bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bifidobacterium Bacteremia: Clinical Characteristics and a Genomic Approach To Assess Pathogenicity
Authors: Esaiassen Eirin , Hjerde Erik , Cavanagh Jorunn Pauline , Simonsen Gunnar Skov , Klingenberg Claus 
Published: May 2017

ABSTRACT

Bifidobacteria are commensals that colonize the orogastrointestinal tract and rarely cause invasive human infections. However, an increasing number of bifidobacterial blood culture isolates has lately been observed in Norway. In order to investigate the pathogenicity of the
Bifidobacterium
species responsible for bacteremia, we studied
Bifidobacterium
isolates from 15 patients for whom cultures of blood obtained from 2013 to 2015 were positive. We collected clinical data and analyzed phenotypic and genotypic antibiotic susceptibility. All isolates (11
Bifidobacterium longum
, 2
B. breve
, and 2
B. animalis
isolates) were subjected to whole-genome sequencing. The 15 patients were predominantly in the extreme lower or upper age spectrum, many were severely immunocompromised, and 11 of 15 had gastrointestinal tract-related conditions. In two elderly patients, the
Bifidobacterium
bacteremia caused a sepsis-like picture, interpreted as the cause of death. Most bifidobacterial isolates had low MICs (≤0.5 mg/liter) to beta-lactam antibiotics, vancomycin, and clindamycin and relatively high MICs to ciprofloxacin and metronidazole. We performed a pangenomic comparison of invasive and noninvasive
B. longum
isolates based on 65 sequences available from GenBank and the sequences of 11 blood culture isolates from this study. Functional annotation identified unique genes among both invasive and noninvasive isolates of
Bifidobacterium
. Phylogenetic clusters of invasive isolates were identified for a subset of the
B. longum
subsp.
longum
isolates. However, there was no difference in the number of putative virulence genes between invasive and noninvasive isolates. In conclusion,
Bifidobacterium
has an invasive potential in the immunocompromised host and may cause a sepsis-like picture. Using comparative genomics, we could not delineate specific pathogenicity traits characterizing invasive isolates.
Meatal Swabs Contain Less Cellular Material and Are Associated with a Decrease in Gram Stain Smear Quality Compared to Urethral Swabs in Men
Authors: Jordan Stephen J. , Schwebke Jane R. , Aaron Kristal J. , Van Der Pol Barbara , Hook Edward W. 
Published: May 2017

ABSTRACT

Urethral swabs are the samples of choice for point-of-care Gram stain testing to diagnose
Neisseria gonorrhoeae
infection and nongonococcal urethritis (NGU) in men. As an alternative to urethral swabs, meatal swabs have been recommended for the collection of urethral discharge to diagnose
N. gonorrhoeae
and
Chlamydia trachomatis
infection in certain populations by nucleic acid amplification testing (NAAT), as they involve a less invasive collection method. However, as meatal swabs could be sampling a reduced surface area and result in fewer collected epithelial cells compared to urethral swabs, the adequacy of meatal swab specimens to collect sufficient cellular material for Gram stain testing remains unknown. We enrolled 66 men who underwent either urethral or meatal swabbing and compared the cellular content and Gram stain failure rate. We measured the difference in swab cellular content using the Cepheid Xpert CT/NG sample adequacy control crossing threshold (SAC
CT
) and determined the failure rate of Gram stain smears (GSS) due to insufficient cellular material. In the absence of discharge, meatal smears were associated with a significant reduction in cellular content (
P
= 0.0118), which corresponded with a GSS failure rate significantly higher than that for urethral swabs (45% versus 3%, respectively;
P
< 0.0001). When discharge was present, there was no difference among results from urethral and meatal swabs. Therefore, if GSS testing is being considered for point-of-care diagnosis of
N. gonorrhoeae
infection or NGU in men, meatal swabs should be avoided in the absence of a visible discharge.
Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses
Authors: Fuchs Jonas , Hölzer Martin , Schilling Mirjam , Patzina Corinna , Schoen Andreas , Hoenen Thomas , Zimmer Gert , Marz Manja , Weber Friedemann , Müller Marcel A. , Kochs Georg 
Published: May 2017

ABSTRACT

Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned
Mx1
cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat
Mx1
genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat
Mx1
genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts.

IMPORTANCE
Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.
Deletion of the
K1L
Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity
Authors: Bravo Cruz Ariana G. , Han Aiguo , Roy Edward J. , Guzmán Arielle B. , Miller Rita J. , Driskell Elizabeth A. , O'Brien William D. , Shisler Joanna L. 
Published: May 2017

ABSTRACT

All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-κB antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a
K1L
-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-κB
in vitro
, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8
+
T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity.

IMPORTANCE
The vaccinia virus (VACV) K1 protein inhibits NF-κB activation among its other antagonistic functions. A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.
Development of Clade-Specific and Broadly Reactive Live Attenuated Influenza Virus Vaccines against Rapidly Evolving H5 Subtype Viruses
Authors: Boonnak Kobporn , Matsuoka Yumiko , Wang Weijia , Suguitan Amorsolo L. , Chen Zhongying , Paskel Myeisha , Baz Mariana , Moore Ian , Jin Hong , Subbarao Kanta 
Published: May 2017

ABSTRACT

We have developed pandemic live attenuated influenza vaccines (pLAIVs) against clade 1 H5N1 viruses on an Ann Arbor cold-adapted (
ca
) backbone that induced long-term immune memory. In 2015, many human infections caused by a new clade (clade 2.2.1.1) of goose/Guangdong (gs/GD) lineage H5N1 viruses were reported in Egypt, which prompted updating of the H5N1 pLAIV. We explored two strategies to generate suitable pLAIVs. The first approach was to modify the hemagglutinin gene of a highly pathogenic wild-type (
wt
) clade 2.2.1.1 virus, A/Egypt/N03434/2009 (Egy/09) (H5N1), with its unmodified neuraminidase (NA) gene; this virus was designated Egy/09
ca
. The second approach was to select a low-pathogenicity avian influenza H5 virus that elicited antibodies that cross-reacted with a broad range of H5 viruses, including the Egypt H5N1 viruses, and contained a novel NA subtype for humans. We selected the low-pathogenicity A/duck/Hokkaido/69/2000 (H5N3) (dk/Hok/00) virus for this purpose. Both candidate vaccines were attenuated and immunogenic in ferrets, inducing antibodies that neutralized homologous and heterologous H5 viruses with different degrees of cross-reactivity; Egy/09
ca
vaccine antisera were more specific for the gs/GD lineage viruses but did not neutralize recent North American isolates (clade 2.3.4.4), whereas antisera from dk/Hok/69
ca
-vaccinated ferrets cross-reacted with clade 2.3.4.4 and 2.2.1 viruses but not clade 1 or 2.1 viruses. When vaccinated ferrets were challenged with homologous and heterologous H5 viruses, challenge virus replication was reduced in the respiratory tract. Thus, the two H5 pLAIV candidates are suitable for clinical development to protect humans from infection with different clades of H5 viruses.

IMPORTANCE
In response to the continuing evolution of H5N1 avian influenza viruses and human infections, new candidate H5 live attenuated vaccines were developed by using two different approaches: one targeted a specific circulating strain in Egypt, and the other was based on a virus that elicits broadly cross-reactive antibodies against a wide range of H5 viruses. Both candidate vaccines were immunogenic and exhibited protective efficacy in ferrets. Our study permits a comparison of the two approaches, and the data support the further development of both vaccine viruses to optimally prepare for the further spread of clade 2.2.1 or 2.3.4.4 viruses.
The C Terminus of the Herpes Simplex Virus UL25 Protein Is Required for Release of Viral Genomes from Capsids Bound to Nuclear Pores
Authors: Huffman Jamie B. , Daniel Gina R. , Falck-Pedersen Erik , Huet Alexis , Smith Greg A. , Conway James F. , Homa Fred L. 
Published: May 2017

ABSTRACT
The herpes simplex virus (HSV) capsid is released into the cytoplasm after fusion of viral and host membranes, whereupon dynein-dependent trafficking along microtubules targets it to the nuclear envelope. Binding of the capsid to the nuclear pore complex (NPC) is mediated by the capsid protein pUL25 and the capsid-tethered tegument protein pUL36. Temperature-sensitive mutants in both pUL25 and pUL36 dock at the NPC but fail to release DNA. The uncoating reaction has been difficult to study due to the rapid release of the genome once the capsid interacts with the nuclear pore. In this study, we describe the isolation and characterization of a truncation mutant of pUL25. Live-cell imaging and immunofluorescence studies demonstrated that the mutant was not impaired in penetration of the host cell or in trafficking of the capsid to the nuclear membrane. However, expression of viral proteins was absent or significantly delayed in cells infected with the pUL25 mutant virus. Transmission electron microscopy revealed capsids accumulated at nuclear pores that retained the viral genome for at least 4 h postinfection. In addition, cryoelectron microscopy (cryo-EM) reconstructions of virion capsids did not detect any obvious differences in the location or structural organization for the pUL25 or pUL36 proteins on the pUL25 mutant capsids. Further, in contrast to wild-type virus, the antiviral response mediated by the viral DNA-sensing cyclic guanine adenine synthase (cGAS) was severely compromised for the pUL25 mutant. These results demonstrate that the pUL25 capsid protein has a critical role in releasing viral DNA from NPC-bound capsids.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) is the causative agent of several pathologies ranging in severity from the common cold sore to life-threatening encephalitic infection. Early steps in infection include release of the capsid into the cytoplasm, docking of the capsid at a nuclear pore, and release of the viral genome into the nucleus. A key knowledge gap is how the capsid engages the NPC and what triggers release of the viral genome into the nucleus. Here we show that the C-terminal region of the HSV-1 pUL25 protein is required for releasing the viral genome from capsids docked at nuclear pores. The significance of our research is in identifying pUL25 as a key viral factor for genome uncoating. pUL25 is found at each of the capsid vertices as part of the capsid vertex-specific component and implicates the importance of this complex for NPC binding and genome release.
Effect of acute intraocular pressure elevation on the minimum rim width in normal, ocular hypertensive and glaucoma eyes
Authors: Sharma Sourabh , Tun Tin A , Baskaran Mani , Atalay Eray , Thakku Sri Gowtham , Liang Zhang , Milea Dan , Strouthidis Nicholas G , Aung Tin , Girard Michael JA 
Published: May 2017

BackgroundTo estimate and compare changes in the Bruch’s membrane opening—minimum rim width (BMO–MRW) and area in normal, ocular hypertensive and glaucoma eyes following acute elevations in intraocular pressure (IOP).MethodsThe optic nerve heads (ONHs) of 104 subjects (31 normals, 20 ocular hypertension (OHT) and 53 with primary glaucoma) were imaged using Spectral-domain optical coherence tomography (OCT; Spectralis, Heidelberg Engineering, Germany). IOP was raised twice by applying a force (0.64 n then 0.9 n) to the anterior sclera using an ophthalmo-dynamometer. After each IOP increment, IOP was held constant, measured with a Tonopen (AVIA applanation tonometer, Reichert, Depew, New York, USA), and ONH was rescanned with OCT. In each OCT volume, BMO–MRW and area were calculated and at each IOP increment.ResultsThe baseline MRW was significantly smaller in glaucoma subjects (174.3±54.3 µm) compared with normal (287.4±42.2 µm, p<0.001) and OHT subjects (255.4±45.3 µm, p<0.001). MRW of glaucoma subjects was significantly thinner at the first and second IOP elevations than that at baseline (both p<0.01), but no significant change was noted in normal and OHT subjects. There was no significant change of BMO area at acute IOP elevations from baseline in all diagnoses (all p>0.05).ConclusionAcute IOP elevation leads to compression of the nerve fibre layers of neuroretinal rim in glaucoma subjects only without changing ONH size. This suggests that the neural and connective tissues at ONH level in glaucoma subjects are more susceptible to acute IOP episodes than OHT or normal controls.
Possible relationship between general and pregnancy-related anxiety during the first half of pregnancy and the birth process: a prospective cohort study
Authors: Koelewijn Johanna Maria , Sluijs Anne Marie , Vrijkotte Tanja G M 
Published: May 2017

ObjectivesThe rate of interventions during childbirth has increased dramatically during the last decades. Maternal anxiety might play a role in the progress of the labour process and interventions during labour. This study aimed to identify associations between anxiety in the first half of pregnancy and the birth process, including any interventions required during labour. In addition, differences in the associations by parity and ethnicity were explored.DesignProspective cohort study.SettingPrimary care midwifery practices and secondary/tertiary care obstetric practices in Amsterdam, participating in the multiethnic ABCD (Amsterdam Born Children and their Development) study (participation rate 96%; response 8266/12 373 (67%)).ParticipantsIncluded were women with singletons, alive at labour start, with a gestational age ≥24 weeks (n=6443).Independent variableGeneral anxiety (State-Trait Anxiety Inventory state) and pregnancy-related anxiety (Pregnancy-Related Anxieties Questionnaire (PRAQ)) were self-reported in the first half of pregnancy.OutcomesAssociations between both forms of anxiety and several indicators of the birth process were analysed. Subgroup analyses were performed for parity and ethnicity.ResultsThe prevalence of high general anxiety (State-Trait Anxiety Inventory score ≥43) and pregnancy-related anxiety (PRAQ score ≥P90) were 30.9% and 11.0%, respectively. After adjustment, in nulliparae, both general anxiety and pregnancy-related anxiety were associated with pain relief and/or sedation (OR for general anxiety 1.23; 95% CI 1.02 to 1.48; OR for pregnancy-related anxiety 1.45; 95% CI 1.14 to 1.85). In multiparae, general anxiety was associated with induction of labour (OR 1.53; 95% CI 1.16 to 2.03) and pregnancy-related anxiety was associated with primary caesarean section (OR 1.66; 95% CI 1.02 to 2.70). Associations were largely similar for all ethnicities.ConclusionsHigh levels of general and pregnancy-related anxiety in early pregnancy contribute modestly to more interventions during the birth process with similar associations between ethnic groups, but with some differences between nulliparae and multiparae.
Feasibility cluster randomised controlled trial of a within-consultation intervention to reduce antibiotic prescribing for children presenting to primary care with acute respiratory tract infection and cough
Authors: Blair Peter S , Turnbull Sophie , Ingram Jenny , Redmond Niamh , Lucas Patricia Jane , Cabral Christie , Hollinghurst Sandra , Dixon Padraig , Peters Tim J , Horwood Jeremy , Little Paul , Francis Nick A , Gilbertson Anna , Jameson Catherine , Hay Alastair D 
Published: May 2017

ObjectiveTo investigate recruitment and retention, data collection methods and the acceptability of a ‘within-consultation’ complex intervention designed to reduce antibiotic prescribing.DesignPrimary care feasibility cluster randomised controlled trial.Setting32 general practices in South West England recruiting children from October 2014 to April 2015.ParticipantsChildren (aged 3 months to <12 years) with acute cough and respiratory tract infection (RTI).InterventionA web-based clinician-focussed clinical rule to predict risk of future hospitalisation and a printed leaflet with individualised child health information for carers, safety-netting advice and a treatment decision record.ControlsUsual practice, with clinicians recording data on symptoms, signs and treatment decisions.ResultsOf 542 children invited, 501 (92.4%) consented to participate, a month ahead of schedule. Antibiotic prescribing data were collected for all children, follow-up data for 495 (98.8%) and the National Health Service resource use data for 494 (98.6%). The overall antibiotic prescribing rates for children’s RTIs were 25% and 15.8% (p=0.018) in intervention and control groups, respectively. We found evidence of postrandomisation differential recruitment: the number of children recruited to the intervention arm was higher (292 vs 209); over half were recruited by prescribing nurses compared with less than a third in the control arm; children in the intervention arm were younger (median age 2 vs 3 years controls, p=0.03) and appeared to be more unwell than those in the control arm with higher respiratory rates (p<0.0001), wheeze prevalence (p=0.007) and global illness severity scores assessed by carers (p=0.045) and clinicians (p=0.01). Interviews with clinicians confirmed preferential recruitment of less unwell children to the trial, more so in the control arm.ConclusionDifferential recruitment may explain the paradoxical antibiotic prescribing rates. Future cluster level studies should consider designs which remove the need for individual consent postrandomisation and embed the intervention within electronic primary care records.Trial registration numberISRCTN 23547970UKCRN study ID16891