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GOAL The aim was to assess proactive specialized inflammatory bowel diseases (IBD) emergency department (ED) consultation and multidisciplinary IBD team (IBD-MDT) intervention on IBD-related patient outcomes after discharge. BACKGROUND Despite advances in patient care, IBD-related ED visits have increased and substantially contribute to the IBD burden. METHODS Consecutive patients with IBD (below 50 y) who visited the ED during November 2017 to April 2018 (intervention group) were compared with patients with IBD that visited the same ED during 2014 to 2017 (standard-care group). The primary outcomes were hospitalization and ED revisits at 30, 90, and 180 days. RESULTS The intervention group (45 patients, mean age 32.43±8.6 y, 57.8% male) and the standard-care group (237 patients) had comparable baseline characteristics, including age, sex, and IBD type, and similar rates of hospital admissions from the ED (46.7% vs. 38.8%, P=0.32). The intervention group more frequently underwent computed tomography (40% vs. 8%, P

In this study, we suggest combining the monitoring of actual examination time used with grades in order to assess examination time extensions in terms of access provision and expected outcome. Usin...

The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume. The objective of this study was to explore whether fingolimod induces secretion of neurotrophins by immune cells. Blood was drawn from 21 patients before the initiation of treatment with fingolimod and at 6 and 12 months of follow-up. The levels of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, β-nerve growth factor, neurotrophin-3, neurotrophin-4, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor were screened in the supernatants of separated T cells and monocyte cultures using a customized, multiplex enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor levels were further validated by a specific enzyme-linked immunosorbent assay. Treatment with fingolimod significantly increased brain-derived neurotrophic factor secretion from T cells. A specific enzyme-linked immunosorbent assay confirmed these results in the supernatant of T cells after 6 and 12 months of therapy. T cells that reach the bloodstream of fingolimod-treated patients with multiple sclerosis may contribute to the neuroprotective effect of this therapy by increased secretion of brain-derived neurotrophic factor. This mechanism of action of fingolimod in patients with multiple sclerosis has not been previously reported.

The purpose of this study is to evaluate how learning disabilities (LDs), in combination with accommodations, affect the performance of a decision-tree to predict the stability of academic behaviou...

Modeling and analysis of students’ performance is a common task that is aimed at identifying important factors that affect the learning process. Typically, the analysis uses one-dimensional input parameters. However, with the advancement of data collections tools, many of the gathered educational datasets have become high-dimensional. Hence, the use of standard statistical methods may be limited in cases that the initial data unit is a vector. This paper proposes to use vector input units, which consist of student performance trajectories, for identifying statistical differences in college performances for several populations of college students. Two kernel based methods named diffusion maps and the kernel two-sample test are utilized. Diffusion maps generates a low-dimensional representation of the data, in which important characteristic factors are identified. The kernel two-sample test is a statistical test for comparing whether high-dimensional samples are drawn from two different probability distributions. The two methods are combined into a unified framework. Two case studies, which are processed similarly, are presented. The first tests for significant distributional differences between students with or without learning disabilities. Our results show that these groups’ performances is significantly different. The second case-study analyzes whether the SAT score impacts students’ performance throughout their 4-year of studies. It was found that significant distribution differences in performance are only present for groups of students having a very high or a very low SAT score. Thus, the SAT score is only weakly correlated to students’ college performance.

Oligodendrocyte precursor cells (OPCs) are present in demyelinated lesions of multiple sclerosis (MS) patients. However, their differentiation into functional oligodendrocytes is insufficient, and most lesions evolve into nonfunctional astroglial scars. Blockade of bone morphogenetic protein (BMP) signaling induces differentiation of OPCs into myelin-producing oligodendrocytes. We studied the effect of specific blockade of BMP-2/4 signaling, by intravenous (IV) treatment with anti-BMP-2/4 neutralizing mAb in both the inflammatory model of relapsing experimental autoimmune encephalomyelitis (R-EAE) and the cuprizone-toxic model of demyelination in mice. Administration of anti-BMP-2/4 to R-EAE-induced mice, on day 9 post-immunization (p.i.), ameliorated R-EAE signs, diminished the expression of phospho-SMAD1/5/8, primarily within the astrocytic lineage, increased the numbers of de novo immature and mature oligodendrocytes, and reduced the numbers of newly generated astrocytes within the spinal cord as early as day 18 p.i. This effect was accompanied with elevated remyelination, manifested by increased density of remyelinating axons (0.8

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.

Background: We aimed to identify subjects that harbor colorectal cancer and will not complete colonoscopy within six months following a positive fecal occult blood test (target population) by artificial intelligence (A.I.) based tools. Methods: We trained and validated a machine learning model based on a dataset of the Clalit Health Services. The entire population included 25,219 subjects aged 50 to 74 years with a positive FOBT result who participated in the screening program between 2011 and 2013. The target population included 202 patients (0.8% of the total cohort; 26.5% of all cancer cases). Multiple socioeconomic, administrative, and laboratory data were collected. The portion of the total population singled out by the model was termed as subjects needed to engage (SNE). Findings: Using two threshold levels the model reduced the number of SNE to 3.85% (of the entire validation cohort), identifying 25.8% of the target population [Positve Predictive Value Value (PPV) 5.1%, 95% Confidence Intrval (CI) 4.4-5.8; Negative Predictive Value (NPV) 99.4%, 95%CI 99.4-99.4; Area Under Receiver Operative Curve (AUROC) 0.74 95%CI 0.73-0.76] or reduced the number of SNE to 15.9%, identifying 55% of the target population (PPV 2.7%, 95%CI 2.4-3.0; NPV 99.5%, 95%CI 99.5-99.6; AUROC 0.74 95%CI 0.73-0.76). Interpretation: An AI-derived tool can successfully identify subjects with a positive FOBT that are at high risk for both harboring CRC and not completing colonoscopy within six months. Implementing this approach may improve FOBT-based CRC screening programs from the first day of a positive FOBT. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The CHS ethical committee authorized the study.

Demyelination, axonal loss and failure of tissue repair characterize MS lesions. Bone morphogenetic proteins (BMPs) signaling is associated with remyelination failure. Coco is one of the BMP antagonists. We found reduced Coco serum levels in relapsing-remitting MS (RR-MS) and primary progressive MS (PP-MS) patients compared to matched healthy controls (HC) and patients with rheumatoid arthritis. Exposure of P19 cells, in the presence of retinoic acid, BMP-2, or BMP-4 to Coco, at average sera level of MS patients failed to induce neuronal phenotype, in contrast to the average sera level of HC. Coco may be a player in the BMP dysregulation and the tissue repair failure in MS.

Blockage of bone morphogenetic protein (BMP) signaling is required for differentiation of neurons and oligodendrocytes from neural stem cells (NSCs). Sera of untreated relapsing-remitting multiple sclerosis (RR-MS) patients expressed significantly higher levels of BMP-2 compared to sera of healthy controls. BMP-2 levels correlated with BMP-4 and -5 levels only in sera of untreated MS patients. Furthermore, sera of untreated patients inhibited the neuronal differentiation of RA-treated P19 cells, which was associated with induction of phospho-SMAD signaling pathway. These results suggest that BMP-2 sera levels may play a role in the failure of remyelination and neuro-regeneration in RR-MS.

The importance of sharing mental health issues with supervisors is well established. However, the decision to disclose such intimate information is complex and is influenced by many intrinsic and extrinsic variables. The purpose of this study is to use machine learning algorithms to develop a tool that supervisors may use to enhance disclosure of mental health issues among their employees. Several interpretable machine learning algorithms are established based on a Kaggle dataset of more than 1,400 participants that measures attitudes towards mental health and prevalence of mental health disorders in the tech workplace. The C4.5 algorithm is chosen as the best classifier of willingness to disclose a mental health disorder to supervisors, based on a variety of classification performance measures. Tailored intervention programs are applied and are shown to have the potential to increase the probability of disclosure by between 20% and 60%.

The substantial availability of hypoxia-inducible factor 1 (HIF-1) for pathophysiological states, such as malignancies and ischemia, is primarily regulated post-translationally through the ubiquitin proteolytic system. The balance between degradation and stabilization of HIF-1α protein is determined by specific E3 ligases. In our search for new E3 ligases that might affect HIF-1α protein expression, we studied the effects of beta-transducin repeat-containing protein (β-TrCP) on the hypoxic pathway in cancer cells. β-TrCP is overexpressed in many tumors and regulates various cellular processes through mediating the degradation of important targets. Unexpectedly, we found that β-TrCP overexpression increases HIF-1α protein expression level as well as HIF-1 transcriptional activity by stabilizing HIF-1α protein and preventing its ubiquitination and proteasomal degradation in prostate cancer cells. By using a proteomic approach, we succeeded in demonstrating that β-TrCP interferes with the association between HIF-1α and HSP70/CHIP, a HIF-1α established E3 ligase complex. Whereas the E3 ligase activity of β-TrCP is well known, antagonizing another E3 ligase is a new mechanism of action of this important E3. We suggest that destroying or suppressing β-TrCP and thereby interrupting the HIF-1 pathway, could be valuable antitumor therapy.

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the hypoxic response pathway. We recently identified a novel interaction between HIF-1α and the mammalian septin family member, septin 9 protein, isoform 1 (SEPT9_i1), a protein product of septin 9 transcript variant 1 (SEPT9_v1). Septins are a highly conserved family of GTP-binding cytoskeletal proteins that are implicated in multiple cellular functions, including oncogenesis. SEPT9_i1 binds and stabilizes HIF-1α protein and stimulates HIF-1 transcriptional activity by preventing its RACK1-mediated ubiquitination and degradation. SEPT9_i1–HIF-1 activation promotes tumor growth and angiogenesis. The effect of SEPT9_v1 silencing in prostate cancer cells was studied. SEPT9_v1 stable knockdown was generated in PC-3 cells using a specific shRNA. SEPT9_v1 silencing reduced HIF-1α protein expression and inhibited HIF-1 transcriptional activity. SEPT9_v1 knockdown affected cell morphology, deregulated cell cycle, and decreased migration. The antiproliferative effect of shSEPT9_v1 was abolished in HIF-1α knockout colon cancer cells. In vivo, SEPT9_i1 depletion reduced HIF-1α protein expression, cellular proliferation, tumor growth, and angiogenesis. These results provide new insights and validation for applying SEPT9_v1 as a potential target for antitumor therapy by interrupting the HIF-1 pathway. Mol Cancer Res; 8(5); 643–52. ©2010 AACR.

Hypoxia-inducible factor 1α (HIF-1α) gene polymorphisms have been investigated for a possible role in mediating genetic predisposition to cancer. Our previous data show that men homozygous to C1772T polymorphism had 4-fold risk to develop prostate cancer. Therefore, we studied the effects of C1772T polymorphism on HIF-1α expression. HIF-1α mRNA expression levels were significantly higher in peripheral blood leukocytes of prostate cancer patients with the TT genotype compared with the CC genotype. Expression of C1772T HIF-1α in HIF-1α knockout cancer cells showed higher expression levels and stabilization of HIF-1α mRNA compared with the wild-type. Mutated HIF-1α protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1α as a gain-of-function mechanism driven by stabilization of HIF-1α mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.

Parathyroid hormone-related protein (PTHrP) expressed by human cancer cells enhances tumor cell growth and metastasis in vivo and it is considered as the major factor responsible for humoral hypercalcemia of malignancy. Hypoxia is a widespread feature of most solid tumors. Here, we studied the effects of hypoxia on PTHrP expression. We found that PTHrP is transcriptionally induced by prolonged (48 h) hypoxia in multiple human cancer and endothelial cell lines. Pharmacological up or downregulation of hypoxia-inducible factor (HIF) resulted in induction or reduction of PTHrP levels, respectively, implying that PTHrP hypoxic induction is mediated by HIF pathway. Analysis of PTHrP promoter revealed that both HIF-1α and HIF-2α subunits bind to specific hypoxia-responsive elements (HRE) within the P2 promoter of PTHrP. However, only HIF-2α can drive direct transcriptional activation, which can be abolished by mutation in the specific HRE. To the best of our knowledge, these results provide for the first time evidence that PTHrP is regulated by hypoxia in cancer and endothelial cells through the HIF-2 pathway. We suggest that HIF-2 induced by intratumoral hypoxia or by other genetic alterations may contribute to the pathogenesis of hypercalcemia of malignancy and cancer aggressiveness by stimulation of PTHrP expression.

On the 17th of August 1999, an earthquake of 7.4 magnitude on the Richter Scale struck the Marmara region in Turkey causing a massive casualties event with an estimated 2680 deaths and 5300 injuries just at the city of Adapazari alone. A field hospital was set up by the Israel Defense Forces at Adapazari in order to provide temporary medical services until regular medical forces recovered. The aim of the paper is to overview the requirements of the nursing staff at a field hospital based on our experience and analysis of the nursing activity at the field hospital at Adapazari. The methods implemented include interviewing all nurses and many of the doctors who took part in the field hospital as well as a review of medical literature about disasters. We found an inverted nurse:phycisian ratio of 1:1.77, as opposed to a 2.5–3:1 ratio in regular civilian hospitals. The nurses in our field hospital had to work longer and more intensive shifts than in a regular hospital. They had to overcome language barriers and cultural differences, and faced difficult hygiene conditions. Our overview analysis of results brought up several recommendations. Firstly, although it is not possible to predict the number and types of casualties, it is necessary to provide an adequate number of nurses (1–1.5:1 nurse:physician ratio). Furthermore, the nurses should be specialized and rotated as needed. Secondly, the language and cultural barriers should not be undermined despite the abundance of translators. Finally, the hygiene status in a field hospital requires management by nurses with active participation of all members.

A reverse transcriptase (RT) cDNA, designated HERV-K-T47D-RT, was isolated from a hormonally treated human breast cancer cell line. The protein product putative sequence is 97% identical to the human endogenous HERV-K retroviral sequences. Recombinant T47D-RT protein was used to generate polyclonal antibodies. The expression of HERV-K-T47D-RT protein increased in T47D cells after treatment with estrogen and progesterone. The RT-associated DNA polymerase activity was substantially increased after over-expressing a chimeric YFP-HERV-K-T47D-RT protein in cells. This RT-associated polymerase activity was significantly reduced by mutating the active site sequence YIDD to SIAA. Moreover, the endogenous RT activity observed in T47D cells was decreased by HERV-K-T47D-RT– specific siRNA, confirming the dependence of the endogenous enzymatic activity. To assess HERV-K-T47D-RT expression in human breast tumors, 110 paraffin sections of breast carcinoma biopsies were stained and subjected to confocal analysis. Twenty-six percent (28/110) of the tumor tissues and 18% (15/85) of the adjacent normal tissue, from the same patients, expressed the RT. HERV-K-T47D-RT expression significantly correlates with poor prognosis for disease-free patients and their overall survival. These results imply that HERV-K-T47D-RT might be expressed in early malignancy and might serve as a novel prognostic marker for breast cancer. Furthermore, these results provide evidence for the possible involvement of endogenous retrovirus in human breast carcinoma.