bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Cytomegalovirus UL54 DNA Polymerase Gene Mutations Selected
In Vitro
That Confer Brincidofovir Resistance
Authors: Chou Sunwen , Ercolani Ronald J. , Lanier E. Randall 
Published: April 2016

ABSTRACT

Eight
in vitro
selection experiments under brincidofovir pressure elicited the known cytomegalovirus DNA polymerase amino acid substitutions N408K and V812L and the novel exonuclease domain substitutions D413Y, E303D, and E303G, which conferred ganciclovir and cidofovir resistance with 6- to 11-fold resistance to brincidofovir or 17-fold when E303G was combined with V812L. The new exonuclease domain I resistance mutations selected under brincidofovir pressure add to the single instance previously reported and show the expected patterns of cross-resistance.
In Vitro
Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii
Authors: Livermore David M. , Mushtaq Shazad , Warner Marina , Woodford Neil 
Published: April 2016

ABSTRACT

Eravacycline and comparators were tested against carbapenem- and tigecycline-resistant
Enterobacteriaceae
and
Acinetobacter
isolates received at the United Kingdom's national reference laboratory. Eravacycline MICs correlated closely with those of tigecycline but mostly were around 2-fold lower; both molecules retained full activity against isolates with high-level tetracycline and minocycline resistance. MIC
90
s of eravacycline and tigecycline were raised ca. 2-fold for carbapenem-resistant
Enterobacteriaceae
compared with carbapenem-susceptible controls, probably reflecting subsets of isolates with increased efflux.
Clarithromycin Leads to Long-Term Survival and Cost Benefit in Ventilator-Associated Pneumonia and Sepsis
Authors: Tsaganos Thomas , Raftogiannis Maria , Pratikaki Maria , Christodoulou Sofia , Kotanidou Anastasia , Papadomichelakis Evangelos , Armaganidis Apostolos , Routsi Christina , Giamarellos-Bourboulis Evangelos J. 
Published: April 2016

ABSTRACT

Increasing numbers of admissions for sepsis impose a heavy burden on health care systems worldwide, while novel therapies have proven both expensive and ineffective. We explored the long-term mortality and hospitalization costs after adjunctive therapy with intravenous clarithromycin in ventilator-associated pneumonia (VAP). Two hundred patients with sepsis and VAP were enrolled in a published randomized clinical trial; 100 were allocated to blind treatment with a placebo and another 100 to clarithromycin at 1 g daily for three consecutive days. Long-term mortality was recorded. The hospitalization cost was calculated by direct quantitation of imaging tests, medical interventions, laboratory tests, nonantibiotic drugs and antibiotics, intravenous fluids, and parenteral and enteral nutrition. Quantities were priced by the respective prices defined by the Greek government in 2002. The primary endpoint was 90-day mortality; cumulative hospitalization cost was the secondary endpoint. All-cause mortality rates on day 90 were 60% in the placebo arm and 43% in the clarithromycin arm (
P
= 0.023); 141 patients were alive on day 28, and mortality rates between days 29 and 90 were 44.4% and 17.4%, respectively (
P
= 0.001). The mean cumulative costs on day 25 in the placebo group and in the clarithromycin group were €14,701.10 and €13,100.50 per patient staying alive, respectively (
P
= 0.048). Respective values on day 45 were €26,249.50 and €19,303.10 per patient staying alive (
P
= 0.011); this was associated with the savings from drugs other than antimicrobials. It is concluded that intravenous clarithromycin for three consecutive days as an adjunctive treatment in VAP and sepsis offers long-term survival benefit along with a considerable reduction in the hospitalization cost. (This study has been registered at ClinicalTrials.gov under registration no. NCT00297674.)
Regulatory Activities of Four ArsR Proteins in Agrobacterium tumefaciens 5A
Authors: Kang Yoon-Suk , Brame Keenan , Jetter Jonathan , Bothner Brian B. , Wang Gejiao , Thiyagarajan Saravanamuthu , McDermott Timothy R. 
Published: April 2016

ABSTRACT

ArsR is a well-studied transcriptional repressor that regulates microbe-arsenic interactions. Most microorganisms have an
arsR
gene, but in cases where multiple copies exist, the respective roles or potential functional overlap have not been explored. We examined the repressors encoded by
arsR1
and
arsR2
(
ars1
operon) and by
arsR3
and
arsR4
(
ars2
operon) in
Agrobacterium tumefaciens
5A. ArsR1 and ArsR4 are very similar in their primary sequences and diverge phylogenetically from ArsR2 and ArsR3, which are also quite similar to one another. Reporter constructs (
lacZ
) for
arsR1
,
arsR2
, and
arsR4
were all inducible by As(III), but expression of
arsR3
(monitored by reverse transcriptase PCR) was not influenced by As(III) and appeared to be linked transcriptionally to an upstream
lysR
-type gene. Experiments using a combination of deletion mutations and additional reporter assays illustrated that the encoded repressors (i) are not all autoregulatory as is typically known for ArsR proteins, (ii) exhibit variable control of each other's encoding genes, and (iii) exert variable control of other genes previously shown to be under the control of ArsR1. Furthermore, ArsR2, ArsR3, and ArsR4 appear to have an activator-like function for some genes otherwise repressed by ArsR1, which deviates from the well-studied repressor role of ArsR proteins. The differential regulatory activities suggest a complex regulatory network not previously observed in ArsR studies. The results indicate that fine-scale ArsR sequence deviations of the reiterated regulatory proteins apparently translate to different regulatory roles.

IMPORTANCE
Given the significance of the ArsR repressor in regulating various aspects of microbe-arsenic interactions, it is important to assess potential regulatory overlap and/or interference when a microorganism carries multiple copies of
arsR
. This study explores this issue and shows that the four
arsR
genes in
A. tumefaciens
5A, associated with two separate
ars
operons, encode proteins exhibiting various degrees of functional overlap with respect to autoregulation and cross-regulation, as well as control of other functional genes. In some cases, differences in regulatory activity are associated with only limited differences in protein primary structure. The experiments summarized herein also present evidence that ArsR proteins appear to have activator functions, representing novel regulatory activities for ArsR, previously known only to be a repressor.
Insensitivity of Diverse and Temporally Variable Particle-Associated Microbial Communities to Bulk Seawater Environmental Parameters
Authors: Yung Cheuk-Man , Ward Christopher S. , Davis Katherine M. , Johnson Zackary I. , Hunt Dana E. 
Published: April 2016

ABSTRACT
There is a growing recognition of the roles of marine microenvironments as reservoirs of biodiversity and as sites of enhanced biological activity and in facilitating biological interactions. Here, we examine the bacterial community inhabiting free-living and particle-associated seawater microenvironments at the Pivers Island Coastal Observatory (PICO). 16S rRNA gene libraries from monthly samples (July 2013 to August 2014) were used to identify microbes in seawater in four size fractions: >63 μm (zooplankton and large particles), 63 to 5 μm (particles), 5 to 1 μm (small particles/dividing cells), and <1 μm (free-living prokaryotes). Analyses of microbial community composition highlight the importance of the microhabitat (e.g., particle-associated versus free-living lifestyle) as communities cluster by size fraction, and the microhabitat explains more of the community variability than measured environmental parameters, including pH, particle concentration, projected daily insolation, nutrients, and temperature. While temperature is statistically associated with community changes in the <1-μm and 5- to 1-μm fractions, none of the measured bulk seawater environmental variables are statistically significant in the larger-particle-associated fractions. These results, combined with high particle-associated community variability, especially in the largest size fraction (i.e., >63 μm), suggest that particle composition, including eukaryotes and their associated microbiomes, may be an important factor in selecting for specific particle-associated bacteria.

IMPORTANCE
By comparing levels of particle-associated and free-living bacterial diversity at a coastal location over the course of 14 months, we show that bacteria associated with particles are generally more diverse and appear to be less responsive to commonly measured environmental variables than free-living bacteria. These diverse and highly variable particle-associated communities are likely driven by differences in particle substrates both within the water column at a single time point and due to seasonal changes over the course of the year.
Origin of Chemical Diversity in Prochloron-Tunicate Symbiosis
Authors: Lin Zhenjian , Torres Joshua P. , Tianero M. Diarey , Kwan Jason C. , Schmidt Eric W. 
Published: April 2016

ABSTRACT

Diversity-generating metabolism leads to the evolution of many different chemicals in living organisms. Here, by examining a marine symbiosis, we provide a precise evolutionary model of how nature generates a family of novel chemicals, the cyanobactins. We show that tunicates and their symbiotic
Prochloron
cyanobacteria share congruent phylogenies, indicating that
Prochloron
phylogeny is related to host phylogeny and not to external habitat or geography. We observe that
Prochloron
exchanges discrete functional genetic modules for cyanobactin secondary metabolite biosynthesis in an otherwise conserved genetic background. The module exchange leads to gain or loss of discrete chemical functional groups. Because the underlying enzymes exhibit broad substrate tolerance, discrete exchange of substrates and enzymes between
Prochloron
strains leads to the rapid generation of chemical novelty. These results have implications in choosing biochemical pathways and enzymes for engineered or combinatorial biosynthesis.

IMPORTANCE
While most biosynthetic pathways lead to one or a few products, a subset of pathways are diversity generating and are capable of producing thousands to millions of derivatives. This property is highly useful in biotechnology since it enables biochemical or synthetic biological methods to create desired chemicals. A fundamental question has been how nature itself creates this chemical diversity. Here, by examining the symbiosis between coral reef animals and bacteria, we describe the genetic basis of chemical variation with unprecedented precision. New compounds from the cyanobactin family are created by either varying the substrate or importing needed enzymatic functions from other organisms or via both mechanisms. This natural process matches successful laboratory strategies to engineer the biosynthesis of new chemicals and teaches a new strategy to direct biosynthesis.
Associations among sedentary and active behaviours, body fat and appetite dysregulation: investigating the myth of physical inactivity and obesity
Authors: Myers Anna , Gibbons Catherine , Finlayson Graham , Blundell John 
Published: April 2016

BackgroundThere is considerable disagreement about the association between free-living physical activity (PA) and sedentary behaviour and obesity. Moreover studies frequently do not include measures that could mediate between PA and adiposity. The present study used a validated instrument for continuous tracking of sedentary and active behaviours as part of habitual daily living, together with measures of energy expenditure, body composition and appetite dysregulation. This cross-sectional study tested the relationship between inactivity and obesity.Methods71 participants (81.7% women) aged 37.4 years (±14) with a body mass index of 29.9 kg/m2(±5.2) were continuously monitored for 6–7 days to track free-living PA (light 1.5–3 metabolic equivalents (METs), moderate 3–6 METs and vigorous >6 METs) and sedentary behaviour (<1.5 METs) with the SenseWear Armband. Additional measures included body composition, waist circumference, cardiovascular fitness, total and resting energy expenditure, and various health markers. Appetite control was assessed by validated eating behaviour questionnaires.ResultsSedentary behaviour (11.06±1.72 h/day) was positively correlated with fat mass (r=0.50, p<0.001) and waist circumference (r=−0.65, p<0.001). Moderate-to-vigorous PA was negatively associated with fat mass (r=−0.72, p<0.001) and remained significantly correlated with adiposity after controlling for sedentary behaviour. Activity energy expenditure was positively associated with the level of PA and negatively associated with fat mass. Disinhibition and binge eating behaviours were positively associated with fat mass (r=0.58 and 0.47, respectively, p<0.001).ConclusionsThis study demonstrated clear associations among objective measures of PA (and sedentary behaviour), energy expenditure, adiposity and appetite control. The data indicate strong links between physical inactivity and obesity. This relationship is likely to be bidirectional.
Factors associated with polypharmacy and excessive polypharmacy in older people with intellectual disability differ from the general population: a cross-sectional observational nationwide study
Authors: O'Dwyer Máire , Peklar Jure , McCallion Philip , McCarron Mary , Henman Martin C 
Published: April 2016

Objectives(1) To evaluate the prevalence of polypharmacy (5–9 medicines) and excessive polypharmacy (10+ medicines) and (2) to determine associated demographic and clinical characteristics in an ageing population with intellectual disabilities (IDs).DesignObservational cross-sectional study.SettingWave One (2009/2010) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA).ParticipantsA nationally representative sample of 753 persons with ID, aged between 41 and 90 years. Participants/proxy reported medicines (prescription and over the counter) taken on a regular basis; medication data was available for 736 participants (98%).Main outcome measures/interventionsParticipants were divided into those with no polypharmacy (0–4 medicines), polypharmacy (5–9 medicines) and excessive polypharmacy (10+ medicines). Medication use patterns were analysed according to demographic variables and reported chronic conditions. A multinomial logistic regression model identified factors associated with polypharmacy (5–9 medicines) and excessive polypharmacy (≥10 medicines).ResultsOverall, 90% of participants reported use of medicines. Polypharmacy was observed in 31.5% of participants and excessive polypharmacy in 20.1%. Living in a residential institution, and reporting a mental health or neurological condition were strongly associated with polypharmacy and excessive polypharmacy after adjusting for confounders, but age or gender had no significant effect.ConclusionsPolypharmacy was commonplace for older adults with ID and may be partly explained by the high prevalence of multimorbidity reported. Review of appropriateness of medication use is essential, as polypharmacy places ageing people with ID at risk of adverse effects.
Adherence to evidence-based drug therapies after myocardial infarction: is geographic variation related to hospital of discharge or primary care providers? A cross-classified multilevel design
Authors: Di Martino Mirko , Alagna Michela , Cappai Giovanna , Mataloni Francesca , Lallo Adele , Perucci Carlo Alberto , Davoli Marina , Fusco Danilo 
Published: April 2016

ObjectivesTo measure the adherence to polytherapy after myocardial infarction (MI), to compare the proportions of variation attributable to hospitals of discharge and to primary care providers, and to identify determinants of adherence to medications.SettingThis is a population-based study. Data were obtained from the Information Systems of the Lazio Region, Italy (5 million inhabitants).ParticipantsPatients hospitalised with incident MI in 2007–2010.Outcome measureThe outcome was chronic polytherapy after MI. Adherence was defined as a medication possession ratio ≥0.75 for at least three of the following drugs: antiplatelets, β-blockers, ACEI angiotensin receptor blockers, statins.Design and analysisA 2-year cohort study was performed. Cross-classified multilevel models were applied to analyse geographic variation and compare proportions of variability attributable to hospitals of discharge and primary care providers. The variance components were expressed as median ORs MORs. If the MOR is 1.00, there is no variation between clusters. If there is considerable between-cluster variation, the MOR will be large.ResultsA total of 9606 patients were enrolled. About 63% were adherent to chronic polytherapy. Adherence was higher for patients discharged from cardiology wards (OR=1.56 vs other wards, p<0.001) and for patients with general practitioners working in group practice (OR=1.14 vs single-handed, p=0.042). A relevant variation in adherence was detected between local health districts (MOR=1.24, p<0.001). When introducing the hospital of discharge as a cross-classified level, the variation between local health districts decreased (MOR=1.13, p=0.020) and the variability attributable to hospitals of discharge was significantly higher (MOR=1.37, p<0.001).ConclusionsSecondary prevention pharmacotherapy after MI is not consistent with clinical guidelines. The relevant geographic variation raises equity issues in access to optimal care. Adherence was influenced more by the hospital that discharged the patient than by the primary care providers. Cross-classified models proved to be a useful tool for defining priority areas for more targeted interventions.
Effects of exercise intensity and nutrition advice on myocardial function in obese children and adolescents: a multicentre randomised controlled trial study protocol
Authors: Dias Katrin A , Coombes Jeff S , Green Daniel J , Gomersall Sjaan R , Keating Shelley E , Tjonna Arnt Erik , Hollekim-Strand Siri Marte , Hosseini Mansoureh Sadat , Ro Torstein Baade , Haram Margrete , Huuse Else Marie , Davies Peter S W , Cain Peter A , Leong Gary M , Ingul Charlotte B 
Published: April 2016

IntroductionThe prevalence of paediatric obesity is increasing, and with it, lifestyle-related diseases in children and adolescents. High-intensity interval training (HIIT) has recently been explored as an alternate to traditional moderate-intensity continuous training (MICT) in adults with chronic disease and has been shown to induce a rapid reversal of subclinical disease markers in obese children and adolescents. The primary aim of this study is to compare the effects of HIIT with MICT on myocardial function in obese children and adolescents.Methods and analysisMulticentre randomised controlled trial of 100 obese children and adolescents in the cities of Trondheim (Norway) and Brisbane (Australia). The trial will examine the efficacy of HIIT to improve cardiometabolic outcomes in obese children and adolescents. Participants will be randomised to (1) HIIT and nutrition advice, (2) MICT and nutrition advice or (3) nutrition advice. Participants will partake in supervised exercise training and/or nutrition sessions for 3 months. Measurements for study end points will occur at baseline, 3 months (postintervention) and 12 months (follow-up). The primary end point is myocardial function (peak systolic tissue velocity). Secondary end points include vascular function (flow-mediated dilation assessment), quantity of visceral and subcutaneous adipose tissue, myocardial structure and function, body composition, cardiorespiratory fitness, autonomic function, blood biochemistry, physical activity and nutrition. Lean, healthy children and adolescents will complete measurements for all study end points at one time point for comparative cross-sectional analyses.Ethics and disseminationThis randomised controlled trial will generate substantial information regarding the effects of exercise intensity on paediatric obesity, specifically the cardiometabolic health of this at-risk population. It is expected that communication of results will allow for the development of more effective evidence-based exercise prescription guidelines in this population while investigating the benefits of HIIT on subclinical markers of disease.Trial registration numberNCT01991106.
The clinical management of hyponatraemia
Authors: Williams David M , Gallagher Maire , Handley Joel , Stephens Jeffrey W 
Published: April 2016

AbstractHyponatraemia is the most common electrolyte disorder seen in clinical practice and the consequences can range from minor symptoms to life-threatening complications including seizures and cardiorespiratory distress. These effects occur as a result of fluid shifts due to deranged serum tonicity and subsequent cerebral oedema. The appropriate assessment and management of patients with hyponatraemia is not always achieved in clinical practice, which is partly related to challenges in teaching with limited clinical guidance. Recently, the European Society of Endocrinology, European Society of Intensive Care Medicine and European Renal Association–European Dialysis and Transplant Association produced clinical practice guidelines to focus on appropriate investigation and management of these patients. Within this manuscript, we highlight the key points from these guidelines, which are most pertinent to doctors of all specialties to improve the care of patients with this common electrolyte disorder.
MAMBO
Authors: Gorgovan Cosmin , d'Antras Amanieu , Luján Mikel 
Published: April 2016

As the ARM architecture expands beyond its traditional embedded domain, there is a growing interest in dynamic binary modification (DBM) tools for general-purpose multicore processors that are part of the ARM family. Existing DBM tools for ARM suffer from introducing large overheads in the execution of applications. The specific questions that this article addresses are (i) how to develop such DBM tools for the ARM architecture and (ii) whether new optimisations are plausible and needed.
We describe the general design of MAMBO, a new DBM tool for ARM, which we release together with this publication, and introduce novel optimisations to handle indirect branches. In addition, we explore scenarios in which it may be possible to relax the transparency offered by DBM tools to allow extra optimisations to be applied. These scenarios arise from analysing the most typical usages: for example, application binaries without handcrafted assembly.
The performance evaluation shows that MAMBO introduces small overheads for SPEC CPU2006 and PARSEC 3.0 when comparing with the execution times of the unmodified programs: a geometric mean overhead of 28% on a Cortex-A9 and of 34% on a Cortex-A15 for CPU2006, and between 27% and 32%, depending on the number of threads, for PARSEC on a Cortex-A15.