic stem cells may derive in part from a changed substate structure that influences their propensity for differentiation

Large-Scale Evidence for the Effect of the COLIA1 Sp1 Polymorphism on Osteoporosis Outcomes: The GENOMOS Study

BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm (2) (CI, 16 to 34 mg/cm (2)) lower in TT homozygotes than the other genotype groups ( p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm (2) (CI, 1 to 42 mg/cm (2)), ( p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases

Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series

Background Several relatively large studies have assessed molecular indicators of colorectal cancer (CRC) prognosis, but most analyses have been restricted to a handful of markers. Methods In stage II/III CRCs from the QUASAR2 clinical trial and from an Australian community-based series, we assessed gene panels for somatic driver mutations and overall mutation burden. We determined molecular pathways of tumorigenesis, and analysed associations with treatment response and prognosis. Findings In QUASAR2 (N=511), TP53, KRAS, BRAF and GNAS mutations were independently associated with shorter relapse-free survival, whereas total somatic mutation burden was associated with longer survival, even after excluding mismatch repair-deficient (MSI+) and POLE-mutant tumours. We successfully validated these associations in the Australian sample set (N=296). In an extended analysis of 1,752 QUASAR2 and Australian CRCs for which KRAS, BRAF and MSI status was available, we found that KRAS and BRAF mutations were specifically associated with poor prognosis in MSI- cancers. This association was not present in MSI+ cancers, and MSI+ tumours with KRAS or BRAF mutation actually had better prognosis than MSI- cancers that were wildtype for KRAS or BRAF. New rare molecular pathways were also uncovered: mutations in the genes NF1 and NRAS from the MAP kinase pathway co-occurred, mutations in TP53 and ATM appeared to be alternative ways of inactivating the DNA damage response pathway. Interpretation A multi-gene panel has identified two previously unreported prognostic associations in CRC involving both TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. We conclude that even a modest-sized gene panel can provide important information for use in clinical practice and out-perform MSI-based models.</p

The potential for out-of-season beef finishing systems on farms in the lower North Island : a thesis presented in partial fulfilment of the requirements for the degree of Master of Applied Science in Agricultural Systems and Management at Massey University, New Zealand

Beef production in New Zealand is strongly seasonal and reflects the pattern of pasture production on which livestock farming is based. Providing a more uniform supply of beef cattle to processors has the potential to improve returns to the New Zealand beef industry, first by increasing the market opportunities for New Zealand products, especially in the more lucrative markets requiring fresh (short shelf-life) beef cuts, and second by improving the utilisation of capital invested in processing. The primary aim of this study was to investigate the potential of Out-of-Season (OOS) beef finishing systems to reduce the seasonality of beef cattle supply to meat processors. The study focused on developing an understanding of the biophysical, social and economic factors that would affect the implementation of OOS polices for a sample of 14 farmers in the lower North Island. A Farming Systems Research (FSR) approach provided the framework for the field work and methods used in the study. A secondary objective of the study was to investigate the applicability of Farming Systems Research (FSR) methods for obtaining an improved understanding of the on-farm implications of OOS finishing systems and thereby enhancing the relevance of the findings to industry stakeholders. The first phase of the study involved semi-structured interviews with eight meat industry key informants. Their views were obtained on the effects of the seasonal pattern of beef cattle supply and the potential of OOS production systems to address this issue. Semi-structured interviews with 14 farmers with contrasting farming resources in a defined study region were then completed. Data was obtained from these farmers in order to identify the constraints, costs and opportunities they associated with OOS beef finishing policies. The final phase of the study included three in-depth case farm studies. The whole-farm computer simulation model StockPolTM was used to investigate and quantify the costs and implications of OOS finishing systems for each case farm. The seasonal pattern of beef cattle supply was confirmed as being a major disadvantage for processors and marketers in the New Zealand meat industry. Processing and marketing representatives believed that on-farm OOS beef finishing systems provided a realistic option for addressing the disadvantages. However, farmers believed that OOS finishing systems were less suited to, and more demanding of, their pasture-based systems. The effects of OOS polices on winter feed levels, summer pasture quality, and soil damage were identified by farmers as constraints to their adoption. The simulation of alternative production systems for the case farms suggested that premiums for cattle produced OOS would need to be about 20% above normal schedule payments in order to compensate for the lower biological efficiency of OOS systems. While it was difficult to formally evaluate the success of the FSR approach, the methods used proved successful in obtaining a detailed understanding of the constraints and impacts of OOS beef finishing systems faced by farmers

Minimally invasive prenatal diagnosis of inherited disorders employing trophoblastic cells shed into the endocervical canal

Fetal (trophoblastic) cellular elements have been detected in transcervical cell (TCC) samples collected from the uterine cavity and cervical canal of pregnant women between 6 and 15 weeks of fetal gestation. These cells, present in a background of maternal material, have been identified utilising various molecular techniques. Chromosome Y specific DNA sequences have been detected using both fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR) assays. Fetal specific short tandem repeat (STR) allele sizes have been identified in TCC samples indicating the presence of fetal DNA. Trophoblast cells have been identified in TCC samples using monoclonal antibodies specific for trophoblast antigens. Using these methods various TCC sampling procedures have been compared for their efficiency of fetal cell retrieval. The safety of TCC sampling has also been assessed by the collection of samples from ongoing pregnancies prior to CVS, and comparison with a control group. The fetal Rh(d) type has been successfully diagnosed from TCC samples collected from Rh(d) negative mothers. Fetal genetic errors have been identified including trisomy 18, trisomy 21, XYY and triploidy. In attempts to identify recessive fetal disorders and X linked diseases, the isolation of trophoblastic elements has been attempted. Numerous methods have been employed to this end including micromanipulation, trophoblast specific mRNA detection, and magnetic activated cell sorting using trophoblast specific antibodies. Multiplex quantitative fluorescent PCR techniques have been developed to test these isolated cell clumps and individual cells for various inherited disorders. These include the detection of sex chromosome complement, chromosome aneuploidies, the delta-F 508 three base pair deletion causing cystic fibrosis, the single base change causing sickle cell anaemia, and a single base change and two deletions causing beta-thalassaemia. To test separated trophoblast cells, and with a view to potential preimplantation diagnosis, large numbers of isolated single cells were tested with these methods and the results assessed