bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pretransplant prophylactic rituximab to prevent Epstein‐Barr virus (EBV) viremia in EBV‐seronegative kidney transplant recipients from EBV‐seropositive donors: results of a pilot study
Authors: Schachtner Thomas , Reinke Petra 
Published: September 2016

AbstractBackgroundBecause of the strikingly increased risk of post‐transplant lymphoproliferative disorder (PTLD) in Epstein‐Barr virus (EBV)‐seronegative kidney transplant recipients (KTRs) from EBV‐seropositive donors—EBV(D+R−), special strategies need to be defined to prevent EBV transmission and EBV viremia.MethodsWe studied all KTRs at our center between 2008 and 2012. Seventeen of 402 KTRs (4.2%) were identified as EBV(D+R−), among which 5 KTRs received kidneys from living donors and 12 KTRs from deceased donors. KTRs undergoing living donation were treated with a single dose of rituximab 4 weeks prior to transplantation. Assessment of EBV seroconversion and EBV viremia was performed.ResultsAmong 12 EBV‐seronegative KTRs from deceased donors, all 12 KTRs (100%) showed EBV seroconversion, 7 KTRs (58%) showed active EBV viremia, and 1 KTR (8%) developed PTLD. In comparison, 3 of 5 KTRs from living donors, who received pretransplant rituximab, remained EBV‐seronegative post transplantation, and no KTR developed EBV viremia (P<.05). All KTRs who received pretransplant rituximab showed excellent allograft function, with no increase in infections or malignancies.ConclusionsOur data suggest that rituximab‐mediated elimination of B cells may prevent transmission of EBV to the recipient, as EBV persistence requires the establishment of a latent infection in recipient B cells. Pretransplant rituximab may prove useful to prevent primary EBV infection in EBV‐seronegative KTRs.
The impact of directly acting antivirals on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C
Authors: Raschzok Nathanael , Schott Eckart , Reutzel‐Selke Anja , Damrah Iman , Gül‐Klein Safak , Strücker Benjamin , Sauer Igor Maximilian , Pratschke Johann , Eurich Dennis , Stockmann Martin 
Published: September 2016

AbstractBackgroundThe new directly acting antivirals (DAAs) enable all‐oral interferon‐free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C.MethodsTwenty‐one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment.ResultsAll patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P<.0001) at the 12‐week follow‐up. In parallel, the tacrolimus trough level to dose ratio decreased from 4.68 down to 2.72 (P=.0004).ConclusionAntiviral treatment with DAAs enabled sustained elimination of recurrent HCV in liver transplant recipients and was associated with a significant improvement of the enzymatic liver function.
Optimal Interval for Success in Judo World-Ranking Competitions
Authors: Franchini Emerson , Takito Monica Y. , da Silva Rodrigo M. , Shiroma Seihati A. , Wicks Lance , Julio Ursula F. 
Published: September 2016

Purpose:To determine the optimal interval between competitions for success in the different events of the judo world tour.Methods:A total of 20,916 female and 29,900 male competition participations in the judo world-tour competitions held between January 2009 and December 2015 were analyzed, considering the dependent variable, winning a medal, and the independent variables, levels of competition.Results:There was an increased probability of winning a medal when the interval was in the 10- to 13-wk range for both male and female athletes competing at Grand Prix, Continental-Championship, and World-Championship events, whereas for Grand Slam, only men had an increased probability of winning a medal in this interval range. Furthermore, men had increased probability of podium positions in Continental Championship, World Master, and Olympic Games when the interval was longer than 14 wk.Conclusion:Optimal interval period between successive competitions varies according to competition level and sex; shorter intervals (6–9 wk) were better for female athletes competing at the lowest competition level (Continental Open), but for most of the competitions, the 10- to 13-wk interval was detected as optimal for both male and female athletes (Grand Prix, Continental Championship, and World Championship), whereas for the ranking-based qualified male competitions (ie, Masters and Olympic Games), a longer period (>14 wk) is needed.
Resolution of a Protracted Serogroup B Meningococcal Outbreak with Whole-Genome Sequencing Shows Interspecies Genetic Transfer
Authors: Mulhall Robert M. , Brehony Carina , O'Connor Lois , Meyler Kenneth , Jolley Keith A. , Bray James , Bennett Desiree , Maiden Martin C. J. , Cunney Robert 
Published: September 2016

ABSTRACT

A carriage study was undertaken (
n
= 112) to ascertain the prevalence of
Neisseria
spp. following the eighth case of invasive meningococcal disease in young children (5 to 46 months) and members of a large extended indigenous ethnic minority Traveller family (
n
= 123), typically associated with high-occupancy living conditions. Nested multilocus sequence typing (MLST) was employed for case specimen extracts. Isolates were genome sequenced and then were assembled
de novo
and deposited into the Bacterial Isolate Genome Sequencing Database (BIGSdb). This facilitated an expanded MLST approach utilizing large numbers of loci for isolate characterization and discrimination. A rare sequence type, ST-6697, predominated in disease specimens and isolates that were carried (
n
= 8/14), persisting for at least 44 months, likely driven by the high population density of houses (
n
= 67/112) and trailers (
n
= 45/112). Carriage for
Neisseria meningitidis
(
P
< 0.05) and
Neisseria lactamica
(
P
< 0.002) (2-sided Fisher's exact test) was more likely in the smaller, more densely populated trailers. Meningococcal carriage was highest in 24- to 39-year-olds (45%,
n
= 9/20). Evidence of horizontal gene transfer (HGT) was observed in four individuals cocolonized by
Neisseria lactamica
and
Neisseria meningitidis
. One HGT event resulted in the acquisition of 26 consecutive
N. lactamica
alleles. This study demonstrates how housing density can drive meningococcal transmission and carriage, which likely facilitated the persistence of ST-6697 and prolonged the outbreak. Whole-genome MLST effectively distinguished between highly similar outbreak strain isolates, including those isolated from person-to-person transmission, and also highlighted how a few HGT events can distort the true phylogenetic relationship between highly similar clonal isolates.
Clinical Significance of Commensal Gram-Positive Rods Routinely Isolated from Patient Samples
Authors: Leal Sixto M. , Jones Melissa , Gilligan Peter H. 
Published: September 2016

ABSTRACT

Commensal bacteria from the skin and mucosal surfaces are routinely isolated from patient samples and considered contaminants. The majority of these isolates are catalase-positive Gram-positive rods from multiple genera routinely classified as diphtheroids. These organisms can be seen upon Gram staining of clinical specimens or can be isolated as the predominant or pure species in culture, raising
a priori
suspicion of a possible involvement in infection. With the development and adoption of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), suspicious isolates are now routinely identified to the species level. In this study, we performed a retrospective data review (2012 to 2015) and utilized site-specific laboratory criteria and chart reviews to identify species within the diphtheroid classification representative of true infection versus contamination. Our data set included 762 isolates from 13 genera constituting 41 bacterial species. Only 18% represented true infection, and 82% were deemed contaminants. Clinically significant isolates were identified in anaerobic wounds (18%), aerobic wounds (30%), blood (5.5%), urine (22%), cerebrospinal fluid (24%), ophthalmologic cultures (8%), and sterile sites (20%). Organisms deemed clinically significant included multiple
Actinomyces
species in wounds,
Propionibacterium
species in joints and cerebrospinal fluid associated with central nervous system hardware,
Corynebacterium kroppenstedtii
(100%) in breast, and
Corynebacterium striatum
in multiple sites. Novel findings include clinically significant urinary tract infections by
Actinomyces neuii
(21%) and
Corynebacterium aurimucosum
(21%). Taken together, these findings indicate that species-level identification of diphtheroids isolated with
a priori
suspicion of infection is essential to accurately determine whether an isolate belongs to a species associated with specific types of infection.
Whole-Genome Multilocus Sequence Typing of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae
Authors: Kluytmans-van den Bergh Marjolein F. Q. , Rossen John W. A. , Bruijning-Verhagen Patricia C. J. , Bonten Marc J. M. , Friedrich Alexander W. , Vandenbroucke-Grauls Christina M. J. E. , Willems Rob J. L. , Kluytmans Jan A. J. W. 
Published: September 2016

ABSTRACT

Molecular typing has become indispensable in the detection of nosocomial transmission of bacterial pathogens and the identification of sources and routes of transmission in outbreak settings, but current methods are labor-intensive, are difficult to standardize, or have limited resolution. Whole-genome multilocus sequence typing (wgMLST) has emerged as a whole-genome sequencing (WGS)-based gene-by-gene typing method that may overcome these limitations and has been applied successfully for several species in outbreak settings. In this study, genus-, genetic-complex-, and species-specific wgMLST schemes were developed for
Citrobacter
spp., the
Enterobacter cloacae
complex,
Escherichia coli
,
Klebsiella oxytoca
, and
Klebsiella pneumoniae
and used to type a national collection of 1,798 extended-spectrum-beta-lactamase-producing
Enterobacteriaceae
(ESBL-E) isolates obtained from patients in Dutch hospitals. Genus-, genetic-complex-, and species-specific thresholds for genetic distance that accurately distinguish between epidemiologically related and unrelated isolates were defined for
Citrobacter
spp., the
E. cloacae
complex,
E. coli
, and
K. pneumoniae
. wgMLST was shown to have higher discriminatory power and typeability than
in silico
MLST. In conclusion, the wgMLST schemes developed in this study facilitate high-resolution WGS-based typing of the most prevalent ESBL-producing species in clinical practice and may contribute to further elucidation of the complex epidemiology of antimicrobial-resistant
Enterobacteriaceae
. wgMLST opens up possibilities for the creation of a Web-accessible database for the global surveillance of ESBL-producing bacterial clones.
Comparison of Minocycline Susceptibility Testing Methods for Carbapenem-Resistant Acinetobacter baumannii
Authors: Wang Peng , Bowler Sarah L. , Kantz Serena F. , Mettus Roberta T. , Guo Yan , McElheny Christi L. , Doi Yohei 
Published: September 2016

ABSTRACT

Treatment options for infections due to carbapenem-resistant
Acinetobacter baumannii
are extremely limited. Minocycline is a semisynthetic tetracycline derivative with activity against this pathogen. This study compared susceptibility testing methods that are used in clinical microbiology laboratories (Etest, disk diffusion, and Sensititre broth microdilution methods) for testing of minocycline, tigecycline, and doxycycline against 107 carbapenem-resistant
A. baumannii
clinical isolates. Susceptibility rates determined with the standard broth microdilution method using cation-adjusted Mueller-Hinton (MH) broth were 77.6% for minocycline and 29% for doxycycline, and 92.5% of isolates had tigecycline MICs of ≤2 μg/ml. Using MH agar from BD and Oxoid, susceptibility rates determined with the Etest method were 67.3% and 52.3% for minocycline, 21.5% and 18.7% for doxycycline, and 71% and 29.9% for tigecycline, respectively. With the disk diffusion method using MH agar from BD and Oxoid, susceptibility rates were 82.2% and 72.9% for minocycline and 34.6% and 34.6% for doxycycline, respectively, and rates of MICs of ≤2 μg/ml were 46.7% and 23.4% for tigecycline. In comparison with the standard broth microdilution results, very major rates were low (∼2.8%) for all three drugs across the methods, but major error rates were higher (∼5.6%), especially with the Etest method. For minocycline, minor error rates ranged from 14% to 37.4%. For tigecycline, minor error rates ranged from 6.5% to 69.2%. The majority of minor errors were due to susceptible results being reported as intermediate. For minocycline susceptibility testing of carbapenem-resistant
A. baumannii
strains, very major errors are rare, but major and minor errors overcalling strains as intermediate or resistant occur frequently with susceptibility testing methods that are feasible in clinical laboratories.
A Library of Infectious Hepatitis C Viruses with Engineered Mutations in the E2 Gene Reveals Growth-Adaptive Mutations That Modulate Interactions with Scavenger Receptor Class B Type I
Authors: Zuiani Adam , Chen Kevin , Schwarz Megan C. , White James P. , Luca Vincent C. , Fremont Daved H. , Wang David , Evans Matthew J. , Diamond Michael S. 
Published: September 2016

ABSTRACT
While natural hepatitis C virus (HCV) infection results in highly diverse quasispecies of related viruses over time, mutations accumulate more slowly in tissue culture, in part because of the inefficiency of replication in cells. To create a highly diverse population of HCV particles in cell culture and identify novel growth-enhancing mutations, we engineered a library of infectious HCV with all codons represented at most positions in the ectodomain of the E2 gene. We identified many putative growth-adaptive mutations and selected nine highly represented E2 mutants for further study: Q412R, T416R, S449P, T563V, A579R, L619T, V626S, K632T, and L644I. We evaluated these mutants for changes in particle-to-infectious-unit ratio, sensitivity to neutralizing antibody or CD81 large extracellular loop (CD81-LEL) inhibition, entry factor usage, and buoyant density profiles. Q412R, T416R, S449P, T563V, and L619T were neutralized more efficiently by anti-E2 antibodies and T416R, T563V, and L619T by CD81-LEL. Remarkably, all nine variants showed reduced dependence on scavenger receptor class B type I (SR-BI) for infection. This shift from SR-BI usage did not correlate with a change in the buoyant density profiles of the variants, suggesting an altered E2-SR-BI interaction rather than changes in the virus-associated lipoprotein-E2 interaction. Our results demonstrate that residues influencing SR-BI usage are distributed across E2 and support the development of large-scale mutagenesis studies to identify viral variants with unique functional properties.

IMPORTANCE
Characterizing variant viruses can reveal new information about the life cycle of HCV and the roles played by different viral genes. However, it is difficult to recapitulate high levels of diversity in the laboratory because of limitations in the HCV culture system. To overcome this limitation, we engineered a library of mutations into the E2 gene in the context of an infectious clone of the virus. We used this library of viruses to identify nine mutations that enhance the growth rate of HCV. These growth-enhancing mutations reduced the dependence on a key entry receptor, SR-BI. By generating a highly diverse library of infectious HCV, we mapped regions of the E2 protein that influence a key virus-host interaction and provide proof of principle for the generation of large-scale mutant libraries for the study of pathogens with great sequence variability.
Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence
Authors: Shao Junjie , Liu Xiaoying , Ly Hinh , Liang Yuying 
Published: September 2016

ABSTRACT

Arenaviruses can cause lethal hemorrhagic fevers in humans with few preventative and therapeutic measures. The arenaviral glycoprotein stable signal peptide (SSP) is unique among signal peptides in that it is an integral component of the mature glycoprotein complex (GPC) and plays important roles not only in GPC expression and processing but also in the membrane fusion process during viral entry. Using the Pichinde virus (PICV) reverse genetics system, we analyzed the effects of alanine substitutions at many conserved residues within the SSP on viral replication in cell culture and in a guinea pig infection model. Our data showed that the K33A, F49A, and C57A mutations abolished GPC-mediated cell entry and therefore could not allow for the generation of viable recombinant viruses, demonstrating that these residues are essential for the PICV life cycle. The G2A mutation caused a marked reduction of cell entry at the membrane fusion step, and while this mutant virus was viable, it was significantly attenuated
in vitro
and
in vivo
. The N20A mutation also reduced membrane fusion activity and viral virulence in guinea pigs, but it did not significantly affect cell entry or viral growth in cell culture. Two other mutations (N37A and R55A) did not affect membrane fusion or viral growth
in vitro
but significantly reduced viral virulence
in vivo
. Taken together, our data suggest that the GPC SSP plays an essential role in mediating viral entry and also contributes to viral virulence
in vivo
.

IMPORTANCE
Several arenaviruses, such as Lassa fever virus, can cause severe and lethal hemorrhagic fever diseases with high mortality and morbidity, and no FDA-approved vaccines or therapies are currently available. Viral entry into cells is mediated by arenavirus GPC that consists of an SSP, the receptor-binding GP1, and transmembrane GP2 protein subunits. Using a reverse genetics system of a prototypic arenavirus, Pichinde virus (PICV), we have shown for the first time in the context of virus infections of cell culture and of guinea pigs that the SSP plays an essential role in mediating the membrane fusion step as well as in other yet-to-be-determined processes during viral infection. Our study provides important insights into the biological roles of GPC SSP and implicates it as a good target for the development of antivirals against deadly human arenavirus pathogens.
Herpes Simplex Virus 1 UL37 Protein Tyrosine Residues Conserved among All Alphaherpesviruses Are Required for Interactions with Glycoprotein K, Cytoplasmic Virion Envelopment, and Infectious Virus Production
Authors: Chouljenko Dmitry V. , Jambunathan Nithya , Chouljenko Vladimir N. , Naderi Misagh , Brylinski Michal , Caskey John R. , Kousoulas Konstantin G. 
Published: September 2016

ABSTRACT

The herpes simplex virus 1 (HSV-1) UL37 protein functions in virion envelopment at
trans
-Golgi membranes, as well as in retrograde and anterograde transport of virion capsids. Recently, we reported that UL37 interacts with glycoprotein K (gK) and its interacting partner protein UL20 (N. Jambunathan, D. Chouljenko, P. Desai, A. S. Charles, R. Subramanian, V. N. Chouljenko, and K. G. Kousoulas, J Virol 88:5927–5935, 2014,
http://dx.doi.org/10.1128/JVI.00278-14
), facilitating cytoplasmic virion envelopment. Alignment of UL37 homologs encoded by alphaherpesviruses revealed the presence of highly conserved residues in the central portion of the UL37 protein. A cadre of nine UL37 site-specific mutations were produced and tested for their ability to inhibit virion envelopment and infectious virus production. Complementation analysis revealed that replacement of tyrosines 474 and 480 with alanine failed to complement the UL37-null virus, while all other mutated UL37 genes complemented the virus efficiently. The recombinant virus DC474-480 constructed with tyrosines 474, 476, 477, and 480 mutated to alanine residues produced a gK-null-like phenotype characterized by the production of very small plaques and accumulation of capsids in the cytoplasm of infected cells. Recombinant viruses having either tyrosine 476 or 477 replaced with alanine produced a wild-type phenotype. Immunoprecipitation assays revealed that replacement of all four tyrosines with alanines substantially reduced the ability of gK to interact with UL37. Alignment of HSV UL37 with the human cytomegalovirus and Epstein-Barr virus UL37 homologs revealed that Y480 was conserved only for alphaherpesviruses. Collectively, these results suggest that the UL37 conserved tyrosine 480 residue plays a crucial role in interactions with gK to facilitate cytoplasmic virion envelopment and infectious virus production.

IMPORTANCE
The HSV-1 UL37 protein is conserved among all herpesviruses, functions in both retrograde and anterograde transport of virion capsids, and plays critical roles in cytoplasmic virion envelopment by interacting with gK. We show here that UL37 tyrosine residues conserved among all alphaherpesviruses serve critical roles in cytoplasmic virion envelopment and interactions with gK.
Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001
Authors: Costa Matthew R. , Pollara Justin , Edwards Regina Whitney , Seaman Michael S. , Gorny Miroslaw K. , Montefiori David C. , Liao Hua-Xin , Ferrari Guido , Lu Shan , Wang Shixia 
Published: September 2016

ABSTRACT
HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design.

IMPORTANCE
The roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used.