Effects of Birthing Room Design on Maternal and Neonate Outcomes: A Systematic Review

Aim: To summarize, categorize, and describe published research on how birthing room design influences maternal and neonate physical and emotional outcomes. Background: The physical healthcare environment has significant effects on health and well-being. Research indicates that birthing environments can impact women during labor and birth. However, summaries of the effects of different environments around birth are scarce. Methods: We conducted a systematic review, searching 10 databases in 2016 and 2017 for published research from their inception dates, on how birthing room design influences maternal and neonate physical and emotional outcomes, using a protocol agreed a priori. The quality of selected studies was assessed, and data were extracted independently by pairs of authors and described in a narrative analysis. Results: In total, 3,373 records were identified and screened by title and abstract; 2,063 were excluded and the full text of 278 assessed for analysis. Another 241 were excluded, leaving 15 articles presenting qualitative and quantitative data from six different countries on four continents. The results of the analysis reveal four prominent physical themes in birthing rooms that positively influence on maternal and neonate physical and emotional outcomes: (1) means of distraction, comfort, and relaxation; (2) raising the birthing room temperature; (3) features of familiarity; and (4) diminishing a technocratic environment. Conclusions: The evidence on how birthing environments affect outcomes of labor and birth is incomplete. There is a crucial need for more research in this field

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Post-delamination magmatism in south-central Anatolia

Quaternary mafic lavas in Central Anatolia provide geochemical insights into melt generation processes following regional delamination of the subducted Tethyan slabs. New geochemical data from the Pleistocene Hasandağ Cinder Cone Province (HCCP) and Karapınar Volcanic Field (KVF) record contributions from subduction-modified lithospheric and sub-lithospheric source domains that are distinct from those sampled elsewhere across Anatolia (e.g., Pearce et al., 1990; Aldanmaz et al., 2006; Keskin, 2007; Chakrabarti et al., 2012; Reid et al., 2017). Hasandağ cinder cones are primarily basaltic, with subordinate trachybasalt and basaltic trachyandesite; Karapınar lavas comprise basalts and andesites with subordinate basaltic trachyandesite and basaltic andesite. Anomalously high Li, Na, Ti and Zr abundances and Ba/Rb values in these South-Central Anatolian primitive mafic lavas suggest significant contribution from metasomatic phases (i.e., amphibole, zircon and rutile); Dy/Ybn values measured in the mafic volcanics indicate melting in the spinel stability field. Correlation between 87Sr/86Sr and εNd in HCCP and KVF lavas indicate pseudo-binary mixing between enriched and depleted endmembers, while εNd-εHf isotopic values that plot above the terrestrial array extend toward sediment compositions sampled from the eastern Mediterranean Sea (Klaver et al., 2015). Together, trace element chemistry and Sr-Nd-Hf-Pb isotope compositions suggest input from a spatially heterogeneous mantle with contributions from depleted MORB-like and recycled sediment sources. The apparent presence of pyroxenite and hydrous metasomes within the HCCP and KVF source regions, and abundant dense mafic cumulates associated with the adjacent Hasandağ stratovolcano, support an unstable small-scale lithospheric density structure in South-Central Anatolia. We suggest regional delamination of the Neotethyan slab on a regional scale caused upwelling asthenosphere to destabilize the remaining Central Anatolian lithosphere and resulted in localized drip melting to produce the mafic volcanism at the HCCP and KVF. Geochemical similarities to Miocene alkali basalts from Galatia and Sivas (Wilson et al., 1997; Varol et al., 2014; Kürkcüoğlu et al., 2015) suggest that this mechanism occurred across Central Anatolia subsequent to Tethys subduction, and thus the ages of monogenetic volcanic activity record the descent of the slab beneath Anatolia. We infer that slab foundering played a more important role in this process than lithospheric loss beneath a tectonically shortened orogen (Göğüs et al., 2017) although further mapping of sedimentary basins and structures is required to resolve this interpretation

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

$\textbf{Background:}$ Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic $\textit{TP53}$ mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). $\textbf{Methods and Findings:}$ We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific $\textit{TP53}$ assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The $\textit{TP53}$ mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson $r$ = 0.59, $p$ 32 cm$^3$, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, $p$ = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. $\textbf{Conclusions:}$ In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.This work was supported by Cancer Research UK Grant numbers: A15601 (JDB), A11906 (NR), A20240 (NR), A18072 (JDB). JDB was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. CAP was supported in part by the Academy of Medical Sciences, the Wellcome Trust, British Heart Foundation and Arthritis Research UK

Patterns of somatic mutation in human cancer genomes

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated. ©2007 Nature Publishing Group.link_to_subscribed_fulltex