bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus
Authors: Ye Fengchun , Zeng Yan , Sha Jingfeng , Jones Tiffany , Kuhne Kurt , Wood Charles , Gao Shou-Jiang 
Published: August 2016

ABSTRACT

A high prevalence of Kaposi's sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological conditions of diabetes contribute to KS development. We found elevated levels of viral lytic gene expression when Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells were cultured in high-glucose medium. To demonstrate the association between high glucose levels and KSHV replication, we xenografted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV cells) into hyperglycemic and normal nude mice. The injected cells expressed significantly higher levels of KSHV lytic genes in hyperglycemic mice than in normal mice. We further demonstrated that high glucose levels induced the production of hydrogen peroxide (H
2
O
2
), which downregulated silent information regulator 1 (SIRT1), a class III histone deacetylase (HDAC), resulting in the epigenetic transactivation of KSHV lytic genes. These results suggest that high blood glucose levels in diabetic patients contribute to the development of KS by promoting KSHV lytic replication and infection.

IMPORTANCE
Multiple epidemiological studies have reported a higher prevalence of classic KS in diabetic patients. By using both
in vitro
and
in vivo
models, we demonstrated an association between high glucose levels and KSHV lytic replication. High glucose levels induce oxidative stress and the production of H
2
O
2
, which mediates the reactivation of latent KSHV through multiple mechanisms. Our results provide the first experimental evidence and mechanistic support for the association of classic KS with diabetes.
Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus
Authors: Ding Shilei , Medjahed Halima , Prévost Jérémie , Coutu Mathieu , Xiang Shi-Hua , Finzi Andrés 
Published: August 2016

ABSTRACT
Binding of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) gp120 exterior envelope glycoprotein to CD4 triggers conformational changes in gp120 that promote its interaction with one of the chemokine receptors, usually CCR5, ultimately leading to gp41-mediated virus-cell membrane fusion and entry. We previously described that topological layers (layer 1, layer 2, and layer 3) in the gp120 inner domain contribute to gp120-trimer association in the unliganded state but also help secure CD4 binding. Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association but is minimally involved in promoting CD4 binding, which could be explained by the existence of a well-conserved tryptophan at position 375 (Trp 375) in HIV-2/SIVsmm. In this study, we investigated the role of SIV layer 3 in viral entry, cell-to-cell fusion, and CD4 binding. We observed that a network of interactions involving some residues of the β8-α5 region in SIVmac239 layer 3 may contribute to CD4 binding by helping shape the nearby Phe 43 cavity, which directly contacts CD4. In summary, our results suggest that layer 3 in SIV has a greater impact on CD4 binding than in HIV-1. This work defines lineage-specific differences in layer 3 from HIV-1 and that from SIV.

IMPORTANCE
CD4-induced conformational changes in the gp120 inner domain involve rearrangements between three topological layers. While the role of layers 1 to 3 for HIV-1 and layers 1 and 2 for SIV on gp120 transition to the CD4-bound conformation has been reported, the role of SIV layer 3 remains unknown. Here we report that SIV layer 3 has a greater impact on CD4 binding than does layer 3 in HIV-1 gp120. This work defines lineage-specific differences in layer 3 from HIV-1 and SIV.
Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses
Authors: Mounce Bryan C. , Cesaro Teresa , Moratorio Gonzalo , Hooikaas Peter Jan , Yakovleva Anna , Werneke Scott W. , Smith Everett Clinton , Poirier Enzo Z. , Simon-Loriere Etienne , Prot Matthieu , Tamietti Carole , Vitry Sandrine , Volle Romain , Khou Cécile , Frenkiel Marie-Pascale , Sakuntabhai Anavaj , Delpeyroux Francis , Pardigon Nathalie , Flamand Marie , Barba-Spaeth Giovanna , Lafon Monique , Denison Mark R. , Albert Matthew L. , Vignuzzi Marco 
Published: August 2016

ABSTRACT

RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise
in vitro
and
in vivo
, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine
N
1
-acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks,
in vitro
and
in vivo
. These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO.

IMPORTANCE
RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target.
Evidence for the Introduction, Reassortment, and Persistence of Diverse Influenza A Viruses in Antarctica
Authors: Hurt Aeron C. , Su Yvonne C. F. , Aban Malet , Peck Heidi , Lau Hilda , Baas Chantal , Deng Yi-Mo , Spirason Natalie , Ellström Patrik , Hernandez Jorge , Olsen Bjorn , Barr Ian G. , Vijaykrishna Dhanasekaran , Gonzalez-Acuna Daniel 
Published: August 2016

ABSTRACT
Avian influenza virus (AIV) surveillance in Antarctica during 2013 revealed the prevalence of evolutionarily distinct influenza viruses of the H11N2 subtype in Adélie penguins. Here we present results from the continued surveillance of AIV on the Antarctic Peninsula during 2014 and 2015. In addition to the continued detection of H11 subtype viruses in a snowy sheathbill during 2014, we isolated a novel H5N5 subtype virus from a chinstrap penguin during 2015. Gene sequencing and phylogenetic analysis revealed that the H11 virus detected in 2014 had a >99.1% nucleotide similarity to the H11N2 viruses isolated in 2013, suggesting the continued prevalence of this virus in Antarctica over multiple years. However, phylogenetic analysis of the H5N5 virus showed that the genome segments were recently introduced to the continent, except for the NP gene, which was similar to that in the endemic H11N2 viruses. Our analysis indicates geographically diverse origins for the H5N5 virus genes, with the majority of its genome segments derived from North American lineage viruses but the neuraminidase gene derived from a Eurasian lineage virus. In summary, we show the persistence of AIV lineages in Antarctica over multiple years, the recent introduction of gene segments from diverse regions, and reassortment between different AIV lineages in Antarctica, which together significantly increase our understanding of AIV ecology in this fragile and pristine environment.

IMPORTANCE
Analysis of avian influenza viruses (AIVs) detected in Antarctica reveals both the relatively recent introduction of an H5N5 AIV, predominantly of North American-like origin, and the persistence of an evolutionarily divergent H11 AIV. These data demonstrate that the flow of viruses from North America may be more common than initially thought and that, once introduced, these AIVs have the potential to be maintained within Antarctica. The future introduction of AIVs from North America into the Antarctic Peninsula is of particular concern given that highly pathogenic H5Nx viruses have recently been circulating among wild birds in parts of Canada and the Unites States following the movement of these viruses from Eurasia via migratory birds. The introduction of a highly pathogenic influenza virus in penguin colonies within Antarctica might have devastating consequences.
ASSESSMENT OF VANCOMYCIN CONCENTRATIONS IN SYRINGES PREPARED WITHIN A WARD SETTING
Authors: Saimbi Sarina , Batchelor Hannah , Whitticase Louise , Holder Gemma , Russell Alison Bedford 
Published: August 2016

AimVancomycin is used as a second line antibiotic in the treatment of late onset neonatal infection for its activity against coagulase negative staphylococci. Vancomycin infusions are prepared within a ward setting for administration to neonates. Differences in preparation techniques on the ward have previously been recognised as a potential source of variation in vancomycin concentrations, as compared to concentrations in pre-made preparations. This study analyses a consecutive series of vancomycin syringes prepared in a ward for administration to neonates, to determine how accurate the concentration of each preparation was compared to the expected concentration.MethodVancomycin concentrations were determined by UV analysis (λ=280 nm) with a UV spectrophotometer (Jenway Genova Plus). A calibration curve for vancomycin was created (R2=0.9996) by manufacturing a series of solutions of vancomycin hydrochloride in glucose 5% w/v.Samples of vancomycin from syringes from which doses were administered to neonates were then analysed to assess their concentration. For each syringe, mean vancomycin concentration±standard deviation was calculated (n=3).Reasonable errors in preparations were calculated based on errors in each step of the preparation process. Theoretical error was calculated based on apparatus used, and experimental error was recorded based on a simulated process. Two preparation methods were compared; the method complying with that described in the local formulary, 1 and an alternative method reported by the nurses preparing the dose.ResultsAnalysis of results showed that concentration of the vancomycin syringes prepared ranged from 0.85 to 8.24 mg/mL. The expected concentration was 4.17 mg/ml.Theoretical error in preparation of vancomycin doses was lower with the formulary-compliant method1 versus an alternative method, as were variations in in vancomycin concentration.Depending on the type of error (theoretical or experimental) and method by which vancomycin syringes were prepared (formulary1 or alternative method), the percentage of syringes with vancomycin concentration outside of the specified ranges varied from 20%–43%. This is higher compared to the findings of the Department of Health2, where it was found that 19.2% of morphine infusions prepared by nurses in the neonatal intensive care unit were outside British Pharmacopoeia concentration limits.ConclusionPreparation of vancomycin doses should follow the formulary method1 to minimise variation in concentration of the final product. Alternatively, pre-made syringes may be preferred as an alternative to ward-made syringes as this removes individualised preparation as a source of error.
A STABILITY STUDY OF OMEPRAZOLE DILUTED IN SODIUM CHLORIDE FOR INTRAVENOUS INFUSION AND DISCUSSION REGARDING CURRENT PRACTICE IN UK PAEDIATRIC INTENSIVE CARE UNITS
Authors: Morris Stephen , Ellard Olivia 
Published: August 2016

BackgroundOmeprazole by intravenous infusion is occasionally warranted in children during episodes of acute upper gastrointestinal bleeding. This is to ensure the continued suppression of stomach acid to reduce the of risk of rebleeding.MethodsCurrent practice in UK paediatric intensive care units varies, but the use of 160 mg/1.73 m3 over 24 hours has previously been reported.1 This is commonly prepared as a 0.8 mg/ml solution changed either at 12 or 24 hrs after preparation depending on reference source used.2-3 The current practice of using a 0.8 mg/ml (40 mg/50 ml) is off label and not endorsed by manufacturers who recommend a maximum concentration of 0.4 mg/ml3.Following these recommendations would lead to a fluid load of 400 ml/1.73 m2 which is likely to be significant. Excess fluid intake has been shown to correlate with increased oxygenation index and increased PICU stay.4The aim of this study is to provide stability data for using 0.8 mg/ml for intravenous infusion which is currently in wide spread despite use a lack of published lack of data in this area.MethodsA series of analytical techniques were performed to assess physical and chemical stability. Test solutions were pre pared by reconstituting Losec® (Omeprazole) 40 mg powder for infusion and diluting to either 50 ml or 100 ml in 0.9% sodium chloride.Reverse phase HPLC analysis was conducted at 0 hrs, 10 hrs and 24 hrs. Particle size was assessed using a zeta potential analyser at 15-minute intervals over 60 minutes.ResultsAt both 40 mg/50 mL and 40 mg/100 mL the concentration of omeprazole remained at 101% and 100% after 10 hours respectively. However, significant degradation was seen at 24 hours as concentrations reduced to 60% and 55% respectively.
EVALUATION OF THE CURRENT PRACTICE OF DELIVERING INTRAVENOUS OPIOIDS INFUSIONS IN A UK PAEDIATRIC HOSPITAL
Authors: Rashed Asia N , Tomlin Stephen 
Published: August 2016

IntroductionOpiate intravenous infusions are the therapy of choice in severe pain. However, administering infusions to children requires complex dosage calculations, rate adjustments and often multiple manipulations of injectable medicines to obtain the final “ready to use” solution for both continuous infusion and additional boluses; potentially putting children at high risk.1 2
AimTo investigate the practice and accuracy of healthcare professionals (HCPs) in hospital theatres and wards in preparing morphine infusions for nurse/patient controlled analgesia (N/PCA) use in a UK children's hospital.MethodsA mixed methods study in which direct observation of HCPs preparing paediatric morphine infusions for N/PCA in theatres and on wards, focus groups with HCPs and quantitative analysis of morphine concentration in the syringe using UV-Vis Spectrophotometer. The British Pharmacopoeia (BP) reference limits of ±7.5% were used to compare label strength (LS) of morphine infusion with measured concentration.ResultsThe preparation of 153 syringes was observed which related to 128 paediatric patients [mean age (±sd) 7.5 years±5.6; 65.3% male]. 64% (98/153) were prepared by anaesthetists in theatres, 36% (55/153) by nurses at ward level.Major differences in preparation methods were identified. The final volume prepared was above the required volume (50 mL) in 35.9% (55/153) preparations. Wearing gloves during preparation was not followed in theatre for 83.7% (82/98) of syringes. No decontamination of morphine ampoules was undertaken during preparation of any syringe. Inconsistency in the appropriate syringe size used to withdraw drug from the ampoule was observed in both theatres and wards. Lack of appreciation of the overage in morphine ampoules by HCPs was identified. Of the syringes analysed 61.5% (48/78) had a concentration outside the BP reference limits (92.5–107.5% of LS), most were in excess (83.3%, 40/48). Of these 20.8% (10/48) deviated by more than +20%, with one deviated by 100%.ConclusionThis study identified that variation in preparation techniques followed by HCPs may result in morphine N/PCA dosages that are significantly higher or lower than that prescribed. Also, lack of understanding of ampoule overage, accuracy of the syringe size used and the ability to measure small volumes led to inaccurate concentrations in prepared infusions.
CHILDREN'S WARFARIN CLINIC-AN AUDIT OF THE NEW PHARMACIST-LED TELEPHONE SERVICE BASED ON A UNIQUE COMPUTERISED SYSTEM COMPARED TO THE WARD BASED PAPER SYSTEM
Authors: Brooks Teresa , Brown Jennifer , Woolley Elaine 
Published: August 2016

AimsTo audit the new pharmacist-led telephone service for warfarin dosing and monitoring of INR, and compare it to the previous system. The previous system was based on the paediatric cardiology ward, dosing by junior medical staff to dose and documented on a paper system. Also to audit the parent satisfaction of the new system.MethodsSearch the computerised system to reveal 73 patients on warfarin with a total of 1547 INRs, and looked for any complications or out of range results. This to be compared to a previous audit of the original system of 44 patients on warfarin with a total of 1289 INRs.For parent/carer satisfaction, a questionnaire was sent to parents/carers of all patients who were under the care of the pharmacist-led children's warfarin clinic.ResultsThe pharmacist-led children's warfarin service was fully compliant for NPSA safety standards for warfarin dosing. There was no significant difference in the safety indicators from the original service and the pharmacist-led service.11 patients (25%) were lost to follow up from the original service, compared to none in the pharmacist-led service. No patients from either service had an inappropriate target INR and every patient had been given the correct information. 38 out of 53 (72%) parents/carers returned the satisfaction survey. 28 (78%) reported that their overall experience of the clinic was excellent and the rest found it satisfactory.DiscussionChanging to the pharmacist-led service has meant that it is now compliant with NPSA standards and the safety indicators are comparable to the original service. The service has generally been very well received, with all parents/carers finding the service at least satisfactory and 78% found it excellent. The pharmacist-led service is unique, as it uses a computerised system for documentation, with the aim to produce a paediatric dosing algorithm.
PAEDIATRIC ADVERSE DRUG REACTIONS (ADRS): A COMPARISON OF A NEWLY DEVELOPED AVOIDABILITY TOOL TO EXISTING HALLAS ASSESSMENTS
Authors: Bracken Louise , Kirkham Jamie , Nunn Anthony , Pirmohamed Munir , Peak Matthew , Turner Mark 
Published: August 2016

AimTo compare a newly developed avoidability assessment tool (AAT) to existing Hallas assessments1 for a set of paediatric ADR cases.MethodThe new AAT was employed to assess 249 case reports of ADRs causing admission to hospital. The case reports contained a description of the ADR, details of suspected and concurrent medication and past medical history. Each case report was independently assessed and an avoidability category assigned. For ADRs categorised as either ‘possibly' or ‘definitely avoidable' a rationale was recorded. A second reviewer independently assessed a purposive sample (10%) for validation and quality assurance purposes.The final outcome was then compared to the Hallas assessments (1) previously completed as part of another study, which was carried out in a consensus group setting. Both tools used categorical scores with the same four point ordinal scale ‘definitely avoidable', ‘possibly avoidable', ‘not avoidable' and ‘unassessable'.ResultsAssessment of the 249 ADR case reports using the new AAT found that 19.3% were either possibly or definitely avoidable. This figure increased to almost 32% for the non-oncology cases (129/249) and decreased to 5.8% for the oncology cases (120/249). This was similar to the Hallas results (1), where overall, 22% of ADRs were deemed either possibly or definitely avoidable.Percentage exact agreement (%EA) was 90% overall; when subcategorised into oncology and non-oncology cases the %EA was found to be 94.2% and 86% respectively. Percentage extreme disagreement (%ED) was 0.8%. The kappa score was 0.71 (95% CI 0.60–0.82) for all cases, 0.54 (95% CI 0.40–0.68) for the oncology cases and 0.73 (95% CI 0.58–0.88) for the non-oncology cases. In total there were 25/249 cases with disagreement. %EA agreement from the validation check was 72%.ConclusionAssessment with the new AAT showed that approximately 19% of all cases were either possibly or definitely avoidable. This was comparable to the Hallas assessments (1). The sub-categorisation of the analysis into oncology and non-oncology cases showed a change in the number of avoidable cases. The avoidability rate increased to almost 32% for the non-oncology cases and decreased to 5.8% for the oncology cases. The reason for this marked difference may be explained by the nature of the oncology ADRs. The most common oncology reactions were neutropenia, thrombocytopenia and anaemia; these are often expected and largely 'not avoidable' given the benefit risk ratio.The AAT was designed specifically for use in paediatrics following difficulty using other tools including Hallas (1). The AAT refers to guidelines and patient history rather than to abstract concepts such as “present-day knowledge of good medical practice” and “effort exceeding the obligatory demands” as per Hallas (1). Further work to identify potentially avoidable ADRs and strategies to prevent them is needed.
Supported self-management of analgesia and related treatments at the end of life
Authors: Campling Natasha , Latter Sue , Richardson Alison , Mulvey Matthew , Bennett Michael 
Published: August 2016

IntroductionAlthough supported self-management has been defined theoretically at end of life (Johnstonet al.,2014), and has empirically been demonstrated to be beneficial within long-term condition management, it is not known how it plays out in the realities of end of life care.AimTo use empirical data to describe supportive self-management within end of life in relation to the specific context of analgesia and related treatmentsMethodsA qualitative approach was taken using semi-structured focus groups and interviews with healthcare professionals and patients/carers. The data were coded in NVivo 11 utilising Framework Analysis.ResultsThe sample comprised 38 participants recruited via two geographical regions in Northern and Southern England. The patient/carer and healthcare professional samples had 19 participants each.Supportive self-management was enacted on a far-reaching continuum from:Expertise and mastery, with full responsibility chosen by the individual, and acceptance of the possibility of risk and the requirements of complex decision-making, through toReduced capabilities and engagement in self-management behaviours, negatively affected by uncontrolled pain, the side-effects of opioids, clinical depression and memory loss, with responsibilities transferred to another (the carer and/or palliative care clinical nurse specialist)ConclusionSupported self-management of analgesia and related treatments at end of life was an ever-changing process affected by the complexity of end of life itself and opioid related fears. The complexity of end of life with continual disease progression, frequent changes in symptoms and side-effects, resulted in fluctuating self-management capabilities of the patient, and in turn fluctuating supportive behaviours of the carer.This work was part of a larger study (SMART) funded by the NIHR’s HTA programme.ReferenceJohnston B, Rogerson L, Macijauskiene J, Blazeviciene A, Cholewka P.An exploration of self-management support in the context of palliative nursing: a modified concept analysis.BMC Nurs2014;13:21