bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of periodicity in perceiving speech in quiet and in background noise
Authors: Steinmetzger Kurt , Rosen Stuart
Published: December 2015

The ability of normal-hearing listeners to perceive sentences in quiet and in background noise was investigated in a variety of conditions mixing the presence and absence of periodicity (i.e., voicing) in both target and masker. Experiment 1 showed that in quiet, aperiodic noise-vocoded speech and speech with a natural amount of periodicity were equally intelligible, while fully periodic speech was much harder to understand. In Experiments 2 and 3, speech reception thresholds for these targets were measured in the presence of four different maskers: speech-shaped noise, harmonic complexes with a dynamically varying F0 contour, and 10 Hz amplitude-modulated versions of both. For experiment 2, results of experiment 1 were used to identify conditions with equal intelligibility in quiet, while in experiment 3 target intelligibility in quiet was near ceiling. In the presence of a masker, periodicity in the target speech mattered little, but listeners strongly benefited from periodicity in the masker. Substantial fluctuating-masker benefits required the target speech to be almost perfectly intelligible in quiet. In summary, results suggest that the ability to exploit periodicity cues may be an even more important factor when attempting to understand speech embedded in noise than the ability to benefit from masker fluctuations.
Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory
Authors: Oliveira Giacomo , Ruggiero Eliana , Stanghellini Maria Teresa Lupo , Cieri Nicoletta , D’Agostino Mattia , Fronza Raffaele , Lulay Christina , Dionisio Francesca , Mastaglio Sara , Greco Raffaella , Peccatori Jacopo , Aiuti Alessandro , Ambrosi Alessandro , Biasco Luca , Bondanza Attilio , Lambiase Antonio , Traversari Catia , Vago Luca , von Kalle Christof , Schmidt Manfred , Bordignon Claudio , Ciceri Fabio , Bonini Chiara
Published: December 2015

Antigen exposure and differentiation phenotype influence long-term persistence of memory T cells after hematopoietic stem cell transplant.
Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging
Authors: Stoffels Ingo , Morscher Stefan , Helfrich Iris , Hillen Uwe , Leyh Julia , Burton Neal C. , Sardella Thomas C. P. , Claussen Jing , Poeppel Thorsten D. , Bachmann Hagen S. , Roesch Alexander , Griewank Klaus , Schadendorf Dirk , Gunzer Matthias , Klode Joachim
Published: December 2015

Optoacoustic imaging strategies can be used to identify metastasis in excised lymph nodes and to determine SLN status in patients noninvasively.
Ebola vaccine R&D: Filling the knowledge gaps
Authors: Medaglini Donata , Harandi Ali M. , Ottenhoff Tom H. M. , Siegrist Claire-Anne , Consortium VSV-EBOVAC , Agnandji Selidji Todagbe , Ahmed Rafi , Anderson Jenna , Auderset Floriane , Borgianni Luisa , Brosnahan Jessica , Ciabattini Annalisa , Engler Olivier , Haks Marielle C. , Heppner Gray , Gerlini Alice , Kremsner Peter Gottfried , Leib Stephen , Monath Thomas , Ndungu Francis , Njuguna Patricia , Page Mark , Pozzi Gianni , Rappuoli Rino , Santoro Francesco
Published: December 2015

An Ebola project harnesses state-of-the-art technologies that illuminate mechanisms of vaccine immunogenicity and reactogenicity.
Response to comment on “One health, one literature: Weaving together veterinary and medical research”
Authors: Christopher Mary M.
Published: December 2015

Comparative knowledge is essential for effective preclinical translational research.
Comparison of Three Biochemical Tests for Rapid Detection of Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae
Authors: Poirel Laurent , Fernández Javier , Nordmann Patrice
Published: December 2015

Enterobacterial isolates producing clavulanic-inhibited extended-spectrum β-lactamases (ESBLs) are increasingly spreading in the community and are often responsible for nosocomial infections. Rapid biochemical tests have been developed recently for their detection. Three tests, namely, the Rapid ESBL NDP test, the β-Lacta test, and the Rapid ESBL Screen, have been evaluated with a collection of 108 well-characterized strains, including wild-type strains, strains producing ESBLs, overexpressed cephalosporinases, and carbapenemases. The ESBL NDP test and the Rapid ESBL Screen (a copy of the ESBL NDP test) are aimed at detecting ESBL producers, while the β-Lacta test is aimed at detecting not only ESBL producers but also cephalosporinase and carbapenemase producers. The sensitivity and specificity for detecting ESBL producers (
n
= 60) were 95% and 100% for the Rapid ESBL NDP test, 80% and 87% (after 30 min) and 92% and 83% (after 2 h) for the Rapid ESBL Screen, and 88% and 71% for the β-Lacta test, respectively. Varied and time-consuming detection (up to 2 h) of ESBLs by the Rapid ESBL Screen and concomitant and varied detection of producers of AmpC and several types of carbapenemases correspond to significant shortcomings of using the Rapid Screen ESBL and β-Lacta tests, respectively.
Establishment of an Algorithm Using prM/E- and NS1-Specific IgM Antibody-Capture Enzyme-Linked Immunosorbent Assays in Diagnosis of Japanese Encephalitis Virus and West Nile Virus Infections in Humans
Authors: Galula Jedhan U. , Chang Gwong-Jen J. , Chuang Shih-Te , Chao Day-Yu
Published: December 2015

The front-line assay for the presumptive serodiagnosis of acute Japanese encephalitis virus (JEV) and West Nile virus (WNV) infections is the premembrane/envelope (prM/E)-specific IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA). Due to antibody cross-reactivity, MAC-ELISA-positive samples may be confirmed with a time-consuming plaque reduction neutralization test (PRNT). In the present study, we applied a previously developed anti-nonstructural protein 1 (NS1)-specific MAC-ELISA (NS1-MAC-ELISA) on archived acute-phase serum specimens from patients with confirmed JEV and WNV infections and compared the results with prM/E containing virus-like particle-specific MAC-ELISA (VLP-MAC-ELISA). Paired-receiver operating characteristic (ROC) curve analyses revealed no statistical differences in the overall assay performances of the VLP- and NS1-MAC-ELISAs. The two methods had high sensitivities of 100% but slightly lower specificities that ranged between 80% and 100%. When the NS1-MAC-ELISA was used to confirm positive results in the VLP-MAC-ELISA, the specificity of serodiagnosis, especially for JEV infection, was increased to 90% when applied in areas where JEV cocirculates with WNV, or to 100% when applied in areas that were endemic for JEV. The results also showed that using multiple antigens could resolve the cross-reactivity in the assays. Significantly higher positive-to-negative (P/N) values were consistently obtained with the homologous antigens than those with the heterologous antigens. JEV or WNV was reliably identified as the currently infecting flavivirus by a higher ratio of JEV-to-WNV P/N values or vice versa. In summary of the above-described results, the diagnostic algorithm combining the use of multiantigen VLP- and NS1-MAC-ELISAs was developed and can be practically applied to obtain a more specific and reliable result for the serodiagnosis of JEV and WNV infections without the need for PRNT. The developed algorithm should provide great utility in diagnostic and surveillance activities in which test accuracy is of utmost importance for effective disease intervention.
Implementation of a Consensus Set of Hypervariable Mycobacterial Interspersed Repetitive-Unit–Variable-Number Tandem-Repeat Loci in Mycobacterium tuberculosis Molecular Epidemiology
Authors: Trovato Alberto , Tafaj Silva , Battaglia Simone , Alagna Riccardo , Bardhi Donika , Kapisyzi Perlat , Bala Silvana , Haldeda Migena , Borroni Emanuele , Hafizi Hasan , Cirillo Daniela Maria
Published: December 2015

This study shows that the addition of a consensus 4-locus set of hypervariable mycobacterial interspersed repetitive-unit–variable-number tandem repeat (MIRU-VNTR) loci to the spoligotyping-24-locus MIRU-VNTR typing strategy is a well-standardized approach that can contribute to an improvement of the true cluster definition while retaining high typeability in non-Beijing strains.
Point-Counterpoint: Reflex Cultures Reduce Laboratory Workload and Improve Antimicrobial Stewardship in Patients Suspected of Having Urinary Tract Infections
Authors: Humphries Romney M. , Dien Bard Jennifer
Published: December 2015

Urinary tract infections (UTIs) are frequent and lead to a large number of clinical encounters. A common management strategy for patients suspected of having a urinary tract infection is to test for pyuria and bacteria by urine analysis (UA) of midstream urine, with initiation of antibiotic therapy and urine culture if one or both tests are positive. Although this practice was first used in an outpatient setting with midstream urine samples, some institutions allow its use in the management of catheterized patients. The ideas behind the reflex urine culture are to limit laboratory workload by not performing culture on negative specimens and to improve antimicrobial stewardship by not giving antimicrobials to patients with negative UA results. The questions are, first, whether reflex urine culture reduces workloads significantly and, second, whether it improves antimicrobial stewardship in the era of increasing numbers of urinary tract infections due to extensively drug-resistant Gram-negative bacilli. Romney Humphries from UCLA supports the idea that reflex urine cultures are of value and describes what reflex parameters are most useful, while Jennifer Dien Bard of Children's Hospital Los Angeles discusses their limitations.
HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4
+
T Cell Responses
Authors: Ranasinghe Srinika , Soghoian Damien Z. , Lindqvist Madelene , Ghebremichael Musie , Donaghey Faith , Carrington Mary , Seaman Michael S. , Kaufmann Daniel E. , Walker Bruce D. , Porichis Filippos
Published: December 2015

Antigen-specific CD4
+
T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4
+
T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4
+
T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4
+
T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4
+
T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4
+
T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4
+
T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4
+
T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4
+
T cells and, to a lesser extent, gp41-specific CD4
+
T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.

IMPORTANCE
One of the earliest discoveries related to CD4
+
T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4
+
T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4
+
T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4
+
T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4
+
T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4
+
T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.
A Novel DNA Motif Contributes to Selective Replication of a Geminivirus-Associated Betasatellite by a Helper Virus-Encoded Replication-Related Protein
Authors: Zhang Tong , Xu Xiongbiao , Huang Changjun , Qian Yajuan , Li Zhenghe , Zhou Xueping
Published: December 2015

Rolling-circle replication of single-stranded genomes of plant geminiviruses is initiated by sequence-specific DNA binding of the viral replication-related protein (Rep) to its cognate genome at the replication origin. Monopartite begomovirus-associated betasatellites can be
trans
replicated by both cognate and some noncognate helper viruses, but the molecular basis of replication promiscuity of betasatellites remains uncharacterized. Earlier studies showed that when tomato yellow leaf curl China virus (TYLCCNV) or tobacco curly shoot virus (TbCSV) is coinoculated with both cognate and noncognate betasatellites, the cognate betasatellite dominates over the noncognate one at the late stages of infection. In this study, we constructed reciprocal chimeric betasatellites between tomato yellow leaf curl China betasatellite and tobacco curly shoot betasatellite and assayed their competitiveness against wild-type betasatellite when coinoculated with TYLCCNV or TbCSV onto plants. We mapped a region immediately upstream of the conserved rolling-circle cruciform structure of betasatellite origin that confers the cognate Rep-mediated replication advantage over the noncognate satellite. DNase I protection and
in vitro
binding assays further identified a novel sequence element termed Rep-binding motif (RBM), which specifically binds to the cognate Rep protein and to the noncognate Rep, albeit at lower affinity. Furthermore, we showed that RBM-Rep binding affinity is correlated with betasatellite replication efficiency in protoplasts. Our data suggest that although strict specificity of Rep-mediated replication does not exist, betasatellites have adapted to their cognate Reps for efficient replication during coevolution.

IMPORTANCE
Begomoviruses are numerous circular DNA viruses that cause devastating diseases of crops worldwide. Monopartite begomoviruses are frequently associated with betasatellites which are essential for induction of typical disease symptoms. Coexistence of two distinct betasatellites with one helper virus is rare in nature. Our previous research showed that begomoviruses can
trans
replicate cognate betasatellites to higher levels than noncognate ones. However, the molecular mechanisms of betasatellites selective replication remain largely unknown. We investigated the interaction between the begomovirus replication-associated protein and betasatellite DNA. We found that the replication-associated protein specifically binds to a motif in betasatellites, with higher affinity for the cognate motif than the noncognate motif. This preference for cognate motif binding determines the selective replication of betasatellites. We also demonstrated that this motif is essential for betasatellite replication. These findings shed new light on the promiscuous yet selective replication of betasatellites by helper geminiviruses.
Investigating the Influence of Ribavirin on Human Respiratory Syncytial Virus RNA Synthesis by Using a High-Resolution Transcriptome Sequencing Approach
Authors: Aljabr Waleed , Touzelet Olivier , Pollakis Georgios , Wu Weining , Munday Diane C. , Hughes Margaret , Hertz-Fowler Christiane , Kenny John , Fearns Rachel , Barr John N. , Matthews David A. , Hiscox Julian A.
Published: December 2015

Human respiratory syncytial virus (HRSV) is a major cause of serious respiratory tract infection. Treatment options include administration of ribavirin, a purine analog, although the mechanism of its anti-HRSV activity is unknown. We used transcriptome sequencing (RNA-seq) to investigate the genome mutation frequency and viral mRNA accumulation in HRSV-infected cells that were left untreated or treated with ribavirin. In the absence of ribavirin, HRSV-specific transcripts accounted for up to one-third of total RNA reads from the infected-cell RNA population. Ribavirin treatment resulted in a >90% reduction in abundance of viral mRNA reads, while at the same time no such reduction was detected for the abundance of cellular transcripts. The presented data reveal that ribavirin significantly increases the frequency of HRSV-specific RNA mutations, suggesting a direct influence on the fidelity of the HRSV polymerase. The presented data show that transitions and transversions occur during HRSV replication and that these changes occur in hot spots along the HRSV genome. Examination of nucleotide substitution rates in the viral genome indicated an increase in the frequency of transition but not transversion mutations in the presence of ribavirin. In addition, our data indicate that in the continuous cell types used and at the time points analyzed, the abundances of some HRSV mRNAs do not reflect the order in which the mRNAs are transcribed.

IMPORTANCE
Human respiratory syncytial virus (HRSV) is a major pediatric pathogen. Ribavirin can be used in children who are extremely ill to reduce the amount of virus and to lower the burden of disease. Ribavirin is used as an experimental therapy with other viruses. The mechanism of action of ribavirin against HRSV is not well understood, although it is thought to increase the mutation rate of the viral polymerase during replication. To investigate this hypothesis, we used a high-resolution approach that allowed us to determine the genetic sequence of the virus to a great depth of coverage. We found that ribavirin did not cause a detectable change in the relative amounts of viral mRNA transcripts. However, we found that ribavirin treatment did indeed cause an increase in the number of mutations, which was associated with a decrease in virus production.
Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors
Authors: Riddick Nadeene E. , Wu Fan , Matsuda Kenta , Whitted Sonya , Ourmanov Ilnour , Goldstein Simoy , Goeken Robert M. , Plishka Ronald J. , Buckler-White Alicia , Brenchley Jason M. , Hirsch Vanessa M.
Published: December 2015

African green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIV
in vivo
, while human-derived CXCR6 and GPR15 also appear to be used
in vitro
. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptors
in vivo
. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4
+
T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4
+
T cells and are potential alternative coreceptors for SIVagm use
in vivo
. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals.

IMPORTANCE
African green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cells
in vivo
, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptors
in vitro
. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGM-derived GPR15 and CXCR6 support SIVagmVer entry
in vitro
and may serve as entry coreceptors for SIVagm
in vivo
, since their mRNAs were detected in AGM memory CD4
+
T cells, the preferred target cells of SIV.
Changes in the Length of the Neuraminidase Stalk Region Impact H7N9 Virulence in Mice
Authors: Bi Yuhai , Xiao Haixia , Chen Quanjiao , Wu Yan , Fu Lifeng , Quan Chuansong , Wong Gary , Liu Jun , Haywood Joel , Liu Yingxia , Zhou Boping , Yan Jinghua , Liu Wenjun , Gao George F.
Published: December 2015

The neuraminidase stalk of the newly emerged H7N9 influenza virus possesses a 5-amino-acid deletion. This study focuses on characterizing the biological functions of H7N9 with varied neuraminidase stalk lengths. Results indicate that the 5-amino-acid deletion had no impact on virus infectivity or replication
in vitro
or
in vivo
compared to that of a virus with a full-length stalk, but enhanced virulence in mice was observed for H7N9 encoding a 19- to 20-amino-acid deletion, suggesting that N9 stalk length impacts virulence in mammals, as N1 stalk length does.
Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells
Authors: Lee Wen Shi , Richard Jonathan , Lichtfuss Marit , Smith Amos B. , Park Jongwoo , Courter Joel R. , Melillo Bruno N. , Sodroski Joseph G. , Kaufmann Daniel E. , Finzi Andrés , Parsons Matthew S. , Kent Stephen J.
Published: December 2015

Lifelong antiretroviral therapy (ART) for HIV-1 does not diminish the established latent reservoir. A possible cure approach is to reactivate the quiescent genome from latency and utilize immune responses to eliminate cells harboring reactivated HIV-1. It is not known whether antibodies within HIV-1-infected individuals can recognize and eliminate cells reactivated from latency through antibody-dependent cellular cytotoxicity (ADCC). We found that reactivation of HIV-1 expression in the latently infected ACH-2 cell line elicited antibody-mediated NK cell activation but did not result in antibody-mediated killing. The lack of CD4 expression on these HIV-1 envelope (Env)-expressing cells likely resulted in poor recognition of CD4-induced antibody epitopes on Env. To examine this further, cultured primary CD4+T cells from HIV-1+subjects were used as targets for ADCC. Theseex vivo-expanded primary cells were modestly susceptible to ADCC mediated by autologous or heterologous HIV-1+serum antibodies. Importantly, ADCC mediated against these primary cells could be enhanced following incubation with a CD4-mimetic compound (JP-III-48) that exposes CD4-induced antibody epitopes on Env. Our studies suggest that with sufficient reactivation and expression of appropriate Env epitopes, primary HIV-1-infected cells can be targets for ADCC mediated by autologous serum antibodies and innate effector cells. The results of this study suggest that further investigation into the potential of ADCC to eliminate reactivated latently infected cells is warranted.

IMPORTANCEAn HIV-1 cure remains elusive due to the persistence of long-lived latently infected cells. An HIV-1 cure strategy, termed “shock and kill,” aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. While recent research efforts have focused on reversing HIV-1 latency, it remains unclear whether preexisting immune responses within HIV-1+individuals can efficiently eliminate the reactivated cells. HIV-1-specific antibodies can potentially eliminate cells reactivated from latency via Fc effector functions by recruiting innate immune cells. Our study highlights the potential role that antibody-dependent cellular cytotoxicity might play in antilatency cure approaches.
Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection
Authors: Kang Moon Cheol , Choi Dong-Hoon , Choi Young Woo , Park Seong Jeong , Namkoong Hong , Park Ki Seok , Ahn So-Shin , Surh Charles D. , Yoon Sun-Woo , Kim Doo-Jin , Choi Jung-ah , Park Yunji , Sung Young Chul , Lee Seung-Woo
Published: December 2015

Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but they have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment with Fc-fused interleukin-7 (IL-7–mFc) protects mice from lethal IAV infections. The protective activity of IL-7–mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7–mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as tissue-resident memory-like T (TRM-like) cells. IL-7–mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. First, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Second, TRM-like cells augment expansion of IAV-specific cytotoxic T lymphocytes (CTLs), in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7–mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in the future.

IMPORTANCEThe major consequence of a highly pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7–mFc pretreatment protected immunologically naive mice from lethal IAV infections. Intranasal pretreatment with IL-7–mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment with IL-7–mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7–mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.
Comparative Mutagenesis of Pseudorabies Virus and Epstein-Barr Virus gH Identifies a Structural Determinant within Domain III of gH Required for Surface Expression and Entry Function
Authors: Möhl Britta S. , Schröter Christina , Klupp Barbara G. , Fuchs Walter , Mettenleiter Thomas C. , Jardetzky Theodore S. , Longnecker Richard
Published: December 2015

Herpesviruses infect cells using the conserved core fusion machinery composed of glycoprotein B (gB) and gH/gL. The gH/gL complex plays an essential but still poorly characterized role in membrane fusion and cell tropism. Our previous studies demonstrated that the conserved disulfide bond (DB) C278/C335 in domain II (D-II) of Epstein-Barr virus (EBV) gH has an epithelial cell-specific function, whereas the interface of D-II/D-III is involved in formation of the B cell entry complex by binding to gp42. To extend these studies, we compared gH of the alphaherpesvirus pseudorabies virus (PrV) with gH of the gammaherpesvirus EBV to identify functionally equivalent regions critical for gH function during entry. We identified several conserved amino acids surrounding the conserved DB that connects three central helices of D-III of PrV and EBV gH. The present study verified that the conserved DB and several contacting amino acids in D-III modulate cell surface expression and thereby contribute to gH function. In line with this finding, we found that DB C404/C439 and T401 are important for cell-to-cell spread and efficient entry of PrV. This parallel comparison between PrV and EBV gH function brings new insights into how gH structure impacts fusion function during herpesvirus entry.

IMPORTANCE
The alphaherpesvirus PrV is known for its neuroinvasion, whereas the gammaherpesvirus EBV is associated with cancer of epithelial and B cell origin. Despite low amino acid conservation, PrV gH and EBV gH show strikingly similar structures. Interestingly, both PrV gH and EBV gH contain a structural motif composed of a DB and supporting amino acids which is highly conserved within the
Herpesviridae
. Our study verified that PrV gH uses a minimal motif with the DB as the core, whereas the DB of EBV gH forms extensive connections through hydrogen bonds to surrounding amino acids, ensuring the cell surface expression of gH/gL. Our study verifies that the comparative analysis of distantly related herpesviruses, such as PrV and EBV, allows the identification of common gH functions. In addition, we provide an understanding of how functional domains can evolve over time, resulting in subtle differences in domain structure and function.
Use and safety of azithromycin in neonates: a systematic review
Authors: Smith Coral , Egunsola Oluwaseun , Choonara Imti , Kotecha Sailesh , Jacqz-Aigrain Evelyne , Sammons Helen
Published: December 2015

Objectives

To identify the use and adverse drug reactions associated with azithromycin in neonates.

Setting

Databases MEDLINE (1948–August 2015), EMBASE (1980–August 2015) and Pubmed (August 2015) were searched for studies on azithromycin in neonates.

Participants

All studies involving neonates (<28 days old) who have received at least a single dose of azithromycin for which safety was evaluated.

Primary and secondary outcome measures

The primary outcome was adverse event (AE) associated with use of azithromycin. Use of azithromycin in neonates was the secondary outcome.

Results

A total of 11 articles involving 473 neonates were identified. 371 AEs were reported. Adverse events were mainly respiratory (358/1000 neonate), neurological (273/1000 neonates) and gastrointestinal (196/1000 neonates) in origin. Azithromycin significantly reduced the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates (RR=0.83, 95% CI 0.71 to 0.98, p=0.02). There was no significant difference in the incidence of elevated liver enzymes between the azithromycin and placebo group (p=0.76). There were four cases of infantile hypertrophic pyloric stenosis (IHPS).

Conclusions

Azithromycin significantly reduces the risk of BPD in preterm neonates. The relationship between azithromycin and IHPS requires further investigation.
Health conditions in a cohort of New Zealand Vietnam veterans: hospital admissions between 1988 and 2009
Authors: Cox Brian , McBride David , Broughton John , Tong Darryl
Published: December 2015

Objectives

To inform the provision of support to veterans by analysing hospital discharge data, thereby identifying which conditions show an excess risk, require specific management strategies and deserve further investigation.

Setting

Tertiary level care, including all public and private New Zealand hospitals.

Participants

All New Zealand Vietnam veterans with service between 1964 and 1972.

Primary outcome measures

Standardised hospitalisation ratios (SHRs) were calculated based on the number of first observed hospital admissions for a condition, those expected being based on New Zealand national hospitalisation rates.

Results

The SHR for all causes of hospitalisation was 1.18, 95% CI 1.15 to 1.21, with modest increases for the major common causes, cardio and cerebrovascular disease. Admission rates for chronic renal failure and chronic obstructive pulmonary disease were highest in the 2006–2009 time period. The highest statistically significant hospitalisation risk was for alcohol-related mental disorder, SHR 1.91, 99% CI 1.39 to 2.43.

Conclusions

Chronic renal failure has limited attribution to veteran service but along with chronic obstructive pulmonary disease has the potential to have high costs both to the individual and the health system. We suggest that routine surveillance of veterans by way of a ‘flag’ in national and primary care databases would facilitate the recognition of service-related conditions and the appropriate provision of healthcare.
Evaluating quality and its determinants in lipid control for secondary prevention of heart disease and stroke in primary care: a study in an inner London Borough
Authors: Dodhia Hiten , Kun Liu , Logan Ellis Hugh , Crompton James , Wierzbicki Anthony S , Williams Helen , Hodgkinson Anna , Balazs John
Published: December 2015

Objectives

To assess quality of management and determinants in lipid control for secondary prevention of cardiovascular disease (CVD) using multilevel regression models.

Design

Cross-sectional study.

Setting

Inner London borough, with a primary care registered population of 378 000 (2013).

Participants

48/49 participating general practices with 7869 patients on heart disease/stroke registers were included.

Outcome measures

(1) Recording of current total cholesterol levels and lipid control according to national evidence-based standards. (2) Assessment of quality by age, sex, ethnicity, deprivation, presence of other risks or comorbidity in meeting both lipid measurement and control standards.

Results

Some process standards were not met. Patients with a current cholesterol measurement >5 mmol/L were less likely to have a current statin prescription (adjusted OR=3.10; 95% CI 2.70 to 3.56). They were more likely to have clustering of other CVD risk factors. Women were significantly more likely to have raised cholesterol after adjustment for other factors (adjusted OR=1.74; 95% CI 1.53 to 1.98).

Conclusions

In this study, the key factor that explained poor lipid control in people with CVD was having no current prescription record of a statin. Women were more likely to have poorly controlled cholesterol (independent of comorbid risk factors and after adjusting for age, ethnicity, deprivation index and practice-level variation). Women with CVD should be offered statin prescription and may require higher statin dosage for improved control.
The abdominal drawing-in manoeuvre for detecting activity in the deep abdominal muscles: is this clinical tool reliable and valid?
Authors: Kaping Karsten , Äng Björn O , Rasmussen-Barr Eva
Published: December 2015

Objective

The abdominal drawing-in manoeuvre (ADIM) is a common clinical tool for manually assessing whether a preferential activation of the deep abdominal muscles in patients with low back pain (LBP) is ‘correct’ or not. The validity and reliability of manual assessment of the ADIM are, however, as yet unknown. This study evaluated the concurrent and discriminative validity and reliability of the manually assessed ADIM.

Design

Single-blinded cross-sectional study.

Settings

General population in Stockholm County, Sweden.

Participants

The study sample comprised 38 participants seeking care for LBP, and 15 healthy subjects.

Measures

The manual ADIM was assessed as correct or not following a standard procedure. Ultrasound imaging (USI) was used as the concurrent reference (gold standard) for the manually assessed ADIM by calculating a ratio of the change in muscle thickness between the resting and the contracted states: the correlation between manual test and USI was calculated. Discriminative validity was analysed by calculating sensitivity and specificity. A sample of 24 participants was analysed with κ coefficients for interobserver reliability between two raters.

Results

The concurrent validity between the manual ADIM and the ADIM–USI ratios showed poor correlations (r=0.13–0.40). The discriminative validity of the manually assessed ADIM to predict LBP showed a sensitivity/specificity of 0.30/0.73, while the ADIM–USI ratio to predict LBP showed 0.19/0.87. The interobserver reliability for the manually assessed ADIM revealed substantial agreement: K=0.71, CI (95%) 0.41 to 1.00.

Conclusions

Although the interobserver reliability of the manually assessed ADIM was high, the concurrent and discriminative validity were both low for examining the preferential activity of the deep abdominal muscles. Neither the manually assessed ADIM nor the ultrasound testing discriminated between participants with LBP and healthy subjects regarding preferential activity of the transversus muscle as this ability/inability was also present in healthy subjects.
High prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia: a nationwide survey
Authors: Sugai Takuro , Suzuki Yutaro , Yamazaki Manabu , Shimoda Kazutaka , Mori Takao , Ozeki Yuji , Matsuda Hiroshi , Sugawara Norio , Yasui-Furukori Norio , Minami Yoshitake , Okamoto Kurefu , Sagae Toyoaki , Someya Toshiyuki
Published: December 2015

Objectives

To clarify the prevalence of underweight and overweight/obesity, and laboratory data for nutritional status in Japanese outpatients and inpatients with schizophrenia.

Design

Cross-sectional study.

Setting

A questionnaire conducted in inpatient and outpatient facilities in Japan.

Participants

The population of adult patients with schizophrenia in Japan (N=23 116).

Main outcome measures

The prevalence of underweight and undernutrition in Japanese inpatients and outpatients with schizophrenia.

Results

We conducted a large-scale investigation of the prevalence of underweight and undernutrition in 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospitals Association between January 2012 and July 2013. There were 7655 outpatients and 15 461 inpatients with schizophrenia. There was a significant difference in the distribution of three body mass index levels between outpatients and inpatients (p<0.001). The proportion of underweight inpatients with schizophrenia was significantly higher than that among outpatients (p<0.001). Age-specific analysis revealed that the proportion of underweight individuals aged ≥40 years was higher in inpatients than in outpatients and in the general Japanese population. The proportion of individuals with hypocholesterolaemia was significantly higher in inpatients with schizophrenia than in outpatients (p<0.001). There was a significant difference in the severity of underweight between outpatients and inpatients with schizophrenia; the proportion of severe underweight in inpatients was twofold higher than in outpatients.

Conclusions

The prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia was higher than in outpatients and the general population. Therefore, the physical risk of inpatients should be carefully considered in clinical practice.
Cost-effectiveness of a European ST-segment elevation myocardial infarction network: results from the CatalanCodi Infartnetwork
Authors: Regueiro Ander , Bosch Julia , Martín-Yuste Victoria , Rosas Alba , Faixedas Maria Teresa , Gómez-Hospital Joan Antoni , Figueras Jaume , Curós Antoni , Cequier Angel , Goicolea Javier , Fernández-Ortiz Antonio , Macaya Carlos , Tresserras Ricard , Pellisé Laura , Sabaté Manel
Published: December 2015

Objectives

To evaluate the cost-effectiveness of the ST-segment elevation myocardial infarction (STEMI) network of Catalonia (Codi Infart).

Design

Cost-utility analysis.

Setting

The analysis was from the Catalonian Autonomous Community in Spain, with a population of about 7.5 million people.

Participants

Patients with STEMI treated within the autonomous community of Catalonia (Spain) included in the IAM CAT II-IV andCodi Infartregistries.

Outcome measures

Costs included hospitalisation, procedures and additional personnel and were obtained according to the reperfusion strategy. Clinical outcomes were defined as 30-day avoided mortality and quality-adjusted life-years (QALYs), before (N=356) and after network implementation (N=2140).

Results

A substitution effect and a technology effect were observed; aggregate costs increased by 2.6%. The substitution effect resulted from increased use of primary coronary angioplasty, a relatively expensive procedure and a decrease in fibrinolysis. Primary coronary angioplasty increased from 31% to 89% with the network, and fibrinolysis decreased from 37% to 3%. Rescue coronary angioplasty declined from 11% to 4%, and no reperfusion from 21% to 4%. The technological effect was related to improvements in the percutaneous coronary intervention procedure that increased efficiency, reducing the average length of the hospital stay. Mean costs per patient decreased from €8306 to €7874 for patients with primary coronary angioplasty. Clinical outcomes in patients treated with primary coronary angioplasty did not change significantly, although 30-day mortality decreased from 7.5% to 5.6%. The incremental cost-effectiveness ratio resulted in an extra cost of €4355 per life saved (30-day mortality) and €495 per QALY. Below a cost threshold of €30 000, results were sensitive to variations in costs and outcomes.

Conclusions

The Catalan STEMI network (Codi Infart) is cost-efficient. Further studies are needed in geopolitical different scenarios.
Primary Care Atrial Fibrillation Service: outcomes from consultant-led anticoagulation assessment clinics in the primary care setting in the UK
Authors: Das Moloy , Panter Lee , Wynn Gareth J , Taylor Rob M , Connor Neil , Mills Joseph D , Kirchhof Paulus , Gupta Dhiraj
Published: December 2015

Objective

Stroke-risk in atrial fibrillation (AF) can be significantly reduced by appropriate thromboembolic prophylaxis. However, National Institute for Health and Care Excellence estimates suggest that up to half of eligible patients with AF are not anticoagulated, with severe consequences for stroke prevention. We aimed to determine the outcome of an innovative Primary Care AF (PCAF) service on anticoagulation uptake in a cohort of high-risk patients with AF in the UK.

Methods

The PCAF service is a novel cooperative pathway providing specialist resources within general practitioner (GP) practices. It utilises a four-phase protocol to identify high-risk patients with AF (CHA2DS2-VASc ≥1) who are suboptimally anticoagulated, and delivers Consultant-led anticoagulation assessment within the local GP practice. We assessed rates of anticoagulation in high-risk patients before and after PCAF service intervention, and determined compliance with newly-initiated anticoagulation at follow-up.

Results

The PCAF service was delivered in 56 GP practices (population 386 624; AF prevalence 2.1%) between June 2012 and June 2014. 1579 high-risk patients with AF with suboptimal anticoagulation (either not taking any anticoagulation or taking warfarin but with a low time-in-therapeutic-range) were invited for review, with 86% attending. Of 1063 eligible patients on no anticoagulation, 1020 (96%) agreed to start warfarin (459 (43%)) or a non-vitamin K antagonist oral anticoagulant (NOAC, 561 (53%)). The overall proportion of eligible patients receiving anticoagulation improved from 77% to 95% (p<0.0001). Additionally, 111/121 (92%) patients suboptimally treated with warfarin agreed to switch to a NOAC. Audit of eight practices after 195 (185–606) days showed that 90% of patients started on a new anticoagulant therapy had continued treatment. Based on data extrapolated from previous studies, around 30–35 strokes per year may have been prevented in these previously under-treated high-risk patients.

Conclusions

Systematic identification of patients with AF with high stroke-risk and consultation in PCAF consultant-led clinics effectively delivers oral anticoagulation to high-risk patients with AF in the community.
Realising their potential? Exploring interprofessional perceptions and potential of the advanced practitioner role: a qualitative analysis
Authors: Jones Aled , Powell Tom , Watkins Dianne , Kelly Daniel
Published: December 2015

Objectives

To explore perceptions of the current practice and future potential of advanced practitioners (APs) from the perspectives of different professional groups in Wales UK.

Design

A qualitative study consisting of nine focus group interviews.

Methods

Initially verbatim transcriptions of each focus group interviews were analysed thematically before themes were merged to represent perceptions for the whole data set.

Participants

Data were gathered from a total of 67 stakeholders—including APs from a variety of professional groups (eg, nursing, physiotherapy, paramedics) as well as managers, workforce developers, educators and medical staff who have a role developing and supporting APs in practice.

Results

The results are presented in four themes: (1) demand, policy context and future priorities, (2) role clarity and standardisation, (3) agreement and understanding of the role and (4) interprofessional working. The context within which current and future AP roles were considered was influenced by inexorable demands for healthcare and the requirements to meet health policy priorities. Developing AP roles were hampered currently by a lack of shared understanding and ‘joined-up’ working between different groups such as medical practitioners, managers, commissioners and educators.

Conclusions

For the AP role to flourish more ‘joined-up’ thinking, support and development opportunities are required between APs, managers, senior clinicians, commissioners and educators. Working together to plan and deliver education, innovation and service delivery is of prime importance to meeting ever increasing complex health needs. This will ensure that future APs are adequately prepared and supported to reach their full potential and help deliver necessary innovations in current models of care delivery.