An observational study was carried out to determine the rate of acute kidney injury (AKI) following surgery for hip fracture at our institution and to look for factors associated with AKI.
...Preoperative creatinine values were compared to post-operative results for all patients who underwent surgery for hip fracture at our institution between 1
January 2015 and 30
September 2016. AKI was defined as an increase in postoperative creatinine, greater than or equal to 1.5 times the preoperative value within 7 days. Chi-squared test and Student's t-test were used to look for factors associated with AKI.
Out of 500 patients, 96 developed an AKI (19.2%). Patients with chronic kidney disease (CKD) were more likely to develop AKI (30.8%) that those without it (17.2%, p = 0.018). Similarly, patients with 2 or more comorbidities were more likely to develop AKI (22.0%) than those without it (12.4%, p = 0.009). No statistically significant association was observed between type of surgery and AKI.
A large proportion of patients following surgery for hip fracture developed AKI. Patients with CKD and the presence of 2 or more comorbidities had significantly higher rates of AKI.
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While Rebecca is not currently a set text for A-Level English Literature, this paper argues that the novel's multi-faceted richness would justify its inclusion in any list of recommended texts. ...Divided into four interconnected parts, the paper offers, firstly, some approaches to the reading and teaching of fiction, generally. The second part presents some framing contexts for illuminating many of Rebecca's preoccupations. These include: ideas about the Gothic tradition and the presentation of Fatal Women in some Romantic literature; some considerations about patriarchy, misogyny, gender and identity; finally, attention is given to the intersection between dream and reality in Rebecca and to the idea of obsession and the double self in two other works by Du Maurier. In the third part, more detailed attention is given to the presentation of character in the novel. The fourth part explores some pedagogical approaches to the novel in the sixth-form classroom.
This paper is predicated on an argument for presenting the Irish short story as a statutory recommendation within the A Level English syllabus in Northern Ireland (and also, perhaps, in syllabi set ...by Examination Boards in other parts of the United Kingdom). Employing a carefully considered literary-critical perspective, the paper offers a detailed evaluation of a representative selection of twentieth-century Irish short stories. The first part, sub-divided into two sections, provides, firstly, some observations about form in the Irish short story and, secondly, it offers some historical and social contexts which provide a backcloth to the evolution of the short story as the twentieth century progressed. The second part, in exploring a carefully selected range of stories, seeks to highlight both their thematic richness and their well-honed craftsmanship. Some of the themes which emerge, and which arguably have universal resonances, include the trauma of emigration, the changing role of women in a society beginning to loosen the shackles of patriarchy, and the inhumanity of war.
Physical forces associated with spaceflight and spaceflight analogue culture regulate a wide range of physiological responses by both bacterial and mammalian cells that can impact infection. However, ...our mechanistic understanding of how these environments regulate host-pathogen interactions in humans is poorly understood. Using a spaceflight analogue low fluid shear culture system, we investigated the effect of Low Shear Modeled Microgravity (LSMMG) culture on the colonization of
Salmonella
Typhimurium in a 3-D biomimetic model of human colonic epithelium containing macrophages. RNA-seq profiling of stationary phase wild type and Δ
hfq
mutant bacteria alone indicated that LSMMG culture induced global changes in gene expression in both strains and that the RNA binding protein Hfq played a significant role in regulating the transcriptional response of the pathogen to LSMMG culture. However, a core set of genes important for adhesion, invasion, and motility were commonly induced in both strains. LSMMG culture enhanced the colonization (adherence, invasion and intracellular survival) of
Salmonella
in this advanced model of intestinal epithelium using a mechanism that was independent of Hfq. Although
S
. Typhimurium Δ
hfq
mutants are normally defective for invasion when grown as conventional shaking cultures, LSMMG conditions unexpectedly enabled high levels of colonization by an isogenic Δ
hfq
mutant. In response to infection with either the wild type or mutant, host cells upregulated transcripts involved in inflammation, tissue remodeling, and wound healing during intracellular survival. Interestingly, infection by the Δ
hfq
mutant led to fewer transcriptional differences between LSMMG- and control-infected host cells relative to infection with the wild type strain. This is the first study to investigate the effect of LSMMG culture on the interaction between
S
. Typhimurium and a 3-D model of human intestinal tissue. These findings advance our understanding of how physical forces can impact the early stages of human enteric salmonellosis.
Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled ...with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.
Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic ...castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.
In evaluating some of Heaney's prose writings about the art of poetry - what I have called his 'Poetics' - the paper explores how those ideas could enhance the teaching of poetry in the upper ...post-primary schools. The paper is divided into four closely interconnected sections. The first section evaluates Heaney's thoughts about the potential centrality of poetry in the English curriculum. In the second section, Heaney's thoughts about the conflict between 'poetry's self-delighting inventiveness' and 'the pressures of reality' are considered, with some complementary attention to a few of Heaney's own Troubles poems. The third section, in evaluating Heaney's critiques of some individual poets, registers some of his valuable specific, as well as more general, pedagogical insights. Finally, his prose thoughts about the wellsprings of poetic creativity are examined, together with a brief critique of his poem 'The Play Way', which is focused on teaching creative writing in a post-primary classroom.
The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line ...therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.
Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 ...and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.
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