bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine
Authors: Chen Xinhui , Castillo-Mancilla Jose R. , Seifert Sharon M. , McAllister Kevin B. , Zheng Jia-Hua , Bushman Lane R. , MaWhinney Samantha , Anderson Peter L. 
Published: June 2016

ABSTRACTTenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC), two nucleos(t)ide analogs (NA), are coformulated as an anti-HIV combination tablet for treatment and preexposure prophylaxis (PrEP). TDF/FTC may have effects on the deoxynucleoside triphosphate (dNTP) pool due to their similar structures and similar metabolic pathways. We carried out a comprehensive clinical study to characterize the effects of TDF/FTC on the endogenous dNTP pool, from baseline to 30 days of TDF/FTC therapy, in both treatment-naive HIV-positive and HIV-negative individuals. dATP, dCTP, dGTP, and TTP were quantified in peripheral blood mononuclear cells (PBMC) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Forty individuals (19 HIV-positive) were enrolled and underwent a baseline visit and then received TDF/FTC for at least 30 days. Longitudinal measurements were analyzed using mixed-model segmented linear regression analysis. The dNTPs were reduced by 14% to 37% relative to the baseline level within 3 days in both HIV-negative and HIV-positive individuals (P≤ 0.003). These reductions persisted to various degrees at day 30. These findings indicate that dNTP pools are influenced by TDF/FTC therapy. This may alter cellular homeostasis and could increase the antiviral effect through a more favorable analog/dNTP ratio. Further work is needed to elucidate mechanisms, to evaluate the clinical significance of these findings, and to further probe differences between HIV-negative and HIV-positive individuals. (This study has been registered at ClinicalTrials.gov under identifier NCT01040091.)
In Vitro
Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71
Authors: Wang Yizhuo , Li Guiming , Yuan Shilin , Gao Qianqian , Lan Ke , Altmeyer Ralf , Zou Gang 
Published: June 2016

ABSTRACT
Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.
Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells
Authors: Rosenberg Charles S. , Zhang Weibo , Bustamante Juan M. , Tarleton Rick L. 
Published: June 2016

ABSTRACTTrypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.
Free Sialic Acid Acts as a Signal That Promotes Streptococcus pneumoniae Invasion of Nasal Tissue and Nonhematogenous Invasion of the Central Nervous System
Authors: Hatcher Brandon L. , Hale Joanetha Y. , Briles David E. 
Published: June 2016

ABSTRACT

Streptococcus pneumoniae
(pneumococcus) is a leading cause of bacterial meningitis and neurological sequelae in children worldwide. Acute bacterial meningitis is widely considered to result from bacteremia that leads to blood-brain barrier breakdown and bacterial dissemination throughout the central nervous system (CNS). Previously, we showed that pneumococci can gain access to the CNS through a nonhematogenous route without peripheral blood infection. This access is thought to occur when the pneumococci in the upper sinus follow the olfactory nerves and enter the CNS through the olfactory bulbs. In this study, we determined whether the addition of exogenous sialic acid postcolonization promotes nonhematogenous invasion of the CNS. Previously, others showed that treatment with exogenous sialic acid post-pneumococcal infection increased the numbers of CFU recovered from an intranasal mouse model of infection. Using a pneumococcal colonization model, an
in vivo
imaging system, and a multiplex assay for cytokine expression, we demonstrated that sialic acid can increase the number of pneumococci recovered from the olfactory bulbs and brains of infected animals. We also show that pneumococci primarily localize to the olfactory bulb, leading to increased expression levels of proinflammatory cytokines and chemokines. These findings provide evidence that sialic acid can enhance the ability of pneumococci to disseminate into the CNS and provide details about the environment needed to establish nonhematogenous pneumococcal meningitis.
Genomic Analysis and Comparison of Two Gonorrhea Outbreaks
Authors: Didelot Xavier , Dordel Janina , Whittles Lilith K. , Collins Caitlin , Bilek Nicole , Bishop Cynthia J. , White Peter J. , Aanensen David M. , Parkhill Julian , Bentley Stephen D. , Spratt Brian G. , Harris Simon R. 
Published: June 2016

ABSTRACT
Gonorrhea is a sexually transmitted disease causing growing concern, with a substantial increase in reported incidence over the past few years in the United Kingdom and rising levels of resistance to a wide range of antibiotics. Understanding its epidemiology is therefore of major biomedical importance, not only on a population scale but also at the level of direct transmission. However, the molecular typing techniques traditionally used for gonorrhea infections do not provide sufficient resolution to investigate such fine-scale patterns. Here we sequenced the genomes of 237 isolates from two local collections of isolates from Sheffield and London, each of which was resolved into a single type using traditional methods. The two data sets were selected to have different epidemiological properties: the Sheffield data were collected over 6 years from a predominantly heterosexual population, whereas the London data were gathered within half a year and strongly associated with men who have sex with men. Based on contact tracing information between individuals in Sheffield, we found that transmission is associated with a median time to most recent common ancestor of 3.4 months, with an upper bound of 8 months, which we used as a criterion to identify likely transmission links in both data sets. In London, we found that transmission happened predominantly between individuals of similar age, sexual orientation, and location and also with the same HIV serostatus, which may reflect serosorting and associated risk behaviors. Comparison of the two data sets suggests that the London epidemic involved about ten times more cases than the Sheffield outbreak.

IMPORTANCE
The recent increases in gonorrhea incidence and antibiotic resistance are cause for public health concern. Successful intervention requires a better understanding of transmission patterns, which is not uncovered by traditional molecular epidemiology techniques. Here we studied two outbreaks that took place in Sheffield and London, United Kingdom. We show that whole-genome sequencing provides the resolution to investigate direct gonorrhea transmission between infected individuals. Combining genome sequencing with rich epidemiological information about infected individuals reveals the importance of several transmission routes and risk factors, which can be used to design better control measures.
Bacterial Hyaluronidase Promotes Ascending GBS Infection and Preterm Birth
Authors: Vornhagen Jay , Quach Phoenicia , Boldenow Erica , Merillat Sean , Whidbey Christopher , Ngo Lisa Y. , Adams Waldorf K. M. , Rajagopal Lakshmi 
Published: June 2016

ABSTRACT

Preterm birth increases the risk of adverse birth outcomes and is the leading cause of neonatal mortality. A significant cause of preterm birth is
in utero
infection with vaginal microorganisms. These vaginal microorganisms are often recovered from the amniotic fluid of preterm birth cases. A vaginal microorganism frequently associated with preterm birth is group B streptococcus (GBS), or
Streptococcus agalactiae
. However, the molecular mechanisms underlying GBS ascension are poorly understood. Here, we describe the role of the GBS hyaluronidase in ascending infection and preterm birth. We show that clinical GBS strains associated with preterm labor or neonatal infections have increased hyaluronidase activity compared to commensal strains obtained from rectovaginal swabs of healthy women. Using a murine model of ascending infection, we show that hyaluronidase activity was associated with increased ascending GBS infection, preterm birth, and fetal demise. Interestingly, hyaluronidase activity reduced uterine inflammation but did not impact placental or fetal inflammation. Our study shows that hyaluronidase activity enables GBS to subvert uterine immune responses, leading to increased rates of ascending infection and preterm birth. These findings have important implications for the development of therapies to prevent
in utero
infection and preterm birth.

IMPORTANCE
GBS are a family of bacteria that frequently colonize the vagina of pregnant women. In some cases, GBS ascend from the vagina into the uterine space, leading to fetal injury and preterm birth. Unfortunately, little is known about the mechanisms underlying ascending GBS infection. In this study, we show that a GBS virulence factor, HylB, shows higher activity in strains isolated from cases of preterm birth than those isolates from rectovaginal swabs of healthy women. We discovered that GBS rely on HylB to avoid immune detection in uterine tissue, but not placental tissue, which leads to increased rates of fetal injury and preterm birth. These studies provide novel insight into the underlying mechanisms of ascending infection.
Evaluation of the uptake and impact of neonatal vitamin A supplementation delivered through the Lady Health Worker programme on neonatal and infant morbidity and mortality in rural Pakistan: an effectiveness trial
Authors: Soofi Sajid , Ariff Shabina , Sadiq Kamran , Habib Atif , Bhatti Zaid , Ahmad Imran , Hussain Masawar , Ali Nabeela , Cousens Simon , Bhutta Zulfiqar A 
Published: June 2016

BackgroundDespite evidence for the benefits of vitamin A supplementation (VAS) among children 6 to 59 months of age, the feasibility of introduction and potential benefit of VAS in the neonatal period in public health programmes is uncertain.ObjectiveThe primary objective was to evaluate the feasibility and effectiveness of early neonatal VAS (single dose of 50 000 international units within 48–72 hours after birth) delivered through the public sector Lady Health Worker (LHW) programme in rural Pakistan and to document its association with a reduction in mortality at 6 months of age.MethodsA community-based, cluster randomised, placebo-controlled trial was undertaken in two districts of rural Pakistan. LHWs dispensed vitamin A/placebo in identical capsules to newborn infants within 48–72 hours of birth. Follow-up visits were undertaken at 1 week of age and every 4 weeks thereafter until 6 months of age.ResultsOf a total of 15 433 consecutive pregnancies among eligible women of reproductive age, 13 225 pregnancies were registered, 12 218 live births identified and 11 028 newborn infants reached by LHWs. Of these, 5380 (49%) received neonatal VAS and 5648 (51%) placebo. The LHWs successfully delivered the capsules to 79% of newborns within 72 hours of birth with no significant adverse effects. Although the proportion of days observed with symptoms of fever, diarrhoea or rapid breathing were lower with neonatal VAS, these differences were not statistically significant. Mortality rates in the two groups were comparable at 6 months of age.ConclusionsWhile our study demonstrated that neonatal VAS was safe and could be feasibly delivered by LHWs in Pakistan as part of their early postnatal visits, the overall lack of benefit on neonatal and 6-month morbidity and mortality in our population suggests the need for further evaluation of this intervention in populations at risk.Trial registration numberClinicalTrials.gov NCT00674089.
Comparison of contemporary preoperative risk models at predicting acute kidney injury after isolated coronary artery bypass grafting: a retrospective cohort study
Authors: Chen Shao-Wei , Chang Chih-Hsiang , Fan Pei-Chun , Chen Yung-Chang , Chu Pao-Hsien , Chen Tien-Hsing , Wu Victor Chien-Chia , Chang Su-Wei , Lin Pyng-Jing , Tsai Feng-Chun 
Published: June 2016

ObjectivesAcute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with short-term and long-term adverse outcomes. The European System for Cardiac Operative Risk Evaluation (EuroSCORE), EuroSCORE II, the Society of Thoracic Surgeons (STS) score and Age, Creatinine and Ejection Fraction (ACEF) score, have been widely used for predicting the operative risk of cardiac surgery. The aim of this study is to investigate the discriminant ability among current available models in predicting postoperative AKI.MethodsFrom January 2010 to December 2012, 353 patients who underwent isolated CABG were enrolled. The clinical characteristics, outcomes and scores of prognostic models were collected. The primary outcome was postoperative AKI, defined based on the Kidney Disease Improving Global Outcome (KDIGO) Clinical Practice Guideline for AKI, in 2012.Results102 patients (28.9%) developed postoperative AKI. For AKI prediction, EuroSCORE II, STS score and ACEF score were all good tools for stage-3 AKI. The ACEF score was shown to have satisfied discriminant ability to predict postoperative AKI with area under a receiver operating characteristic curve: 0.781±0.027, (95% CI 0.729 to 0.834, p value <0.001). Multivariate logistic analysis identified that lower ejection fraction and higher serum creatinine were independent risk factors for AKI.ConclusionsThe simple and extremely user-friendly ACEF score can accurately identify the risk of postoperative AKI and has shown satisfactory discriminant ability when compared with other systems. The ACEF score might be the easiest tool for predicting postoperative AKI.
What evidence is there for a delay in diagnostic coding of RA in UK general practice records? An observational study of free text
Authors: Ford Elizabeth , Carroll John , Smith Helen , Davies Kevin , Koeling Rob , Petersen Irene , Rait Greta , Cassell Jackie 
Published: June 2016

ObjectivesMuch research with electronic health records (EHRs) uses coded or structured data only; important information captured in the free text remains unused. One dimension of EHR data quality assessment is ‘currency’ or timeliness, that is, data are representative of the patient state at the time of measurement. We explored the use of free text in UK general practice patient records to evaluate delays in recording of rheumatoid arthritis (RA) diagnosis. We also aimed to locate and quantify disease and diagnostic information recorded only in text.SettingUK general practice patient records from the Clinical Practice Research Datalink.Participants294 individuals with incident diagnosis of RA between 2005 and 2008; 204 women and 85 men, median age 63 years.Primary and secondary outcome measuresAssessment of (1) quantity and timing of text entries for disease-modifying antirheumatic drugs (DMARDs) as a proxy for the RA disease code, and (2) quantity, location and timing of free text information relating to RA onset and diagnosis.ResultsInflammatory markers, pain and DMARDs were the most common categories of disease information in text prior to RA diagnostic code; 10–37% of patients had such information only in text. Read codes associated with RA-related text included correspondence, general consultation and arthritis codes. 64 patients (22%) had DMARD text entries >14 days prior to RA code; these patients had more and earlier referrals to rheumatology, tests, swelling, pain and DMARD prescriptions, suggestive of an earlier implicit diagnosis than was recorded by the diagnostic code.ConclusionsRA-related symptoms, tests, referrals and prescriptions were recorded in free text with 22% of patients showing strong evidence of delay in coding of diagnosis. Researchers using EHRs may need to mitigate for delayed codes by incorporating text into their case-ascertainment strategies. Natural language processing techniques have the capability to do this at scale.
A school-based intervention incorporating smartphone technology to improve health-related fitness among adolescents: rationale and study protocol for the NEAT and ATLAS 2.0 cluster randomised controlled trial and dissemination study
Authors: Lubans David R , Smith Jordan J , Peralta Louisa R , Plotnikoff Ronald C , Okely Anthony D , Salmon Jo , Eather Narelle , Dewar Deborah L , Kennedy Sarah , Lonsdale Chris , Hilland Toni A , Estabrooks Paul , Finn Tara L , Pollock Emma , Morgan Philip J 
Published: June 2016

IntroductionPhysical inactivity has been described as a global pandemic. Interventions aimed at developing skills in lifelong physical activities may provide the foundation for an active lifestyle into adulthood. In general, school-based physical activity interventions targeting adolescents have produced modest results and few have been designed to be ‘scaled-up’ and disseminated. This study aims to: (1) assess the effectiveness of two physical activity promotion programmes (ie, NEAT and ATLAS) that have been modified for scalability; and (2) evaluate the dissemination of these programmes throughout government funded secondary schools.Methods and analysisThe study will be conducted in two phases. In the first phase (cluster randomised controlled trial), 16 schools will be randomly allocated to the intervention or a usual care control condition. In the second phase, the Reach, Effectiveness, Adoption, Implementation and Maintenance (Re-AIM) framework will be used to guide the design and evaluation of programme dissemination throughout New South Wales (NSW), Australia. In both phases, teachers will be trained to deliver the NEAT and ATLAS programmes, which will include: (1) interactive student seminars; (2) structured physical activity programmes; (3) lunch-time fitness sessions; and (4) web-based smartphone apps. In the cluster RCT, study outcomes will be assessed at baseline, 6 months (primary end point) and 12-months. Muscular fitness will be the primary outcome and secondary outcomes will include: objectively measured body composition, cardiorespiratory fitness, flexibility, resistance training skill competency, physical activity, self-reported recreational screen-time, sleep, sugar-sweetened beverage and junk food snack consumption, self-esteem and well-being.Ethics and disseminationThis study has received approval from the University of Newcastle (H-2014-0312) and the NSW Department of Education (SERAP: 2012121) human research ethics committees. This study is funded by the Australian Research Council (FT140100399) and the NSW Department of Education.Trial registration numberACTRN12615000360516; Pre-results.
Utility of models to predict 28-day or 30-day unplanned hospital readmissions: an updated systematic review
Authors: Zhou Huaqiong , Della Phillip R , Roberts Pamela , Goh Louise , Dhaliwal Satvinder S 
Published: June 2016

ObjectiveTo update previous systematic review of predictive models for 28-day or 30-day unplanned hospital readmissions.DesignSystematic review.Setting/data sourceCINAHL, Embase, MEDLINE from 2011 to 2015.ParticipantsAll studies of 28-day and 30-day readmission predictive model.Outcome measuresCharacteristics of the included studies, performance of the identified predictive models and key predictive variables included in the models.ResultsOf 7310 records, a total of 60 studies with 73 unique predictive models met the inclusion criteria. The utilisation outcome of the models included all-cause readmissions, cardiovascular disease including pneumonia, medical conditions, surgical conditions and mental health condition-related readmissions. Overall, a wide-range C-statistic was reported in 56/60 studies (0.21–0.88). 11 of 13 predictive models for medical condition-related readmissions were found to have consistent moderate discrimination ability (C-statistic ≥0.7). Only two models were designed for the potentially preventable/avoidable readmissions and had C-statistic >0.8. The variables ‘comorbidities’, ‘length of stay’ and ‘previous admissions’ were frequently cited across 73 models. The variables ‘laboratory tests’ and ‘medication’ had more weight in the models for cardiovascular disease and medical condition-related readmissions.ConclusionsThe predictive models which focused on general medical condition-related unplanned hospital readmissions reported moderate discriminative ability. Two models for potentially preventable/avoidable readmissions showed high discriminative ability. This updated systematic review, however, found inconsistent performance across the included unique 73 risk predictive models. It is critical to define clearly the utilisation outcomes and the type of accessible data source before the selection of the predictive model. Rigorous validation of the predictive models with moderate-to-high discriminative ability is essential, especially for the two models for the potentially preventable/avoidable readmissions. Given the limited available evidence, the development of a predictive model specifically for paediatric 28-day all-cause, unplanned hospital readmissions is a high priority.