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The rapid response system concept is one of the first patient-centered and organizational-wide systems aimed at preventing deaths and serious adverse events. It has been strongly argued that we need a benchmark that reflects the care of a deteriorating patient across the organization using a 'score to door time'; that is, the time from the first vital sign abnormality to admission to the ICU. The study by Oglesby and colleagues highlights serious issues, especially delays, which could adversely impact on patient care, and the study proposes that we concentrate more on measuring patient care from a broad perspective. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair., Methods: We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation., Results: We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells., Conclusions: Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs., (© 2024. The Author(s).)

Background: Clinical frailty among older adults admitted to intensive care has been proposed as an important determinant of patient outcomes. Among this group of patients, an acute episode of delirium is also common, but its relationship to frailty and increased risk of mortality has not been extensively explored. Therefore, the aim of this study was to explore the relationship between clinical frailty, delirium and hospital mortality of older adults admitted to intensive care., Methods: This study is part of a Delirium in Intensive Care (Deli) Study. During the initial 6-month baseline period, clinical frailty status on admission to intensive care, among adults aged 50 years or more; acute episodes of delirium; and the outcomes of intensive care and hospital stay were explored., Results: During the 6-month baseline period, 997 patients, aged 50 years or more, were included in this study. The average age was 71 years (IQR, 63-79); 55% were male (n = 537). Among these patients, 39.2% (95% CI 36.1-42.3%, n = 396) had a Clinical Frailty Score (CFS) of 5 or more, and 13.0% (n = 127) had at least one acute episode of delirium. Frail patients were at greater risk of an episode of delirium (17% versus 10%, adjusted rate ratio ( adj RR) = 1.71, 95% confidence interval (CI) 1.20-2.43, p = 0.003), had a longer hospital stay (2.6 days, 95% CI 1-7 days, p = 0.009) and had a higher risk of hospital mortality (19% versus 7%, adj RR = 2.54, 95% CI 1.72-3.75, p < 0.001), when compared to non-frail patients. Patients who were frail and experienced an acute episode of delirium in the intensive care had a 35% rate of hospital mortality versus 10% among non-frail patients who also experienced delirium in the ICU., Conclusion: Frailty and delirium significantly increase the risk of hospital mortality. Therefore, it is important to identify patients who are frail and institute measures to reduce the risk of adverse events in the ICU such as delirium and, importantly, to discuss these issues in an open and empathetic way with the patient and their families.

Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Struvite was observed within the microalgae biofilm matrix of an outdoor, pilot-scale rotating algal biofilm reactor (RABR) designed to remove nitrogen and phosphorus from municipal anaerobic digester filtrate. The bottom layer of cells (2.5-month growth) and two top layers of cells (1-week and 2.5-month growth) were evaluated on east- and west-facing sides of the RABR. Sun orientation and shading effects of upper biofilm layers impacted the species composition and microalgae content of the bottom biofilm layers. Struvite formed within the microalgae biofilm matrix, and a higher struvite content appeared to be correlated with a higher microalgae content. The highest struvite content (expressed as %wt. of total solids) was observed in the east- and west-facing bottom layers of growth and west-facing 1-week growth (5.0%, 4.3%, and 4.1%, respectively). The lowest struvite content was observed in east- and west-facing 2.5-month growth and east-facing 1-week growth (1.1%, 1.5%, and 1.1%, respectively). Despite RABR influent component ion molar ratios with potential for various magnesium and calcium precipitates, microalgae biofilm provided pH and nucleation sites favorable to struvite precipitation. This evaluation is the first in the refereed literature the authors are aware of that reports on the association of struvite formation in the presence of a microalgae biofilm.

Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression., Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region., Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

Background: Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear., Results: Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants., Conclusions: We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.

Our population is ageing, and this is also reflected in the ageing of the hospital and intensive care population. Along with ageing, there is also an increase in age-related chronic health conditions or comorbidities, which in turn affects the patient's functional state. There is an increasing need to describe a patient's clinical condition in terms of their functional capacity, such as frailty. Frailty is an age-related syndrome which reduces physiological and cognitive reserves. As a result, frailty increases people's vulnerability to insults such as infection and trauma. The concept of frailty also indicates prognosis and levels of health from a patient's perspective rather than simply from the acute reason for admission to the intensive care unit. Understanding the concept of frailty may facilitate our awareness of long-term outcomes after intensive care and being a trigger for considering its prognostic implications and the need to honestly and empathetically begin discussions with patients and their carers and how the patient's own goals of care could be established around this information., (Copyright © 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

This corrects the article DOI: 10.1038/ncomms5999.

Introduction: Despite widespread availability of clinical practice guidelines (CPGs), considerable gaps continue between the care that is recommended ('appropriate care') and the care provided. Problems with current CPGs are commonly cited as barriers to providing 'appropriate care'.Our study aims to develop and test an alternative method to keep CPGs accessible and up to date. This method aims to mitigate existing problems by using a single process to develop clinical standards (embodied in clinical indicators) collaboratively with researchers, healthcare professionals, patients and consumers. A transparent and inclusive online curated (purpose-designed, custom-built, wiki-type) system will use an ongoing and iterative documentation process to facilitate synthesis of up-to-date information and make available its provenance. All participants are required to declare conflicts of interest. This protocol describes three phases: engagement of relevant stakeholders; design of a process to develop clinical standards (embodied in indicators) for 'appropriate care' for common medical conditions; and evaluation of our processes, products and feasibility., Methods and Analysis: A modified e-Delphi process will be used to gain consensus on 'appropriate care' for a range of common medical conditions. Clinical standards and indicators will be developed through searches of national and international guidelines, and formulated with explicit criteria for inclusion, exclusion, time frame and setting. Healthcare professionals and consumers will review the indicators via the wiki-based modified e-Delphi process. Reviewers will declare conflicts of interest which will be recorded and managed according to an established protocol. The provenance of all indicators and suggestions included or excluded will be logged from indicator inception to finalisation. A mixed-methods formative evaluation of our research methodology will be undertaken., Ethics and Dissemination: Human Research Ethics Committee approval has been received from the University of South Australia. We will submit the results of the study to relevant journals and offer national and international presentations., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)

Background: Health care-associated infections (HAI) have been shown to increase length of stay, the cost of care, and rates of hospital deaths (Kaye and Marchaim, J Am Geriatr Soc 62(2):306-11, 2014; Roberts and Scott, Med Care 48(11):1026-35, 2010; Warren and Quadir, Crit Care Med 34(8):2084-9, 2006; Zimlichman and Henderson, JAMA Intern Med 173(22):2039-46, 2013). Importantly, infections acquired during a hospital stay have been shown to be preventable (Loveday and Wilson, J Hosp Infect 86:S1-70, 2014). In particular, due to more invasive procedures, mechanical ventilation, and critical illness, patients cared for in the intensive care unit (ICU) are at greater risk of HAI and associated poor outcomes. This meta-analysis aims to summarise the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce infection., Methods: A systematic literature search was undertaken to identify trials assessing the effectiveness of CHG bathing to reduce risk of infection, among adult intensive care patients. Infections included were: bloodstream infections; central line-associated bloodstream infections (CLABSI); catheter-associated urinary tract infections; ventilator-associated pneumonia; methicillin-resistant Staphylococcus aureus (MRSA); vancomycin-resistant Enterococcus; and Clostridium difficile. Summary estimates were calculated as incidence rate ratios (IRRs) and 95% confidence/credible intervals. Variation in study designs was addressed using hierarchical Bayesian random-effects models., Results: Seventeen trials were included in our final analysis: seven of the studies were cluster-randomised crossover trials, and the remaining studies were before-and-after trials. CHG bathing was estimated to reduce the risk of CLABSI by 56% (Bayesian random effects IRR = 0.44 (95% credible interval (CrI), 0.26, 0.75)), and MRSA colonisation and bacteraemia in the ICU by 41% and 36%, respectively (IRR = 0.59 (95% CrI, 0.36, 0.94); and IRR = 0.64 (95% CrI, 0.43, 0.91)). The numbers needed to treat for these specific ICU infections ranged from 360 (CLABSI) to 2780 (MRSA bacteraemia)., Conclusion: This meta-analysis of the effectiveness of CHG bathing to reduce infections among adults in the ICU has found evidence for the benefit of daily bathing with CHG to reduce CLABSI and MRSA infections. However, the effectiveness may be dependent on the underlying baseline risk of these events among the given ICU population. Therefore, CHG bathing appears to be of the most clinical benefit when infection rates are high for a given ICU population.

Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER + ) breast cancer (per-g allele OR ER + = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10 -30 ). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER - ) breast cancer (lead SNP rs6864776: per-a allele OR ER - = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10 -12 ), and a single signal 3 SNP (rs200229088: per-t allele OR ER + = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10 -05 ). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

An obligatory anaerobic, Gram-stain-negative coccobacillus with black-pigmented colonies was isolated from the oral cavity of selected Australian marsupial species. Phenotypic and molecular criteria showed that this bacterium was a distinct species within the genus Porphyromonas, and was closely related to Porphyromonas gingivalis and Porphyromonas gulae. This putative novel species and P. gulae could be differentiated from P. gingivalis by catalase activity. Further characterization by multi-locus enzyme electrophoresis of glutamate dehydrogenase and malate dehydrogenase enzyme mobility and matrix-assisted laser desorption ionization time-of-flight MS showed that this putative novel species could be differentiated phenotypically from P. gingivalis and P. gulae. Definitive identification by 16S rRNA gene sequencing showed that this bacterium belonged to a unique monophyletic lineage, phylogenetically distinct from P. gingivalis (94.9 % similarity) and P. gulae (95.5 %). This also was supported by 16S-23S rRNA intergenic spacer region and glutamate dehydrogenase gene sequencing. A new species epithet, Porphyromonas loveana sp. nov., is proposed for this bacterium, with DSM 28520T (=NCTC 13658T=UQD444T=MRK101T), isolated from a musky rat kangaroo, as the type strain.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.

The development of ICUs as the final option for seriously ill patients, especially the elderly frail patient at the end of his/her life, has meant that intensivists have increasingly taken on the role of diagnosing the dying. Our society, and even our medical colleagues, do not necessarily understand what we can achieve in ICUs, and even more importantly, what we cannot achieve. The next crucial step for us as individuals, and through our professional bodies, is to engage our society in discussions on our role and encourage debate and discussion, being aware of the controversies that will inevitably result. Birthing in the 1950s was medicalised without discussion with women and their families. In a similar manner, dying has been medicalised in the twenty-first century. It has not been a conspiracy and the use of futile and expensive treatment at the EoL transition is not necessarily anyone's choice. The specialty of intensive care has a particularly important role in facilitating discussions with our society in order to define different ways of managing dying.

The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)