bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome Profiling of the Virus-Induced Innate Immune Response in Pteropus vampyrus and Its Attenuation by Nipah Virus Interferon Antagonist Functions
Authors: Glennon Nicole B. , Jabado Omar , Lo Michael K. , Shaw Megan L.
Published: May 2015

Bats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. As the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. Using next-generation transcriptome sequencing (mRNA-seq), we profiled the transcriptional response of
Pteropus vampyrus
bat kidney (PVK) cells to Newcastle disease virus (NDV), an avian paramyxovirus known to elicit a strong innate immune response in mammalian cells. The
Pteropus
genus is a known reservoir of Nipah virus (NiV) and Hendra virus (HeV). Analysis of the 200 to 300 regulated genes showed that genes for interferon (IFN) and antiviral pathways are highly upregulated in NDV-infected PVK cells, including genes for beta IFN, RIG-I, MDA5, ISG15, and IRF1. NDV-infected cells also upregulated several genes not previously characterized to be antiviral, such as RND1, SERTAD1, CHAC1, and MORC3. In fact, we show that MORC3 is induced by both IFN and NDV infection in PVK cells but is not induced by either stimulus in human A549 cells. In contrast to NDV infection, HeV and NiV infection of PVK cells failed to induce these innate immune response genes. Likewise, an attenuated response was observed in PVK cells infected with recombinant NDVs expressing the NiV IFN antagonist proteins V and W. This study provides the first global profile of a robust virus-induced innate immune response in bats and indicates that henipavirus IFN antagonist mechanisms are likely active in bat cells.

IMPORTANCE
Bats are the reservoir host for many highly pathogenic human viruses, including henipaviruses, lyssaviruses, severe acute respiratory syndrome coronavirus, and filoviruses, and many other viruses have also been isolated from bats. Viral infections are reportedly asymptomatic or heavily attenuated in bat populations. Despite their ecological importance to viral maintenance, research into their immune system and mechanisms for viral control has only recently begun. Nipah virus and Hendra virus are two paramyxoviruses associated with high mortality rates in humans and whose reservoir is the
Pteropus
genus of bats. Greater knowledge of the innate immune response of
P. vampyrus
bats to viral infection may elucidate how bats serve as a reservoir for so many viruses.
Presence of a
trs
-Like Motif Promotes Rep-Mediated Wild-Type Adeno-Associated Virus Type 2 Integration
Authors: Petri Karl , Gabriel Richard , Agundez Leticia , Fronza Raffaele , Afzal Saira , Kaeppel Christine , Linden R. Michael , Henckaerts Els , Schmidt Manfred
Published: May 2015

High-throughput integration site (IS) analysis of wild-type adeno-associated virus type 2 (wtAAV2) in human dermal fibroblasts (HDFs) and HeLa cells revealed that juxtaposition of a Rep binding site (RBS) and terminal resolution site (
trs
)-like motif leads to a 4-fold-increased probability of wtAAV integration. Electrophoretic mobility shift assays (EMSAs) confirmed binding of Rep to off-target RBSs. For the first time, we show Rep protein off-target nicking activity, highlighting the importance of the nicking substrate for Rep-mediated integration.
HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms
Authors: Reszka-Blanco Natalia J. , Sivaraman Vijay , Zhang Liguo , Su Lishan
Published: May 2015

Plasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-α). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-α production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs, which contributes to pathogenesis.

IMPORTANCE
Plasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear. We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-α production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings thus provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs and contributes to HIV-1 pathogenesis. These novel findings will be of great interest to those working on the roles of IFN and pDCs in HIV-1 pathogenesis in general and on the interaction of HIV-1 with pDCs in particular.
Different Temporal Effects of Ebola Virus VP35 and VP24 Proteins on Global Gene Expression in Human Dendritic Cells
Authors: Ilinykh Philipp A. , Lubaki Ndongala M. , Widen Steven G. , Renn Lynnsey A. , Theisen Terence C. , Rabin Ronald L. , Wood Thomas G. , Bukreyev Alexander
Published: May 2015

Ebola virus (EBOV) causes a severe hemorrhagic fever with a deficient immune response, lymphopenia, and lymphocyte apoptosis. Dendritic cells (DC), which trigger the adaptive response, do not mature despite EBOV infection. We recently demonstrated that DC maturation is unblocked by disabling the innate response antagonizing domains (IRADs) in EBOV VP35 and VP24 by the mutations R312A and K142A, respectively. Here we analyzed the effects of VP35 and VP24 with the IRADs disabled on global gene expression in human DC. Human monocyte-derived DC were infected by wild-type (wt) EBOV or EBOVs carrying the mutation in VP35 (EBOV/VP35m), VP24 (EBOV/VP24m), or both (EBOV/VP35m/VP24m). Global gene expression at 8 and 24 h was analyzed by deep sequencing, and the expression of interferon (IFN) subtypes up to 5 days postinfection was analyzed by quantitative reverse transcription-PCR (qRT-PCR). wt EBOV induced a weak global gene expression response, including markers of DC maturation, cytokines, chemokines, chemokine receptors, and multiple IFNs. The VP35 mutation unblocked the expression, resulting in a dramatic increase in expression of these transcripts at 8 and 24 h. Surprisingly, DC infected with EBOV/VP24m expressed lower levels of many of these transcripts at 8 h after infection, compared to wt EBOV. In contrast, at 24 h, expression of the transcripts increased in DC infected with any of the three mutants, compared to wt EBOV. Moreover, sets of genes affected by the two mutations only partially overlapped. Pathway analysis demonstrated that the VP35 mutation unblocked pathways involved in antigen processing and presentation and IFN signaling. These data suggest that EBOV IRADs have profound effects on the host adaptive immune response through massive transcriptional downregulation of DC.

IMPORTANCEThis study shows that infection of DC with EBOV, but not its mutant forms with the VP35 IRAD and/or VP24 IRAD disabled, causes a global block in expression of host genes. The temporal effects of mutations disrupting the two IRADs differ, and the lists of affected genes only partially overlap such that VP35 and VP24 IRADs each have profound effects on antigen presentation by exposed DC. The global modulation of DC gene expression and the resulting lack of their maturation represent a major mechanism by which EBOV disables the T cell response and suggests that these suppressive pathways are a therapeutic target that may unleash the T cell responses during EBOV infection.
Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38
Authors: Bai Yadan , Xuan Baoqin , Liu Haiyan , Zhong Jin , Yu Dong , Qian Zhikang
Published: May 2015

The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and anabolic metabolism and is a critical host factor activated by human cytomegalovirus (HCMV) for successful infection. The multifunctional HCMV protein pUL38 previously has been reported to activate mTORC1 by binding to and antagonizing tuberous sclerosis complex protein 2 (TSC2) (J. N. Moorman et al., Cell Host Microbe 3:253–262, 2008,
http://dx.doi.org/10.1016/j.chom.2008.03.002
). pUL38 also plays a role in blocking endoplasmic reticulum stress-induced cell death during HCMV infection. In this study, we showed that a mutant pUL38 lacking the N-terminal 24 amino acids (pHA-UL38
25–331
) was fully functional in suppressing cell death during infection. Interestingly, pHA-UL38
25–331
lost the ability to interact with TSC2 but retained the ability to activate mTORC1, although to a lesser extent than full-length pHA-UL38. Recombinant virus expressing pHA-UL38
25–331
replicated with ∼10-fold less efficiency than the wild-type virus at a low multiplicity of infection (MOI), but it grew similarly well at a high MOI, suggesting an MOI-dependent importance of pUL38-TSC2 interaction in supporting virus propagation. Site-directed mutational analysis identified a TQ motif at amino acid residues 23 and 24 as critical for pUL38 interaction with TSC2. Importantly, when expressed in isolation, the TQ/AA substitution mutant pHA-UL38 TQ/AA was capable of activating mTORC1 just like pHA-UL38
25–331
. We also created TSC2-null U373-MG cell lines by CRISPR genome editing and showed that pUL38 was capable of further increasing mTORC1 activity in TSC2-null cells. Therefore, this study identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners.

IMPORTANCE
HCMV, like other viruses, depends exclusively on its host cell to propagate. Therefore, it has developed methods to protect against host stress responses and to usurp cellular processes to complete its life cycle. mTORC1 is believed to be important for virus replication, and HCMV maintains high mTORC1 activity despite the stressful cellular environment associated with infection. mTORC1 inhibitors suppressed HCMV replication
in vitro
and reduced the incidence of HCMV reactivation in transplant recipients. We demonstrated that mTORC1 was activated by HCMV protein pUL38 in both TSC2-dependent and TSC2-independent manners. The pUL38-independent mode of mTORC1 activation also has been reported. These novel findings suggest the evolution of sophisticated approaches whereby HCMV activates mTORC1, indicating its importance in the biology and pathogenesis of HCMV.
Historical Outbreaks of Simian Hemorrhagic Fever in Captive Macaques Were Caused by Distinct Arteriviruses
Authors: Lauck Michael , Alkhovsky Sergey V. , Bào Yīmíng , Bailey Adam L. , Shevtsova Zinaida V. , Shchetinin Alexey M. , Vishnevskaya Tatyana V. , Lackemeyer Matthew G. , Postnikova Elena , Mazur Steven , Wada Jiro , Radoshitzky Sheli R. , Friedrich Thomas C. , Lapin Boris A. , Deriabin Petr G. , Jahrling Peter B. , Goldberg Tony L. , O'Connor David H. , Kuhn Jens H.
Published: May 2015

Simian hemorrhagic fever (SHF) is lethal for macaques. Based on clinical presentation and serological diagnosis, all reported SHF outbreaks were thought to be caused by different strains of the same virus, simian hemorrhagic fever virus (SHFV;
Arteriviridae
). Here we show that the SHF outbreaks in Sukhumi in 1964 and in Alamogordo in 1989 were caused not by SHFV but by two novel divergent arteriviruses. Our results indicate that multiple divergent simian arteriviruses can cause SHF.
A Rhesus Rhadinovirus Viral Interferon (IFN) Regulatory Factor Is Virion Associated and Inhibits the Early IFN Antiviral Response
Authors: Morin Gabriela , Robinson Bridget A. , Rogers Kelsey S. , Wong Scott W.
Published: May 2015

The interferon (IFN) response is the earliest host immune response dedicated to combating viral infection. As such, viruses have evolved strategies to subvert this potent antiviral response. Two closely related gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and rhesus macaque rhadinovirus (RRV), are unique in that they express viral homologues to cellular interferon regulatory factors (IRFs), termed viral IRFs (vIRFs). Cellular IRFs are a family of transcription factors that are particularly important for the transcription of type I IFNs. Here, we demonstrate a strategy employed by RRV to ensure rapid inhibition of virus-induced type I IFN induction. We found that RRV vIRF R6, when expressed ectopically, interacts with a transcriptional coactivator, CREB-binding protein (CBP), in the nucleus. As a result, phosphorylated IRF3, an important transcriptional regulator in beta interferon (IFN-β) transcription, fails to effectively bind to the IFN-β promoter, thus inhibiting the activation of IFN-β genes. In addition, we found R6 within RRV virion particles via immunoelectron microscopy and, furthermore, that virion-associated R6 is capable of inhibiting the type I IFN response by preventing efficient binding of IRF3/CBP complexes to the IFN-β promoter in the context of infection. The work shown here is the first example of a vIRF being associated with either the KSHV or RRV virion. The presence of this immunomodulatory protein in the RRV virion provides the virus with an immediate mechanism to evade the host IFN response, thus enabling the virus to effectively establish an infection within the host.

IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are the only viruses known to encode viral homologues to cellular interferon regulatory factors (IRFs), known as vIRFs. In KSHV, these proteins have been shown to play major roles in a variety of cellular processes and are particularly important in the evasion of the host type I interferon (IFN) response. In this study, we delineate the immunomodulatory mechanism of an RRV vIRF and its ability to assist the virus in rapid immune evasion by being prepackaged within the virion, thus providing evidence, for the first time, of a virion-associated vIRF. This work further contributes to our understanding of the mechanisms behind immunomodulation by the RRV vIRFs during infection.
Clustered Regularly Interspaced Short Palindromic Repeat-Dependent, Biofilm-Specific Death of Pseudomonas aeruginosa Mediated by Increased Expression of Phage-Related Genes
Authors: Heussler Gary E. , Cady Kyle C. , Koeppen Katja , Bhuju Sabin , Stanton Bruce A. , O’Toole George A.
Published: May 2015

The
c
lustered
r
egularly
i
nterspaced
s
hort
p
alindromic
r
epeat (CRISPR)/
C
RISPR-
as
sociated (CRISPR/Cas) system is an adaptive immune system present in many archaea and bacteria. CRISPR/Cas systems are incredibly diverse, and there is increasing evidence of CRISPR/Cas systems playing a role in cellular functions distinct from phage immunity. Previously, our laboratory reported one such alternate function in which the type 1-F CRISPR/Cas system of the opportunistic pathogen
Pseudomonas aeruginosa
strain UCBPP-PA14 (abbreviated as
P. aeruginosa
PA14) inhibits both biofilm formation and swarming motility when the bacterium is lysogenized by the bacteriophage DMS3. In this study, we demonstrated that the presence of just the DMS3 protospacer and the protospacer-adjacent motif (PAM) on the
P. aeruginosa
genome is necessary and sufficient for this CRISPR-dependent loss of these group behaviors, with no requirement of additional DMS3 sequences. We also demonstrated that the interaction of the CRISPR system with the DMS3 protospacer induces expression of SOS-regulated phage-related genes, including the well-characterized pyocin operon, through the activity of the nuclease Cas3 and subsequent RecA activation. Furthermore, our data suggest that expression of the phage-related genes results in bacterial cell death on a surface due to the inability of the CRISPR-engaged strain to downregulate phage-related gene expression, while these phage-related genes have minimal impact on growth and viability under planktonic conditions. Deletion of the phage-related genes restores biofilm formation and swarming motility while still maintaining a functional CRISPR/Cas system, demonstrating that the loss of these group behaviors is an indirect effect of CRISPR self-targeting.

IMPORTANCE
The various CRISPR/Cas systems found in both archaea and bacteria are incredibly diverse, and advances in understanding the complex mechanisms of these varied systems has not only increased our knowledge of host-virus interplay but has also led to a major advancement in genetic engineering. Recently, increasing evidence suggested that bacteria can co-opt the CRISPR system for functions besides adaptive immunity to phage infection. This study examined one such alternative function, and this report describes the mechanism of type 1-F CRISPR-dependent loss of the biofilm and swarming in the medically relevant opportunistic pathogen
Pseudomonas aeruginosa
. Since both biofilm formation and swarming motility are important in the virulence of
P. aeruginosa
, a full understanding of how the CRISPR system can regulate such group behaviors is fundamental to developing new therapeutics.
Novel Mechanism for Scavenging of Hypochlorite Involving a Periplasmic Methionine-Rich Peptide and Methionine Sulfoxide Reductase
Authors: Melnyk Ryan A. , Youngblut Matthew D. , Clark Iain C. , Carlson Hans K. , Wetmore Kelly M. , Price Morgan N. , Iavarone Anthony T. , Deutschbauer Adam M. , Arkin Adam P. , Coates John D.
Published: May 2015

Reactive chlorine species (RCS) defense mechanisms are important for bacterial fitness in diverse environments. In addition to the anthropogenic use of RCS in the form of bleach, these compounds are also produced naturally through photochemical reactions of natural organic matter and
in vivo
by the mammalian immune system in response to invading microorganisms. To gain insight into bacterial RCS defense mechanisms, we investigated
Azospira suillum
strain PS, which produces periplasmic RCS as an intermediate of perchlorate respiration. Our studies identified an RCS response involving an RCS stress-sensing sigma/anti-sigma factor system (SigF/NrsF), a soluble hypochlorite-scavenging methionine-rich periplasmic protein (MrpX), and a putative periplasmic methionine sulfoxide reductase (YedY1). We investigated the underlying mechanism by phenotypic characterization of appropriate gene deletions, chemogenomic profiling of barcoded transposon pools, transcriptome sequencing, and biochemical assessment of methionine oxidation. Our results demonstrated that SigF was specifically activated by RCS and initiated the transcription of a small regulon centering around
yedY1
and
mrpX
. A
yedY1
paralog (
yedY2
) was found to have a similar fitness to
yedY1
despite not being regulated by SigF. Markerless deletions of
yedY2
confirmed its synergy with the SigF regulon. MrpX was strongly induced and rapidly oxidized by RCS, especially hypochlorite. Our results suggest a mechanism involving hypochlorite scavenging by sacrificial oxidation of the MrpX in the periplasm. Reduced MrpX is regenerated by the YedY methionine sulfoxide reductase activity. The phylogenomic distribution of this system revealed conservation in several
Proteobacteria
of clinical importance, including uropathogenic
Escherichia coli
and
Brucella
spp., implying a putative role in immune response evasion
in vivo
.

IMPORTANCE
Bacteria are often stressed in the environment by reactive chlorine species (RCS) of either anthropogenic or natural origin, but little is known of the defense mechanisms they have evolved. Using a microorganism that generates RCS internally as part of its respiratory process allowed us to uncover a novel defense mechanism based on RCS scavenging by reductive reaction with a sacrificial methionine-rich peptide and redox recycling through a methionine sulfoxide reductase. This system is conserved in a broad diversity of organisms, including some of clinical importance, invoking a possible important role in innate immune system evasion.
Identification of Quorum-Sensing Inhibitors Disrupting Signaling between Rgg and Short Hydrophobic Peptides in Streptococci
Authors: Aggarwal Chaitanya , Jimenez Juan Cristobal , Lee Hyun , Chlipala George E. , Ratia Kiira , Federle Michael J.
Published: May 2015

Bacteria coordinate a variety of social behaviors, important for both environmental and pathogenic bacteria, through a process of intercellular chemical signaling known as quorum sensing (QS). As microbial resistance to antibiotics grows more common, a critical need has emerged to develop novel anti-infective therapies, such as an ability to attenuate bacterial pathogens by means of QS interference. Rgg quorum-sensing pathways, widespread in the phylumFirmicutes, employ cytoplasmic pheromone receptors (Rgg transcription factors) that directly bind and elicit gene expression responses to imported peptide signals. In the human-restricted pathogenStreptococcus pyogenes, the Rgg2/Rgg3 regulatory circuit controls biofilm development in response to the short hydrophobic peptides SHP2 and SHP3. Using Rgg-SHP as a model receptor-ligand target, we sought to identify chemical compounds that could specifically inhibit Rgg quorum-sensing circuits. Individual compounds from a diverse library of known drugs and drug-like molecules were screened for their ability to disrupt complexes of Rgg and FITC (fluorescein isothiocyanate)-conjugated SHP using a fluorescence polarization (FP) assay. The best hits were found to bind Rgg3in vitrowith submicromolar affinities, to specifically abolish transcription of Rgg2/3-controlled genes, and to prevent biofilm development inS. pyogeneswithout affecting bacterial growth. Furthermore, the top hit, cyclosporine A, as well as its nonimmunosuppressive analog, valspodar, inhibited Rgg-SHP pathways in multiple species ofStreptococcus. The Rgg-FITC-peptide-based screen provides a platform to identify inhibitors specific for each Rgg type. Discovery of Rgg inhibitors constitutes a step toward the goal of manipulating bacterial behavior for purposes of improving health.

IMPORTANCEThe global emergence of antibiotic-resistant bacterial infections necessitates discovery not only of new antimicrobials but also of novel drug targets. Since antibiotics restrict microbial growth, strong selective pressures to develop resistance emerge quickly in bacteria. A new strategy to fight microbial infections has been proposed, namely, development of therapies that decrease pathogenicity of invading organisms while not directly inhibiting their growth, thus decreasing selective pressure to establish resistance. One possible means to this goal is to interfere with chemical communication networks used by bacteria to coordinate group behaviors, which can include the synchronized expression of genes that lead to disease. In this study, we identified chemical compounds that disrupt communication pathways regulated by Rgg proteins in species ofStreptococcus. Treatment of cultures ofS. pyogeneswith the inhibitors diminished the development of biofilms, demonstrating an ability to control bacterial behavior with chemicals that do not inhibit growth.
Fungal Traits That Drive Ecosystem Dynamics on Land
Authors: Treseder Kathleen K. , Lennon Jay T.
Published: May 2015

Fungi contribute extensively to a wide range of ecosystem processes, including decomposition of organic carbon, deposition of recalcitrant carbon, and transformations of nitrogen and phosphorus. In this review, we discuss the current knowledge about physiological and morphological traits of fungi that directly influence these processes, and we describe the functional genes that encode these traits. In addition, we synthesize information from 157 whole fungal genomes in order to determine relationships among selected functional genes within fungal taxa. Ecosystem-related traits varied most at relatively coarse taxonomic levels. For example, we found that the maximum amount of variance for traits associated with carbon mineralization, nitrogen and phosphorus cycling, and stress tolerance could be explained at the levels of order to phylum. Moreover, suites of traits tended to co-occur within taxa. Specifically, the genetic capacities for traits that improve stress tolerance—β-glucan synthesis, trehalose production, and cold-induced RNA helicases—were positively related to one another, and they were more evident in yeasts. Traits that regulate the decomposition of complex organic matter—lignin peroxidases, cellobiohydrolases, and crystalline cellulases—were also positively related, but they were more strongly associated with free-living filamentous fungi. Altogether, these relationships provide evidence for two functional groups: stress tolerators, which may contribute to soil carbon accumulation via the production of recalcitrant compounds; and decomposers, which may reduce soil carbon stocks. It is possible that ecosystem functions, such as soil carbon storage, may be mediated by shifts in the fungal community between stress tolerators and decomposers in response to environmental changes, such as drought and warming.
Aceruloplasminaemia: a rare but important cause of iron overload
Authors: Doyle Adam , Rusli Ferry , Bhathal Prithi
Published: May 2015

We present a case of a 20-year-old man referred to our service with iron overload and mildly deranged liver biochemistry. Although liver histopathology was consistent with haemochromatosis, iron studies were not consistent with this diagnosis. Serum ceruloplasmin levels were undetectable, leading to a diagnosis of aceruloplasminaemia. Unlike other iron overload disorders, neurological complications are a unique feature of this illness, and often irreversible, once established. The patient was treated with iron chelation prior to the onset of neurological injury, and experienced progressive normalisation of his ferritin and liver biochemistry. This is one of the youngest diagnosed cases in the published literature and, crucially, was a rare case of diagnosis and treatment prior to the onset of neurological sequelae. This is presented alongside a review of previously published cases of aceruloplasminaemia, including responses to iron chelation therapy.
Unexpected rare complication of the facial paralysis in a patient with an antrochoanal polyp following canine fossa puncture
Authors: Kim Ah-Young , Choi Myoung Su
Published: May 2015

Canine fossa puncture (CFP) combined with endoscopic sinus surgery is a simple and effective method for treating antrochoanal polyps, particularly those that originate in the anterior, inferior or medial aspect of the antrum. Several complications can occur following CFP, including facial paraesthesia and dental numbness. However, facial palsy is extremely rare after CFP. We postulated that a possible mechanism of facial palsy is pressure injury to the soft tissues adjacent to the puncture site, which can damage the buccal branch of the facial nerve during CFP.
IgA-dominant postinfectious glomerulonephritis induced by methicillin-sensitiveStaphylococcus aureus
Authors: Caetano Joana , Pereira Fernando , Oliveira Susana , Delgado Alves José
Published: May 2015

A 56-year-old man with alcohol-associated cirrhosis, arterial hypertension and diabetes, presented with a 1-month history of fever, lumbar back pain and lower limb weakness. MRI revealed a spinal epidural abscess extending from the cervical to the dorsolumbar spine. A methicillin-sensitiveStaphylococcus aureusstrain was isolated on blood cultures. Meropenem was initially started with no response, and then changed to vancomycin. During treatment, the patient’s condition progressed with anasarca and renal failure with nephrotic-range proteinuria. The renal biopsy showed a membranoproliferative glomerulonephritis with IgA deposition. After completing 2 months of antibiotic therapy the patient recovered from the neurological deficits, with a complete resolution of the abscess and partial recovery of renal function and proteinuria.
Laparoscopic retrieval of an intra-abdominal air gun pellet
Authors: Oliphant Zoe , Tudor Edward , Bamford Richard , Mahon David
Published: May 2015

A 19-year-old man presented to the emergency department following an air gun pellet injury to the abdomen. He was clinically stable and underwent laparoscopic retrieval of the pellet, which was found embedded in the small bowel mesentery. He recovered fully and was discharged after 2 days. We further discuss air gun-related injuries.
Schwannoma of the sigmoid colon
Authors: Çakır Tuğrul , Aslaner Arif , Yaz Müjgan , Gündüz Umut rıza
Published: May 2015

Colonic schwannomas are very rare gastrointestinal tumours originating from Schwann cells, which form the neural sheath. Primary schwannomas of the lower gastrointestinal tract are very rare and usually benign in nature. However, if they are not surgically removed, malign degeneration can occur. We report a case of a 79-year-old woman who presented to our clinic with rectal bleeding and constipation. She underwent a lower gastrointestinal tract endoscopy. A mass subtotally obstructing the lumen of the sigmoid colon was seen and biopsies were taken. Histopathological examination indicated a suspicion of gastrointestinal tumour and the patient underwent sigmoid colon resection after preoperative evaluation by laboratory analysis, abdominal ultrasonography and CT. Her postoperative course was uneventful and she was discharged on the fifth day for outpatient control. The histopathology report revealed schwannoma of the sigmoid colon. This was a case of schwannoma of the sigmoid colon that was successfully treated with total resection.
Abnormal excessive per vagina (PV) bleeding on Esmya–selective progesterone receptor modulator (SPRM) in a symptomatic patient with uterine fibroid
Authors: Matytsina-Quinlan Lyubov , Matytsina Laura
Published: May 2015

A woman in her late 40s presented with excessive per vagina (PV) bleeding and uterine fibroid. She reported excessive PV bleeding after starting Esmya; she was brought in by ambulance to the emergency department with profuse bleeding. Abnormal uterine bleeding (AUB) developed after selective progesterone receptor modulator (SPRM) administration in this symptomatic patient with uterine fibroid. The drug was withheld and surgical treatment considered. Progressive deterioration of PV bleeding after receiving SPRM led to an urgentlaparoscopictotal hysterectomy, which had to be postponed due to severe anaemia. Surgery took place regardless because the excessive bleeding continued. Histology revealed a 6 cm submucosal uterine fibroid (SMUF) and adenomyosis. Physicians prescribing SPRMs to stop PV bleeding should be aware of potential AUB, which could lead to urgent hysterectomy. The mechanism of action of SPRMs is not clearly understood. Awareness of the side effects of Esmya, such as AUB, must be kept in mind when administering SPRMs.
Occipital condyle fracture in a patient with occipitalisation of the atlas
Authors: Burke Shane M , Huhta Taylor A , Mackel Charles E , Riesenburger Ron I
Published: May 2015

Occipital condyle fractures and occipitalisation of the atlas are rare entities of the craniocervical junction. To the best of our knowledge, a patient presenting with a traumatic occipital condyle fracture and pre-existing occipitalisation of the atlas has not been previously reported. We report the case of a 79-year-old man presenting with an Anderson and Montesano type III fracture through a fused occipital condyle and lateral mass. This fracture was noted to extend into the transverse foramen and the C1–C2 joint space. The transverse ligament and ligamentum flavum were calcified but not disrupted and the atlantodental interval was within normal limits. The neurological examination was unremarkable with the exception of neck pain. The patient was treated conservatively and placed in a rigid cervical collar for 10 weeks with serial CT studies to monitor healing of the fracture. At 4 months of follow-up, the patient was pain free with nearly complete resolution of his occipital condyle fracture.
USING SIMULATION TO IMPROVE PROFESSIONAL PERFORMANCE OF CRITICAL CARE NURSES AT KING ABDUL-AZIZ MEDICAL CITY, RIYADH
Authors: Aljuaid Maha
Published: May 2015

Introduction

Health care institutions strive to develop orientation programs that are effective and efficient to prepare nurses entering to critical care. Clinical education must have combined knowledge of physical, behavioural and technical clinical education (American Association of Critical Care Nurses, 2004).

Objectives:

1. To identify the effect of simulation based education in standardizing nursing orientation

2. To share the experience of KAMC-R in utilizing simulation education to improve patient safety and the quality of care

Background

Simulation provides safe learning environment, allows debriefing, and stimulates critical thinking skills (Critical Care Nursing, 2007). Neuro Critical Care unit (NCCU) at King Abdul-Aziz Medical City (KAMC-R) faces influx of new nurses; therefore continuous education is imperative to those nurses. Simulation education strategy is utilized to improve technical and non-technical skills for new nurses. The critical care collaborative leadership adopted simulation based education to replace the old nursing orientation. The new‖orientation program piloted in Trauma ICU and Surgical ICU for two months, it was then implemented into all adult critical care units.

Methodology

Clinical resource nurses (CRNs) are the educators who run the program to the new staff. Clinical skills are validated by using Mosby skills checklist in which nurses demonstrate the skills on high fidelity simulation manikins.

Results

December 2010, nurses' anecdotal reports used to evaluate the experience of NCCU in utilizing simulation education. 32 nurses reported increase nursing knowledge, and improve technical skills. April 2014, survey was conducted to evaluate the effectiveness of the new orientation participated by CRNs, practice facilitators, and new nurses. The result showed that using of simulation enhances nursing knowledge and skills, simulation activities are engaging, and staffs build more confidence.

Conclusion

A healthy learning environment is essential for optimal nursing training. Nursing orientation requires abundant resources to ensure patient safety and competency of critical care nurses.
AN INTRODUCTION TO DEBRIEFING
Authors: Davies Joanne
Published: May 2015

The interactive workshop will cover the basic elements of Debriefing. Introduce a tool that can guide debriefs. Allow time for expert modelling and practice using the tools provided.

Learning Objectives

By the end of this session participants should be able to:

1. Identify the three different approaches to debriefing

2. Identify the defining criteria for using the different approaches

3. Describe the value of exploring participant frames

4. Describe the RUST model

5. Use the OPIC (Observation, Point of View, Inquiry/Curiosity) Cognitive aid to practice debriefing in the learning activity

The Sidra Sim Team would run this interactive session with 4–5 team members.
THE EFFICACY OF MEDICAL SIMULATION COURSE ON IMPROVING ULTRASOUND—GUIDED CENTRAL VENOUS CATHETER INSERTION
Authors: Alyousef Sawsan M , Almaani Mohammed , Zahraa Jihad , Hassan Ali , Lababidi Hani
Published: May 2015

Background

While insertion of CVC (central venous catheter) is common, it is an intricate procedure and not risk-free. Traditionally, inexperienced residents learn to insert CVC on real patients and thus can put patients' life at risk. One way to reduce medical errors is to use high-fidelity simulation for training tomorrow's practitioners on ultrasound-guided CVC insertion.

Objective

To evaluate the efficacy of medical simulation based learning course on knowledge and skills improvement on ultrasound-guided CVC insertion.

Methods

A pre-assessment was performed through a pre-test and hands-on skill assessment for central line insertion under U/S guidance (Internal Jugular, Subclavian or Femoral lines) utilizing a standardized checklist. All candidates then attended one day course that included theoretical and hands-on simulation training using phantoms. A post-test and hands-on assessment was performed at the end of the day.

Results

Twenty residents from Internal Medicine and Paediatrics were enrolled in the study at King Fahad Medical City Simulation Center. There was significant improvement in the knowledge based training: 90% showed significant increase in their MCQ scores (p<0.001), 10% had equal scores and none showed decline in their scores. For the hands-on skills: All 20 candidates showed significant improvement in their skills (p<0.001).

Conclusion

A one day simulation course on CVC insertion under ultrasound guidance significantly improves the knowledge and skills for residents in training programs.

Recommendations

Such courses and other similar should be compulsory for all Residents training programs as it is called safe training.
TEACHING THE TEACHERS—WHAT EDUCATION AND TRAINING NEEDS ARISE AMONG TEACHERS THROUGH THE USE OF SIMULATION IN THE EDUCATION OF EMS PERSONNEL IN THE GERMAN HEALTH CARE SYSTEM
Authors: Wessels Michael , Geuen Manuel
Published: May 2015

Background & Purpose

The professional qualifications of paramedics in the emergency services are not uniform at the federal level across Germany. Federalism leads to a considerable heterogeneity of regional regulations and curricula for training at the state-approved emergency services School. This results in an uneven transfer of knowledge of action skills, scientific findings as well as inconsistent application of appropriate teaching methods. Finally, this culminates in an inconsistent qualification of EMS personnel.

To illustrate the needs of teachers in simulation in training and continuing education of EMS personnel.

Methods

Based on a systematic literature review and expert interviews on training and further education of non-medical personnel in emergency care simulation was analysed as a teaching method from an educational perspective. For a standardized carrying out of the interviews a unified interview guide was used. The statements of the experts were analysed with the software MAXQDA.

Results

Through simulation, in conjunction with debriefings an outstanding benefit for the direct learning from mistakes is made possible, both in the whole group as well as in the setting of reality (train where you work). This supports a long-needed culture of errors in emergency service as well as improving patient safety in emergency response. This requires intensive training of the teaching staff in pedagogy and technology. Further research needs were identified for potential fields of application of simulation in the training of EMS personnel.

Conclusions

Simulation provides for the training of emergency services personnel, particularly in view of the new profession of emergency paramedics (Notfallsanitäter) and their advanced performance skills extensive opportunities. With the help of simulation abilities and skills as well as inter-professional teamwork can be taught and improved individualized. In fact, simulation contributes to improving patient safety and guideline- based care of emergency patients.
HOW TO IMPLEMENT SIMULATION BASED EDUCATION IN A NEW MEDICAL SCHOOL
Authors: Raad Vanda Abi
Published: May 2015

Background

Simulation based Education has become an integral part of medical education from undergraduate to postgraduate levels.

Summary of work

The integration of simulation into a medical curriculum requires informed implementation in ways that take advantage of simulation's unique ability to facilitate guided application of new knowledge. Simulation offers an experiential learning environment that is ideally suited to the goal-directed learning needed in undergraduate and postgraduate education. Various types of curricula might be developed such as cognitive, communication and procedural skills. Also, a broad range of simulation methodologies can be employed to service the specific educational programs. Part-task trainers, mannequin-based simulation, virtual reality, in-situ techniques, hybrid configurations, screen-based simulations and encounters with ‘standardized’ patients, nurses or physician colleagues all can play a role in the anaesthesia curriculum. Determining which components of a curriculum are enhanced using simulation-based education, and incorporating the exercises into the existing model, result in more goal directed and sustained use of the tool.

Summary of results

Examples of the integration of simulation based education in the undergraduate and postgraduate curriculum at the Lebanese American University-School of Medicine will be discussed.

Conclusions

To optimize both the learning and assessment experience of simulation, educators should remember the principles of effective simulation, the advantages/disadvantages of simulation as well as the goals-tools match.
DEVELOPMENT OF A JOINT INJECTION/ASPIRATION SIMULATION COURSE FOR SPECIALITY TRAINEES IN RHEUMATOLOGY
Authors: Omer Rasha , Sabanathan Anetha , Dunkley Lisa , Purva Makani
Published: May 2015

Background

The JRCPTB* Training curriculum for Rheumatology mandates that trainees should be able to:

1. Describe the surface anatomy of the musculoskeletal system

2. Gain competences in joint and soft tissue injections.

This is usually achieved in an informal basis. Simulation can provide a realistic learning opportunity to develop this skill. We designed and ran a simulation course to aid trainees in achieving these competencies.

Methodology

10 junior rheumatology trainees were invited to participate. The course started with a lecture which covered indications and contraindications to procedures including a summary of results from a regional survey of Rheumatology consultants and registrars on joint injection techniques. Faculty consisted of 4 Rheumatology Consultants and 3 Senior Registrars. At least one faculty member per station was present to provide instructions. Actors were used to demonstrate knee, shoulder and ankle/foot surface anatomy. Instructors demonstrated elbow, hand and wrist anatomy on themselves. Self-reported level of confidence using Likert score Pre and Post workshop questionnaires were used for evaluation.

Results

9/10 of the trainees felt that the session met their learning objectives. Confidence levels increased non-significantly in performing wrist, carpel tunnel, glenohumeral, subacromial and knee injection. Confidence levels increased significantly in performing ankle, acromoclavicular, elbow and epicondyle injections.

Conclusions

It is possible to successfully run a simulated joint injection course which can improve confidence levels in trainees.
REVIEW OF A PILOT STUDY, INTRODUCING LAB TUTOR™ SOFTWARE TO FINAL YEAR NURSING STUDENTS (N=95) WITH THE AIM OF IMPROVING THEIR SIMULATED LEARNING EXPERIENCE
Authors: Simpson Jack
Published: May 2015

Background

Online simulation provides an alternative approach to hands-on simulation and a number of software packages are becoming available to educators. Lab Tutor™ is an online, immersive learning platform, which aims to bridge the gap between theory and practice, by using real patient case studies along with interactive exercises. We introduced Lab Tutor™ software as an integral part of our year 3 clinical skills module, alongside the use of the SimMan 3G Advanced Human Patient Simulator (AHPS), with the aim of providing students with a more immersive simulation experience.

Methodology

We introduced LabTutor™ to final year nursing students at the beginning of an 11-week clinical skills module. On completion of the module we evaluated the use of the software and whether the students considered that using the interactive software improved their knowledge of disease processes and management of patients.

Results

We will present the evaluation results from this pilot study. However, early feedback from students indicates that the introduction of LabTutor™ improved understanding of disease processes as well as their management. We are also in the process of developing a number of patient scenarios, using existing LabTutor™ patients, for use on the SimMan 3G AHPS. We also hope to present the early outcomes of this development.
Does transport time help explain the high trauma mortality rates in rural areas? New and traditional predictors assessed by new and traditional statistical methods
Authors: Røislien Jo , Lossius Hans Morten , Kristiansen Thomas
Published: May 2015

Background

Trauma is a leading global cause of death. Trauma mortality rates are higher in rural areas, constituting a challenge for quality and equality in trauma care. The aim of the study was to explore population density and transport time to hospital care as possible predictors of geographical differences in mortality rates, and to what extent choice of statistical method might affect the analytical results and accompanying clinical conclusions.

Methods

Using data from the Norwegian Cause of Death registry, deaths from external causes 1998–2007 were analysed. Norway consists of 434 municipalities, and municipality population density and travel time to hospital care were entered as predictors of municipality mortality rates in univariate and multiple regression models of increasing model complexity. We fitted linear regression models with continuous and categorised predictors, as well as piecewise linear and generalised additive models (GAMs). Models were compared using Akaike's information criterion (AIC).

Results

Population density was an independent predictor of trauma mortality rates, while the contribution of transport time to hospital care was highly dependent on choice of statistical model. A multiple GAM or piecewise linear model was superior, and similar, in terms of AIC. However, while transport time was statistically significant in multiple models with piecewise linear or categorised predictors, it was not in GAM or standard linear regression.

Conclusions

Population density is an independent predictor of trauma mortality rates. The added explanatory value of transport time to hospital care is marginal and model-dependent, highlighting the importance of exploring several statistical models when studying complex associations in observational data.