Statewide retrospective study of low acuity emergency presentations in New South Wales, Australia: who, what, where and why?

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Abstract Objective The present study aims to use a statewide population-based registry to assess the prevalence of low acuity emergency department (ED) presentations, describe the trend in presentation rates and to determine whether they were associated with various presentation characteristics such as the type of hospital as well as clinical and demographic variables. Design and setting This was a retrospective analysis of a population-based registry of ED presentations in New South Wales (NSW). Generalised estimating equations with log links were used to determine factors associated with low acuity presentations to account for repeat presentations and the possibility of clustering of outcomes. Participants Patients were included in this analysis if they presented to an ED between January 2010 and December 2014. The outcomes of interest were low acuity presentation, defined as those who self-presented (were not transported by ambulance), were assigned a triage category of 4 or 5 (semiurgent or non-urgent) and discharged back to usual residence from ED. Results There were 10.7 million ED presentations analysed. Of these, 45% were classified as a low acuity presentation. There was no discernible increase in the rate of low acuity presentations across NSW between 2010 and 2014. The strongest predictors of low acuity ED presentation were age <40 years of age (OR 1.77); injury or musculoskeletal administrative and non-urgent procedures (OR 2.96); ear, nose and throat, eye or oral (OR 5.53); skin or allergy-type presenting problems (OR 2.84). Conclusions Low acuity ED presentations comprise almost half of all ED presentations. Alternative emergency models of care may help meet the needs of these patients

The genomic road to invasion - examining the similarities and differences in the genomes of associated oral pre-cancer and cancer samples.

Background: It is frequently assumed that pre-invasive lesions are simpler precursors of cancer, and will contain a limited subset of the genomic changes seen in their associated invasive disease. Driver mutations are thought to occur early, but it is not known how many of these are present in pre-invasive lesions. These assumptions need to be tested with the increasing focus on both personalised cancer treatments, and early detection methodologies. Methods: We examined genomic copy number changes in 256 pre-invasive and invasive samples from 69 oral cancer patients. Forty-eight samples from 16 patients were further examined using exome sequencing. Results: Evidence of a shared ancestor of both dysplasia and carcinoma was seen in all but one patient. One third of dysplasias showed independent copy number events. The remainder had a similar or simpler copy number pattern to the carcinoma. All dysplasias examined contained somatic mutations absent in the related carcinoma. Previously observed copy number changes and TP53 mutations were very frequently observed, and almost always shared between dysplasia and carcinoma. Other gene changes were more sporadic. Pathway analysis confirmed that each patient’s disease developed in a different way. Examining the numbers of shared mutations, and the rate of accumulation of mutations showed evidence that all samples contain a population of sub-clones, with little evidence of selective advantage of a subset of these. Conclusions: These findings suggest that most of the genomic changes driving oral cancer occur in the pre-cancerous state by way of gradual random accumulation rather than a dramatic single event

A computational index derived from whole-genome copy number analysis is a novel tool for prognosis in early stage lung squamous cell carcinoma.

AbstractSquamous cell carcinoma of the lung is remarkable for the extent to which the same chromosomal abnormalities are detected in individual tumours. We have used next generation sequencing at low coverage to produce high resolution copy number karyograms of a series of 89 non-small cell lung tumours specifically of the squamous cell subtype. Because this methodology is able to create karyograms from formalin-fixed paraffin-embedded material, we were able to use archival stored samples for which survival data were available and correlate frequently occurring copy number changes with disease outcome. No single region of genomic change showed significant correlation with survival. However, adopting a whole-genome approach, we devised an algorithm that relates to total genomic damage, specifically the relative ratios of copy number states across the genome. This algorithm generated a novel index, which is an independent prognostic indicator in early stage squamous cell carcinoma of the lung

Using next-generation sequencing for high resolution multiplex analysis of copy number variation from nanogram quantities of DNA from formalin-fixed paraffin-embedded specimens

The use of next-generation sequencing technologies to produce genomic copy number data has recently been described. Most approaches, however, reply on optimal starting DNA, and are therefore unsuitable for the analysis of formalin-fixed paraffin-embedded (FFPE) samples, which largely precludes the analysis of many tumour series. We have sought to challenge the limits of this technique with regards to quality and quantity of starting material and the depth of sequencing required. We confirm that the technique can be used to interrogate DNA from cell lines, fresh frozen material and FFPE samples to assess copy number variation. We show that as little as 5 ng of DNA is needed to generate a copy number karyogram, and follow this up with data from a series of FFPE biopsies and surgical samples. We have used various levels of sample multiplexing to demonstrate the adjustable resolution of the methodology, depending on the number of samples and available resources. We also demonstrate reproducibility by use of replicate samples and comparison with microarray-based comparative genomic hybridization (aCGH) and digital PCR. This technique can be valuable in both the analysis of routine diagnostic samples and in examining large repositories of fixed archival material

Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.

PURPOSE: Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. PATIENTS AND METHODS: We defined a molecular high-grade (MHG) group by applying a gene expression-based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. RESULTS: The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. CONCLUSION: MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.Supported by Bloodwise grant number 15002: Precision Medicine for Aggressive Lymphoma. The Randomized Evaluation of Molecular-Guided Therapy for DLBCL With Bortezomib (REMoDL-B) trial was endorsed by Cancer Research UK, reference number CRUKE/10/024, and Janssen-Cillag provided funding. A.S. is partly funded by the National Institute for Health Research Oxford Biomedical Research Centre. D.R.W. acknowledges UK Medical Research Council grant MR/L01629X/1 for infrastructure support

Interactome Analyses Identify Ties of PrPC and Its Mammalian Paralogs to Oligomannosidic N-Glycans and Endoplasmic Reticulum-Derived Chaperones

The physiological environment which hosts the conformational conversion of the cellular prion protein (PrPC) to disease-associated isoforms has remained enigmatic. A quantitative investigation of the PrPC interactome was conducted in a cell culture model permissive to prion replication. To facilitate recognition of relevant interactors, the study was extended to Doppel (Prnd) and Shadoo (Sprn), two mammalian PrPC paralogs. Interestingly, this work not only established a similar physiological environment for the three prion protein family members in neuroblastoma cells, but also suggested direct interactions amongst them. Furthermore, multiple interactions between PrPC and the neural cell adhesion molecule, the laminin receptor precursor, Na/K ATPases and protein disulfide isomerases (PDI) were confirmed, thereby reconciling previously separate findings. Subsequent validation experiments established that interactions of PrPC with PDIs may extend beyond the endoplasmic reticulum and may play a hitherto unrecognized role in the accumulation of PrPSc. A simple hypothesis is presented which accounts for the majority of interactions observed in uninfected cells and suggests that PrPC organizes its molecular environment on account of its ability to bind to adhesion molecules harboring immunoglobulin-like domains, which in turn recognize oligomannose-bearing membrane proteins

The presence of placeholders modulates the naso-temporal asymmetry in the remote distractor effect

The remote distractor effect (RDE) is a well-known and robust phenomenon whereby latencies of saccades are increased when a distractor is presented simultaneously along with the saccade target. Studies of the RDE in patients with a loss of vision in one visual field (hemianopia) following damage to primary visual cortex have provided conflicting results. Rafal, Smith, Krantz, Cohen, and Brennan (1990) reported a naso-temporal asymmetry in the RDE in patients with hemianopias, with a greater influence of distractors presented in their blind temporal visual field. This asymmetry was not observed in typically sighted controls. By contrast, Walker, Mannan, Maurer, Pambakian, and Kennard (2000) observed no effect of distractors presented to either the blind nasal or blind temporal hemifield of hemianopes, but the naso-temporal asymmetry was observed in typically sighted controls. The present study addressed one potential methodological differences between the two studies by investigating the inhibitory effect of a distractor on saccade latency in neurotypical participants. Here participants were tested monocularly and the effect of a nasal/temporal hemifield distractor on saccade latency observed in the presence or absence of peripheral placeholders. Our results showed a naso-temporal asymmetry in the magnitude of the RDE in the no placeholder condition, with a greater RDE when the distractor was presented in the temporal visual field. However, in the placeholder condition the opposite asymmetry was observed, that is an increased RDE when the distractor was presented in the nasal visual field. Our results suggest that the presence/absence of a placeholder might be the critical factor explaining the discrepancy between Rafal et al. (1990) and Walker et al. (2000) in participants without visual field loss. The current results can be interpreted in terms of additional inhibitory or attentional processes that bias selection towards stimuli in the nasal hemifield in the presence of placeholders, still, the mechanisms underlying these effects remain unclear