A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable

Background Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) provides a small but significant survival benefit. Nevertheless, controversies on applying NAC remain because the limited benefit must be weight against chemotherapy-related toxicity and the delay of definitive local treatment. Therefore, there is a clear clinical need for tools to guide treatment decisions on NAC in MIBC. Here, we aimed to validate a previously reported 20-gene expression signature that predicted lymph node-positive disease at radical cystectomy in clinically node-negative MIBC patients, which would be a justification for upfront chemotherapy. Methods We studied diagnostic transurethral resection of bladder tumors (dTURBT) of 150 MIBC patients (urothelial carcinoma) who were subsequently treated by radical cystectomy and pelvic lymph node dissection. RNA was isolated and the expression level of the 20 genes was determined on a qRT-PCR platform. Normalized Ct values were used to calculate a risk score to predict the presence of node-positive disease. The Cancer Genome Atlas (TCGA) RNA expression data was analyzed to subsequently validate the results. Results In a univariate regression analysis, none of the 20 genes significantly correlated with nodepositive disease. The area under the curve of the risk score calculated by the 20-gene expression signature was 0.54 (95% Confidence Interval: 0.44-0.65) versus 0.67 for the model published by Smith et al. Node-negative patients had a significantly lower tumor grade at TURBT (p = 0.03), a lower pT stage (p<0.01) and less frequent lymphovascular invasion (13% versus 38%, p<0.01) at radical cystectomy than node-positive patients. In addition, in the TCGA data, none of the 20 genes was differentially expressed in node-negative versus node-positive patients. Conclusions We conclude that a 20-gene expression signature developed for nodal staging of MIBC at radical cystectomy could not be validated on a qRT-PCR platform in a large cohort of dTURBT specimens

Guillain-Barré syndrome following varicella-zoster virus infection

We describe the frequency, clinical features, and electrophysiological and immunological phenotypes of Guillain-Barré Syndrome (GBS) patients treated at a single institution in Bangladesh who had preceding chicken pox (primary Varicella-zoster virus [VZV] infection) within 4 weeks of GBS onset. A literature review of GBS cases preceding VZV infection is also provided. Diagnosis of GBS was based on the National Institute of Neurological Disorders and Stroke criteria for GBS. Serum anti-VZV IgM and IgG antibodies were quantified by indirect chemiluminescence immunoassay (CLIA); anti-Campylobacter jejuni IgG, IgM, and IgA antibodies and anti-ganglioside GM1 IgM and IgG antibodies, by enzyme-linked immunosorbent assays. Neurophysiologic subtypes were categorized following the Hadden criteria. Of 536 patients with GBS, 7 (1.3%) had chicken pox within 4 weeks before GBS onset. Four of the seven cases were male (age range, 23 to 40 years old). All seven patients were bed-bound, six had sensory symptoms, and three required mechanical ventilation for respiratory failure. All seven patients had CSF albuminocytologic dissociation and evidence of demyelination in nerve conduction studies. Anti-VZV IgM antibodies were present and anti-GM1 and anti-Campylobacter jejuni lipo-oligosaccharides (LOS) were negative in all cases. All patients had excellent outcome at 1 year (able to run). A systematic literature review of GBS cases related to VZV revealed 39 previously reported patients with comparable clinical presentations and outcomes, of which 36 had neurophysiologic evidence of demyelination. VZV infection is associated with the demyelinating subtype of GBS, clearly distinct from the axonal form of GBS that predominate in countries like Bangladesh

Predictors of self-perceived cultural responsiveness in entry-level physiotherapy students in Australia and Aotearoa New Zealand

Background: Ensuring physiotherapy students are well prepared to work safely and effectively in culturally diverse societies upon graduation is vital. Therefore, determining whether physiotherapy programs are effectively developing the cultural responsiveness of students is essential. This study aimed to evaluate the level of self-perceived cultural responsiveness of entry level physiotherapy students during their training, and explore the factors that might be associated with these levels. Methods: A cross sectional study of physiotherapy students from nine universities across Australia and Aotearoa New Zealand was conducted using an online self-administered questionnaire containing three parts: The Cultural Competence Assessment tool, Altemeyer’s Dogmatism scale, and the Marlowe-Crowne social desirability scale- short form. Demographic data relating to university, program, and level of study were also collected. Data was analysed using one-way ANOVA, t-tests and multiple regression analysis. Results: A total of 817 (19% response rate) students participated in this study. Overall, students had a moderate level of self-perceived cultural responsiveness (Mean (SD) = 5.15 (0.67)). Fewer number of weeks of clinical placement attended, lower levels of dogmatism, and greater social desirability were related to greater self-perceived cultural responsiveness. Additionally, fourth year undergraduate students perceived themselves to be less culturally responsive than first and second year students (p < 0.05). Conclusions: These results provide educators with knowledge about the level of self-perceived cultural responsiveness in physiotherapy students, and the factors that may need to be assessed and addressed to support the development of culturally responsive practice

Long-term follow-up of retrograde colonic irrigation for defaecation disturbances

Objective. Irrigation of the distal part of the large bowel is a nonsurgical alternative for patients with defaecation disturbance. In our institution, all patients with defaecation disturbances, not responding to medical treatment and biofeedback therapy, were offered retrograde colonic irrigation (RCI). This study is aimed at evaluating the long-term feasibility and outcome of RCI. Methods. Between 1989 and 2001, a consecutive series of 267 patients was offered RCI. All patients received instructions about RCI by one of our enterostomal therapists. Twenty-eight patients were lost to follow-up. A detailed questionnaire was sent by mail to 239 patients. The total response rate was 79% (190 patients). Based on the returned questionnaires it became clear the 21 (11%) patients never started RCI. The long-term feasibility and outcome of RCI was therefore assessed in the remaining group of 169 patients. Thirty-two patients were admitted with soiling, 71 patints with faecal incontinence, 37 patients with obstructed defaecation and 29 had defaecation disturbance after low anterior resection or pouch surgery. Results. According to the returned questionnaires, RCI was considered effective by 91 (54%) patients. Among patients with soling and faecal incontinence, RCI was found to be effective in, respectively, 47 and 41% of the subjects. Despite of the reported effectiveness, 10 (67%) patients with soiling and 5 (17%) patients with faecal incontinence decide to stop. Among patients with obstructed defaecation and those with defaecation disturbances after low anterior resection or pouch surgery the effectiveness of RCI was found to be 65 and 79%, respectively. None of these patients ceased their therapy. The overall succes-rate of long-term RCI was therefore 45%. Conclusions. Long-term RCI is beneficial for 45% of patients with defaecation disturbance. In the group of patients who considered RCI effective and beneficial, discontinuation of therapy was only observe among those with soiling and faecal incontinence

Spatial Light Modulators for the Manipulation of Individual Atoms

We propose a novel dipole trapping scheme using spatial light modulators (SLM) for the manipulation of individual atoms. The scheme uses a high numerical aperture microscope to map the intensity distribution of a SLM onto a cloud of cold atoms. The regions of high intensity act as optical dipole force traps. With a SLM fast enough to modify the trapping potential in real time, this technique is well suited for the controlled addressing and manipulation of arbitrarily selected atoms.Comment: 9 pages, 5 figure

Urinary peptide panel for prognostic assessment of bladder cancer relapse

Non-invasive tools stratifying bladder cancer (BC) patients according to the risk of relapse are urgently needed to guide clinical intervention. As a follow-up to the previously published study on CE-MSbased urinary biomarkers for BC detection and recurrence monitoring, we expanded the investigation towards BC patients with longitudinal data. Profling datasets of BC patients with follow-up information regarding the relapse status were investigated. The peptidomics dataset (n=98) was split into training and test set. Cox regression was utilized for feature selection in the training set. Investigation of the entire training set at the single peptide level revealed 36 peptides being strong independent prognostic markers of disease relapse. Those features were further integrated into a Random Forest-based model evaluating the risk of relapse for BC patients. Performance of the model was assessed in the test cohort, showing high signifcance in BC relapse prognosis [HR=5.76, p-value=0.0001, c-index=0.64]. Urinary peptide profles integrated into a prognostic model allow for quantitative risk assessment of BC relapse highlighting the need for its incorporation in prospective studies to establish its value in the clinical management of BC

Enhanced Enterovirus D68 Replication in Neuroblastoma Cells Is Associated with a Cell Culture-Adaptive Amino Acid Substitution in VP1

Since its emergence in the United States in 2014, enterovirus D68 (EV-D68) has been and is associated with severe respiratory diseases and acute flaccid myelitis. Even though EV-D68 has been shown to replicate in different neuronal cells in vitro, it is currently poorly understood which viral factors contribute to the ability to replicate efficiently in cells of the central nervous system and whether this feature is a clade-specific feature. Here, we determined the replication kinetics of clinical EV-D68 isolates from (sub)clades A, B1, B2, B3, and D1 in human neuroblastoma cells (SK-N-SH). Subsequently, we compared sequences to identify viral factors associated with increased viral replication. All clinical isolates replicated in SK-N-SH cells, although there was a large difference in efficiency. Efficient replication of clinical isolates was associated with an amino acid substitution at position 271 of VP1 (E271K), which was acquired during virus propagation in vitro. Recognition of heparan sulfate in addition to sialic acids was associated with increased attachment, infection, and replication. Removal of heparan sulfate resulted in a decrease in attachment, internalization, and replication of viruses with E271K. Taken together, our study suggests that the replication kinetics of EV-D68 isolates in SKN-SH cells is not a clade-specific feature. However, recognition of heparan sulfate as an additional receptor had a large effect on phenotypic characteristics in vitro. These observations emphasize the need to compare sequences from virus stocks with clinical isolates in order to retrieve phenotypic characteristics from original virus isolates. IMPORTANCE Enterovirus D68 (EV-D68) causes mild to severe respiratory disease and is associated with acute flaccid myelitis since 2014. Currently, the understanding of the ability of EV-D68 to replicate in the central nervous system (CNS), and whether it is associated with a specific clade of EV-D68 viruses or specific viral factors, is lacking. Comparing different EV-D68 clad

Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus.

Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (ΦSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component