bluuebunny/crossref_metadata_2025 huggingface dataset:
Funding issues and options for pharmacists providing sessional services to rural hospitals in Australia
Authors: Tan Amy CW , Emmerton Lynne M , Hattingh H Laetitia , La Caze Adam
Published: January 2015

Objective Many of Australia’s rural hospitals operate without an on-site pharmacist. In some, community pharmacists have sessional contracts to provide medication management services to inpatients. This paper discusses the funding arrangements of identified sessional employment models to raise awareness of options for other rural hospitals. Methods Semistructured one-on-one interviews were conducted with rural pharmacists with experience in a sessional employment role (n = 8) or who were seeking sessional arrangements (n = 4). Participants were identified via publicity and referrals. Interviews were conducted via telephone or Skype for ~40–55 min each, recorded and analysed descriptively. Results A shortage of state funding and reliance on federal funding was reported. Pharmacists accredited to provide medication reviews claimed remuneration via these federal schemes; however, restrictive criteria limited their scope of services. Funds pooling to subsidise remuneration for the pharmacists was evident and arrangements with local community pharmacies provided business frameworks to support sessional services. Conclusion Participants were unaware of each other’s models of practice, highlighting the need to share information and these findings. Several similarities existed, namely, pooling funds and use of federal medication review remuneration. Findings highlighted the need for a stable remuneration pathway and business model to enable wider implementation of sessional pharmacist models. What is known about the topic? Many rural hospitals lack an optimal workforce to provide comprehensive health services, including pharmaceutical services. One solution to address medication management shortfalls is employment of a local community pharmacist or consultant pharmacist on a sessional basis in the hospital. There is no known research into remuneration options for pharmacists providing sessional hospital services. What does this paper add? Viability of services and financial sustainability are paramount in rural healthcare. This paper describes and compares the mechanisms initiated independently by hospitals or pharmacists to meet the medication needs of rural hospital patients. Awareness of the funding arrangements provides options for health service providers to extend services to other rural communities. What are the implications for practitioners? Rural practitioners who identify unmet service needs may be inspired to explore funding arrangements successfully implemented by our participants. Innovative use of existing funding schemes has potential to create employment options for rural practitioners and increase provision of services in rural areas.
Implementing antimicrobial stewardship in the Australian private hospital system: a qualitative study
Authors: Cotta Menino O. , Robertson Megan S. , Marshall Caroline , Thursky Karin A. , Liew Danny , Buising Kirsty L.
Published: January 2015

Objective
To explore organisational factors and barriers contributing to limited uptake of antimicrobial stewardship (AMS) in Australian private hospitals and to determine solutions for AMS implementation.

Methods
A qualitative study using a series of focus group discussions was conducted in a large private hospital making use of a semistructured interview guide to facilitate discussion among clinical and non-clinical stakeholders. A thematic analysis using five sequential components that mapped and interpreted emergent themes surrounding AMS implementation was undertaken by a multidisciplinary team of researchers.

Results
Analysis revealed that autonomy of consultant specialists was perceived as being of greater significance in private hospitals compared with public hospitals. Use of an expert team providing antimicrobial prescribing advice and education without intruding on existing patient–specialist relationships was proposed by participants as an acceptable method of introducing AMS in private hospitals. There was more opportunity for nursing and pharmacist involvement, as well as empowering patients. Opportunities were identified for the hospital executive to market an AMS service as a feature that promoted excellence in patient care.

Conclusions
Provision of advice from experts, championing by clinical leaders, marketing by hospital executives and involving nurses, pharmacists and patients should be considered during implementation of AMS in private hospitals.

What is known about the topic?
Hospital-wide AMS programs have been shown to be an effective means to address the problem of accelerating antimicrobial resistance. However, current literature predominantly focuses on evaluation of AMS activities rather than on improving implementation success. In addition, most research on hospital AMS programs is from the public hospital sector. AMS is now part of new National Safety and Quality Health Service accreditation standards mandatory for all Australian hospitals; however, uptake of AMS in private hospitals lags behind public hospitals. Australian private hospitals are fundamentally different to public hospitals and there is more information needed to determine how AMS can best be introduced in these hospitals.

What does this paper add?
Further investigation on how AMS can be implemented into private hospitals is urgently required. The qualitative work detailed in the present study provides a means of tailoring AMS strategies on the basis of organisational factors that may be considered unique to Australian private hospitals.

What are the implications for practitioners?
Clinical and hospital executive stakeholders in the private hospital sector will be able to use solutions presented herein as a blueprint for designing sustainable AMS programs within their private healthcare facilities.
The Interaction between Remote Chiral Centres: A Pseudoracemic Example
Authors: Bernhardt Paul V. , Carman Raymond M. , Le Tri T.
Published: January 2015

High resolution 13C NMR, supported by X-ray crystallography, shows the true nature of the trichloro derivative from manool or sclareol as a mixture of diastereomers comprising 70 % 13R and 30 % 13S isomers.
The influence of an offshore artificial reef on the abundance of fish in the surrounding pelagic environment
Authors: Scott Molly E. , Smith James A. , Lowry Michael B. , Taylor Matthew D. , Suthers Iain M.
Published: January 2015

Artificial reefs are a popular fisheries management tool, but the effect of these reefs on the abundance of fish in the surrounding pelagic environment is uncertain. Pelagic baited remote underwater video (PBRUV) was used to observe the fish assemblage surrounding an offshore artificial reef (OAR), near Sydney, Australia. PBRUVs were deployed at three distances (30, 100, 500m) from the OAR, and compared with a drop camera deployed directly over the OAR. There was a significantly greater abundance of fish on the OAR, but no significant difference in abundance at the 30-, 100- or 500-m distances. Two highly mobile non-resident species (Seriola lalandi, Pseudocaranx dentex) were significantly more abundant on the OAR, but this association was not detected 30m away. The lack of a significant difference in total fish abundance, or in assemblage composition, between the 30-, 100- and 500-m distances suggests that any association with the OAR is on a localised scale (<30m). One exception was the ocean leatherjacket (Nelusetta ayraudi), which had an association detected 100m from the OAR. This predominantly small-scale effect may be influenced by the proximity of this OAR to numerous natural reefs.
Effects of dietary quercetin on female fertility in mice: implication of transglutaminase 2
Authors: Beazley Kelly E. , Nurminskaya Maria
Published: January 2015

Use of the dietary supplement quercetin is on the rise. Because previous studies imply an inhibitory effect of quercetin on male fertility, we explored the effects of this flavonoid on fertility in female mice. Birth outcomes, and ovarian morphology in 4-week-old offspring, were assessed in mice receiving dietary quercetin (5 mg kg–1 day–1) for 9 months during two breeding periods: from 2 to 6 months (prime reproductive age) and 8 to11 months of age. Quercetin increased birth spacing, leading to a 60% reduction in the number of litters, but enhanced folliculogenesis in ovaries of female offspring. While in young females quercetin caused an almost 70% increase in litter size, in older animals this effect was reversed. Consistent with the inhibitory activity of quercetin on the enzyme transglutaminase 2 (TG2), genetic ablation of TG2 in mice mirrors the effects of quercetin on birth outcomes and follicular development. Further, TG2-null mice lack responsiveness to quercetin ingestion. Our study shows for the first time that dietary quercetin can cause reduced reproductive potential in female mice and implies that TG2 may regulate ovarian ageing.
Actin crosslinking protein filamin A during early pregnancy in the rat uterus
Authors: Madawala Romanthi J. , Poon Connie E. , Dowland Samson N. , Murphy Christopher R.
Published: January 2015

During early pregnancy the endometrium undergoes a major transformation in order for it to become receptive to blastocyst implantation. The actin cytoskeleton and plasma membrane of luminal uterine epithelial cells (UECs) and the underlying stromal cells undergo dramatic remodelling to facilitate these changes. Filamin A (FLNA), a protein that crosslinks actin filaments and also mediates the anchorage of membrane proteins to the actin cytoskeleton, was investigated in the rat uterus at fertilisation (Day 1) and implantation (Day 6) to determine the role of FLNA in actin cytoskeletal remodelling of UECs and decidua during early pregnancy. Localisation of FLNA in UECs at the time of fertilisation was cytoplasmic, whilst at implantation it was distributed apically; its localisation is under the influence of progesterone. FLNA was also concentrated to the first two to three stromal cell layers at the time of fertilisation and shifted to the primary decidualisation zone at the time of implantation. This shift in localisation was found to be dependent on the decidualisation reaction. Protein abundance of the FLNA 280-kDa monomer and calpain-cleaved fragment (240 kDa) did not change during early pregnancy in UECs. Since major actin cytoskeletal remodelling occurs during early pregnancy in UECs and in decidual cells, the changing localisation of FLNA suggests that it may be an important regulator of cytoskeletal remodelling of these cells to allow uterine receptivity and decidualisation necessary for implantation in the rat.
Creation of DNA aptamers against recombinant bone morphogenetic protein 15
Authors: Lin Jun Sheng , Kauff Alexia , Diao Yong , Yang Huiyong , Lawrence Steve , Juengel Jennifer L.
Published: January 2015

The oocyte-derived growth factor bone morphogenetic protein (BMP) 15 plays important roles in fertility, but its mechanism of action differs between species. Generation of BMP15-binding molecules, as an essential investigation tool, would be helpful to provide valuable insight into the underlying biological features of BMP15. The BMP15-binding molecules could be antibodies or aptamers. Aptamers have many advantages over antibodies as macromolecular ligands for target proteins. DNA aptamers can be obtained by a method of Systematic Evolution of Ligands by EXponential enrichment (SELEX) beginning with a pool of random sequences. However, the success of this technique cannot be guaranteed if the initial pool lacks candidate sequences. Herein, we report on the creation of DNA aptamers by means of modified SELEX. The modification included enhanced mutation and progressive selection during an in vitro evolutionary process. As a proof-of-principle, we started from a single sequence instead of a multiple-sequence pool. Functional aptamers against the recombinant BMP15 were successfully created and identified.
The relationship of mindfulness and self-compassion to desired wildland fire leadership
Authors: Waldron Alexis L. , Ebbeck Vicki
Published: January 2015

A quantitative approach was adopted to explore facets of mindfulness and self-compassion in relation to their ability to predict crewmembers’ perceptions of their supervisors’ leadership capabilities. The sample comprised 43 wildland fire crews consisting of their primary supervisors (n = 43) and crewmembers (n = 246). A partial least-squares path modelling approach was employed to test hypotheses regarding the relationships among mindfulness, self-compassion and leadership. Findings revealed that supervisor scores on mindfulness were significant predictors of crewmember-rated scores of supervisor leadership. Although not as strong, aspects of self-compassion were also significant predictors of perceived supervisor leadership. Unlike mindfulness, the aspects of self-compassion that predicted supervisor leadership were more varied between desirable self-compassion scores and undesirable self-compassion scores. Overall, the results indicate that mindfulness and self-compassion were predictors of desired wildland fire leadership by crewmembers; these results suggest potential functions that mindfulness and self-compassion could serve in the development of leaders in wildland firefighting.
Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells
Authors: Foxman Ellen F. , Storer James A. , Fitzgerald Megan E. , Wasik Bethany R. , Hou Lin , Zhao Hongyu , Turner Paul E. , Pyle Anna Marie , Iwasaki Akiko
Published: January 2015

Significance

Rhinovirus is the most frequent cause of the common cold, as well as one of the most important causes of asthma exacerbations. Most rhinovirus strains replicate better at the cooler temperatures found in the nasal cavity than at lung temperature, but the underlying mechanisms are not known. Using a mouse-adapted virus, we found that airway epithelial cells supporting rhinovirus replication initiate a more robust antiviral defense response through RIG-I–like receptor (RLR)–dependent interferon secretion and enhanced interferon responsiveness at lung temperature vs. nasal cavity temperature. Airway cells with genetic deficiencies in RLR or type I interferon receptor signaling supported much higher levels of viral replication at 37 °C. Thus, cooler temperatures can enable replication of the common cold virus, at least in part, by diminishing antiviral immune responses.
Dried whole-plant
Artemisia annua
slows evolution of malaria drug resistance and overcomes resistance to artemisinin
Authors: Elfawal Mostafa A. , Towler Melissa J. , Reich Nicholas G. , Weathers Pamela J. , Rich Stephen M.
Published: January 2015

Significance

Evolution of malaria parasite drug resistance has thwarted efforts to control this deadly disease. Use of drug combinations has been proposed to slow that evolution. Artemisinin is a favorite drug in the global war on malaria and is frequently used in combination therapies. Here we show that using the whole plant (
Artemisia annua
) from which artemisinin is derived can overcome parasite resistance and is actually more resilient to evolution of parasite resistance; i.e., parasites take longer to evolve resistance, thus increasing the effective life span of the therapy.
Intracellular Cl
−
as a signaling ion that potently regulates Na
+
/HCO3
−
transporters
Authors: Shcheynikov Nikolay , Son Aran , Hong Jeong Hee , Yamazaki Osamu , Ohana Ehud , Kurtz Ira , Shin Dong Min , Muallem Shmuel
Published: January 2015

Significance

Cl
−
is the major cellular anion that controls the intracellular activity of many ions, the membrane potential, and transepithelial fluid and electrolyte secretion. How cells sense intracellular Cl
−
(Cl
−
in
) to coordinate all Cl
−
-dependent activities is not known. We report a molecular mechanism for Cl
−
in
sensing that involves interaction of Cl
−
with GXXXP-containing sites and show how these sites are used to regulate the activity of several Na
+
-HCO
3
−
cotransporters. Although these transporters do not transport Cl
−
, they sense Cl
−
in
in a manner specific for each transporter that is suitable for the transporter physiological activity. Our data has fundamental implications for the role of Cl
−
in cellular ion homeostasis and fluid and electrolyte secretion.
Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction
Authors: Rincón-Cortés Millie , Barr Gordon A. , Mouly Anne Marie , Shionoya Kiseko , Nuñez Bestina S. , Sullivan Regina M.
Published: January 2015

Significance

Infant trauma induces preference learning about trauma-linked cues but negatively programs neurobehavioral development. Despite clinical evidence that trauma-linked cues remain powerful throughout life, the mechanisms underlying the interaction between infant trauma cues and the long-term effects of trauma are unknown. Using a rodent model of trauma bonding, which produces a life-long preferred odor and enduring effects that parallel the sequelae of child abuse, we show that the infant trauma odor rescues adult depressive-like behavior and amygdala dysfunction. Assessment of neural mechanism implicates amygdala serotonin (5-HT) and glucocorticoids (GCs). Our findings suggest that trauma-linked cues have an unexpected positive value in adulthood (i.e., antidepressant properties) and may provide insight as to why victims of childhood abuse are attracted to abuse-related cues.
Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding
Authors: Lu Jinghua , Chu Jonathan , Zou Zhongcheng , Hamacher Nels B. , Rixon Mark W. , Sun Peter D.
Published: January 2015

Significance

Fc gamma receptor I (FcγRI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. It is the sole high-affinity receptor for IgG and plays a significant role in immunotherapy. To date, there is no structural information available on how the receptor recognizes its antibody ligands, however. Consequently, the mechanism of its high-affinity IgG binding remains unclear. We report the first structure of the high-affinity Fc receptor in complex with IgG-Fc. The structural work reveals a direct receptor recognition of Fc glycan as a major factor in receptor affinity. This is the first example of Fc receptor making direct glycan contact through protein residues. The results have implications for the use of glycan engineering in immunotherapy.
Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO
Authors: Li Qiang , Wang Ping , Ye Keqiang , Cai Hua
Published: January 2015

Significance

Therapies for myocardial infarction consequent to ischemia/reperfusion injury (I/R) have been lacking. The netrin-1 receptor deleted in colorectal cancer (DCC) mediates netrin-1–dependent cardioprotective signaling. It is anticipated that any means of augmenting DCC signaling may induce cardioprotection on its own and enhance netrin-1/NO–dependent cardioprotection. The present study identifies a novel mechanism by which NO upregulates DCC abundance. NO inhibits seven in absentia homolog (SIAH), an E3 ubiquitin ligase that suppresses DCC. Inhibition of SIAH by in vivo RNA interference markedly reduces infarct size to improve cardiac function that was determined by echocardiography. Combined with netrin-1 perfusion, it further potentiated netrin-1’s cardioprotective effect. SIAH may therefore serve as a novel therapeutic target for myocardial infarction, particularly those suffering from cardiac I/R injury.
Variation in Rapa Nui (Easter Island) land use indicates production and population peaks prior to European contact
Authors: Stevenson Christopher M. , Puleston Cedric O. , Vitousek Peter M. , Chadwick Oliver A. , Haoa Sonia , Ladefoged Thegn N.
Published: January 2015

Significance

Our paper evaluates a long-standing debate and examines whether the prehistoric population of Rapa Nui experienced a significant demographic collapse prior to European contact in AD 1722. We have used dates from hydrated obsidian artifacts recovered from habitation sites as a proxy for land use over time. The analysis suggests region-specific dynamics that include the abandonment of leeward and interior locations. These temporal land-use patterns correlate with rainfall variation and soil quality. This analysis demonstrates that the concept of “collapse” is a misleading characterization of prehistoric human population dynamics. As a result, we see our approach as useful in the study of other prehistoric societies for which a sudden demographic collapse has been proposed in prehistory.
Cdc45 (cell division cycle protein 45) guards the gate of the Eukaryote Replisome helicase stabilizing leading strand engagement
Authors: Petojevic Tatjana , Pesavento James J. , Costa Alessandro , Liang Jingdan , Wang Zhijun , Berger James M. , Botchan Michael R.
Published: January 2015

Significance

Cell division control protein 45 (Cdc45), a RecJ homologue, is essential in all eukaryotes. Cdc45 functions with the replisome CMG helicase where minichromosome maintenance (Mcm2–7) proteins provide motor activity for unwinding duplex during replication. We report that the dynamic gate between Mcm subunits 2 and 5, which is essential for the initial loading of the motor, may be an Achilles heel because the leading strand may slip from its central channel in an open gate state. Studies show that the side channel formed by the Cdc45 and GINS works as a trap and guards this gate; the Recombination protein J fold is key for this activity. We propose that this new function for Cdc45 will be important for fork integrity during the S-phase in response to double-strand breaks or replication stress.
Theory of point contact spectroscopy in correlated materials
Authors: Lee Wei-Cheng , Park Wan Kyu , Arham Hamood Z. , Greene Laura H. , Phillips Philip
Published: January 2015

Significance

Point-contact spectroscopy is a bulk spectroscopic probe that has been reliably used to map out bosonic and superconducting order parameter spectra via quasiparticle classical and Andreev scattering, respectively. We previously showed this technique to be exquisitely sensitive to an effective density of states specifically arising from non-Fermi liquid behavior, and in the case of the iron pnictides and chalcogenides, electronic nematicity manifesting as a zero bias conductance peak corresponds to an increased effective density of states at the Fermi level arising from orbital fluctuations. We developed a quantum mechanical theory to show how this technique reveals such effective density of states while being insensitive to gapless Fermi surface reconstructions and is therefore a valuable filter for detecting non-Fermi liquid behavior.
DOMAINS REARRANGED METHYLTRANSFERASE3 controls DNA methylation and regulates RNA polymerase V transcript abundance in
Arabidopsis
Authors: Zhong Xuehua , Hale Christopher J. , Nguyen Minh , Ausin Israel , Groth Martin , Hetzel Jonathan , Vashisht Ajay A. , Henderson Ian R. , Wohlschlegel James A. , Jacobsen Steven E.
Published: January 2015

Significance

DNA methylation, a chemical mark on chromatin, while not affecting DNA's primary sequence, plays important roles in silencing “bad DNA” that would become deleterious to cells if abnormally expressed. This DNA methylation-mediated silencing system against bad DNA is tightly regulated to prevent the misplacement of methylation on “good DNA.” In
Arabidopsis thaliana
, DOMAINS REARRANGED METHYLTRANSFERASE2 (DRM2) controls RNA-directed DNA methylation in a pathway that also involves the plant-specific RNA Polymerase V (Pol V). The
Arabidopsis
genome also encodes an evolutionarily conserved but catalytically inactive methyltransferase, DRM3. Here, we investigate the molecular mechanism of DRM3 action on DNA methylation and its dynamic regulation of Pol V transcription. Together, this study sheds further light on the mechanism of RNA-directed DNA methylation.
Neutrophil-related factors as biomarkers in EAE and MS
Authors: Rumble Julie M. , Huber Amanda K. , Krishnamoorthy Gurumoorthy , Srinivasan Ashok , Giles David A. , Zhang Xu , Wang Lu , Segal Benjamin M.
Published: January 2015

A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR+ CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR+ CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS.
Bioenergy Supply and Environmental Impacts on Cropland: Insights from Multi‐market Forecasts in a Great Lakes Subregional Bioeconomic Model
Authors: Egbendewe‐Mondzozo Aklesso , Swinton Scott M. , Kang Shujiang , Post Wilfred M. , Binfield Julian C. , Thompson Wyatt
Published: January 2015

Using subregional models of crop production choices in central Wisconsin and southwest Michigan, we predict biomass production, land use, and environmental impacts with details that are unavailable from national scale models. When biomass prices are raised exogenously, we find that the subregional models overestimate the supply, the land use, and the beneficial environmental aspects of perennial biomass crops. Multi‐market price feedbacks tied to realistic policy parameters predict high threshold absolute prices for biomass to enter production, resulting in intensified production of biomass from annual grain crops with damaging environmental impacts. Multi‐market feedbacks also predict regional specialization in energy biomass production in areas with lower yields of food crops. Policies promoting biofuels will not necessarily generate environmental benefits in the absence of environmental regulations.
In vitro antifungal activity and in vivo antibiofilm activity of cerium nitrate against Candida species
Authors: Silva-Dias Ana , Miranda Isabel M. , Branco Joana , Cobrado Luís , Monteiro-Soares Matilde , Pina-Vaz Cidália , Rodrigues Acácio G.
Published: January 2015

Objectives

The objective of this study was to clarify the antifungal properties of cerium, a lanthanide member, against Candida species. A comprehensive study with planktonic and sessile cells was performed. The ability of cerium nitrate (CN) to impair in vitro and in vivo biofilm formation was evaluated and its potential use in biofilm treatment was also evaluated.

Methods

Forty-eight clinical isolates of different Candida species and the type strain ATCC 90028 were tested according to the protocol M27-A3. The MICs and minimum lethal concentrations were determined. A time–kill assay was performed and a cytometric kinetic study was performed using live/dead markers. Biofilm inhibition and biofilm susceptibility in the presence of cerium was evaluated by quantification of the biofilm metabolic activity and total biomass with XTT and crystal violet assays, respectively. CN in vivo efficacy as a coating for medical indwelling devices was evaluated for the first time for Candida parapsilosis, using a mouse subcutaneous foreign body model using polyurethane catheter segments. Scanning electron microscopy was used to assess biofilm architecture after CN treatment.

Results

The MICs for planktonic cells correlated with severe cellular metabolic activity impairment and membrane damage after 3 h of incubation. Moreover, CN efficiently prevented biofilm formation both in vitro and in vivo in segments of polyurethane catheters. At higher concentrations, it was also able to disorganize and almost eradicate preformed biofilms.

Conclusions

Our results strongly suggest that CN application in the clinical setting might be effective in preventing the formation of biofilm-associated infections, namely through catheter coating and ultimately as an antimicrobial lock therapy.
Dynamics of MDR Enterobacter cloacae outbreaks in a neonatal unit in Nepal: insights using wider sampling frames and next-generation sequencing
Authors: Stoesser N. , Sheppard A. E. , Shakya M. , Sthapit B. , Thorson S. , Giess A. , Kelly D. , Pollard A. J. , Peto T. E. A. , Walker A. S. , Crook D. W.
Published: January 2015

Objectives

There are limited data on Enterobacter cloacae outbreaks and fewer describing these in association with NDM-1. With whole-genome sequencing, we tested the hypothesis that a cluster of 16 E. cloacae bacteraemia cases in a Nepali neonatal unit represented a single clonal outbreak, using a wider set of epidemiologically unrelated clinical E. cloacae isolates for comparison.

Methods

Forty-three isolates were analysed, including 23 E. cloacae and 3 Citrobacter sp. isolates obtained from blood cultures from 16 neonates over a 3 month period. These were compared with two contemporaneous community-associated drug-resistant isolates from adults, a unit soap dispenser isolate and a set of historical invasive isolates (n = 14) from the same geographical locality.

Results

There were two clear neonatal outbreaks and one isolated case in the unit. One outbreak was associated with an NDM-1 plasmid also identified in a historical community-associated strain. The smaller, second outbreak was likely associated with a contaminated soap dispenser. The two community-acquired adult cases and three sets of historical hospital-associated neonatal isolates represented four additional genetic clusters.

Conclusions

E. cloacae infections in this context represent several different transmission networks, operating at the community/hospital and host strain/plasmid levels. Wide sampling frames and high-resolution typing methods are needed to describe the complex molecular epidemiology of E. cloacae outbreaks, which is not appropriately reflected by routine susceptibility phenotypes. Soap dispensers may represent a reservoir for E. cloacae and bacterial strains and plasmids may persist in hospitals and in the community for long periods, sporadically being involved in outbreaks of disease.
Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort
Authors: Trubiano J. A. , Crowe A. , Worth L. J. , Thursky K. A. , Slavin M. A.
Published: January 2015

Objectives

The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.

Methods

As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.

Results

The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%).

Conclusions

Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.
Association of guideline-based antimicrobial therapy and outcomes in healthcare-associated pneumonia
Authors: Rothberg Michael B. , Zilberberg Marya D. , Pekow Penelope S. , Priya Aruna , Haessler Sarah , Belforti Raquel , Skiest Daniel , Lagu Tara , Higgins Thomas L. , Lindenauer Peter K.
Published: January 2015

Objectives

Guidelines for treatment of healthcare-associated pneumonia (HCAP) recommend empirical therapy with broad-spectrum antimicrobials. Our objective was to examine the association between guideline-based therapy (GBT) and outcomes for patients with HCAP.

Patients and methods

We conducted a pharmacoepidemiological cohort study at 346 US hospitals. We included adults hospitalized between July 2007 and June 2010 for HCAP, defined as patients admitted from a nursing home, with end-stage renal disease or immunosuppression, or discharged from a hospital in the previous 90 days. Outcome measures included in-hospital mortality, length of stay and costs.

Results

Of 85 097 patients at 346 hospitals, 31 949 (37.5%) received GBT (one agent against MRSA and at least one against Pseudomonas). Compared with patients who received non-GBT, those who received GBT had a heavier burden of chronic disease and more severe pneumonia. GBT was associated with higher mortality (17.1% versus 7.7%, P < 0.001). Adjustment for demographics, comorbidities, propensity for treatment with GBT and initial severity of disease decreased, but did not eliminate, the association (OR 1.39, 95% CI 1.32–1.47). Using an adaptation of an instrumental variable analysis, GBT was not associated with higher mortality (OR 0.93, 95% CI 0.75–1.16). Adjusted length of stay and costs were also higher with GBT.

Conclusions

Among patients who met HCAP criteria, GBT was not associated with lower adjusted mortality, length of stay or costs in any analyses. Better criteria are needed to identify patients at risk for MDR infections who might benefit from broad-spectrum antimicrobial coverage.
Clinical characteristics and treatment outcomes of patients with candidaemia due to Candida parapsilosis sensu lato species at a medical centre in Taiwan, 2000–12
Authors: Chen Chien-Yuan , Sheng Wang-Hui , Huang Sheng-Yi , Chou Wen-Chien , Yao Ming , Tang Jih-Luh , Tsay Woei , Tien Hwei-Fang , Hsueh Po-Ren
Published: January 2015

Objectives

To investigate the clinical characteristics and treatment outcomes of adult patients with Candida parapsilosis sensu lato candidaemia.

Methods

We evaluated data in the mycology database of the National Taiwan University Hospital and on patients diagnosed with candidaemia due to C. parapsilosis sensu lato species from 2000 to 2012. Isolates were identified to the species level by conventional identification methods, MALDI-TOF and gene sequencing analysis.

Results

A total of 323 adult patients with candidaemia caused by C. parapsilosis sensu lato species were evaluated, including 256 (79.3%) patients with C. parapsilosis sensu stricto, 34 (10.5%) with Candida orthopsilosis and 33 (10.2%) with Candida metapsilosis. There were 222 men and 101 women and the median age was 60 years (range 18–103 years). Among them, 178 (55%) had an underlying diagnosis of cancer. The overall 30 day mortality rate was 25% (n = 80). Multivariate analysis revealed that shock (P < 0.001), antifungal therapy (P = 0.002), central catheter removal (P = 0.02) and abdominal surgery (P = 0.043) were independent prognostic factors for patients with candidaemia due to C. parapsilosis sensu lato species. There were no significant differences in 30 day mortality rate among patients with candidaemia caused by the three different species (P = 0.770). All isolates of C. metapsilosis, C. orthopsilosis and C. parapsilosis sensu stricto were susceptible to voriconazole. WT isolates were susceptible to itraconazole, posaconazole and amphotericin B.

Conclusions

There were no significant differences in 30 day mortality among patients with candidaemia caused by C. parapsilosis sensu stricto, C. metapsilosis or C. orthopsilosis. The currently used antifungal agents exhibited good in vitro activities against C. parapsilosis sensu lato species isolates.
How is income generated by outpatient parenteral antibiotic treatment (OPAT) in the UK? Analysis of payment tariffs for cellulitis
Authors: Jones G. R. , Cumming D. V. E. , Honeywell G. , Ball R. , Sanderson F. , Seaton R. A. , Healy B. , Hedderwick S. , Gilchrist M. ,   on behalf of the BSAC OPAT Standing Committee, Dryden Matthew , Gilchrist Mark , Seaton Andrew , Chapman Ann , Laundy Matthew , Patel Sanjay , Jones Graeme , Cumming Debbie , Sanderson Frances , Jefferies Lorrayne , Hanlon Sue O. , Owen Kate , Snape Sue , Hills Tim
Published: January 2015

Objectives

We determined the available mechanisms to generate income from outpatient parenteral antimicrobial therapy (OPAT) in the UK and calculated the revenue generated from treatment of an episode of cellulitis.

Methods

Revenue was calculated for patients receiving treatment for cellulitis as an inpatient and for patients receiving OPAT by a series of different payment pathways. Selected established OPAT services in Northern Ireland, Scotland and Wales, where Payment-by-Results (PbR) does not operate, were contacted to determine individual national funding arrangements.

Results

In England, a traditional inpatient episode for uncomplicated cellulitis requiring 7 days of treatment generated £1361 of revenue, while OPAT generated revenue ranging from £773 to £2084 for the same length of treatment depending on the payment pathway used. Treatment using OPAT to avoid admission entirely generated £2084, inpatient admission followed by transfer to a virtual OPAT ward at day 2 generated £1361 and inpatient admission followed by discharge from hospital to OPAT at day 2 generated £773. In Northern Ireland, Scotland and Wales block contracts were used and no income was calculable for an individual episode of cellulitis.

Conclusions

No single funding mechanism supports OPAT across the UK. In England, revenue generated by OPAT providers from treatment of cellulitis varied with the OPAT payment pathway used, but equalled or exceeded the income generated from equivalent inpatient care. Cost savings for OPAT and reuse of released inpatient beds will increase revenue further. A single OPAT tariff is proposed.
Antifungal activity of compounds targeting the Hsp90-calcineurin pathway against various mould species
Authors: Lamoth Frédéric , Alexander Barbara D. , Juvvadi Praveen R. , Steinbach William J.
Published: January 2015

Objectives

Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species.

Methods

The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.)

Results

FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity.

Conclusions

Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds.
Losing history: how extinctions prune features from the tree of life
Authors: Davies T. Jonathan
Published: January 2015

Biodiversity provides many valuable services to humanity; however, rapid expansion of the human population has placed increasing pressure on natural systems, and it has been suggested that we may be entering a sixth mass extinction. There is an urgent need, therefore, to prioritize conservation efforts if we are to maintain the provisioning of such service in the future. Phylogenetic diversity (PD), the summed branch lengths that connect species on the tree-of-life, might provide a valuable metric for conservation prioritization because it has been argued to capture feature diversity. Frequently, PD is estimated in millions of years, and therefore implicitly assumes an evolutionary model in which features diverge gradually over time. Here, I explore the expected loss of feature diversity when this assumption is violated. If evolution tends to slow down over time, as might be the case following adaptive radiations, losses of feature diversity might be relatively small. However, if evolution occurs in rapid bursts, following a punctuated model, impacts of extinctions might be much greater. PD captures many important properties, but if we use it as a proxy for feature diversity, we first need to ensure that we have the correct evolutionary model.
Animal models of epilepsy: legacies and new directions
Authors: Grone Brian P. , Baraban Scott C.
Published: January 2015

Human epilepsies encompass a wide variety of clinical, behavioral and electrical manifestations. Correspondingly, studies of this disease in nonhuman animals have brought forward an equally wide array of animal models, i.e. species and acute or chronic seizure induction protocols. Epilepsy research has a long history of comparative anatomical and physiological studies on a range of mostly mammalian species. Nonetheless, a relatively limited number of rodent models emerged as the primary choices for most epilepsy-related investigations. In many cases these animal models are selected based on convenience or tradition, though technical or experimental rationale does, and should, factor into these decisions. More complex mammalian brains and, especially, genetic model organisms including zebrafish have been studied less but offer significant advantages that are being widely recognized.
Rethinking inheritance, yet again: inheritomes, contextomes and dynamic phenotypes
Authors: Prasad N. G. , Dey Sutirth , Joshi Amitabh , Vidya T. N. C.
Published: January 2015

In recent years, there have been many calls for an extended evolutionary synthesis, based in part upon growing evidence for non-genetic mechanisms of inheritance, i.e., similarities in phenotype between parents and offspring that are not due to shared genes. While there has been an impressive marshalling of evidence for diverse forms of non-genetic inheritance (epigenetic, ecological, behavioural, symbolic), there have been relatively few studies trying to integrate the different forms of inheritance into a common conceptual structure, a development that would be important to formalizing elements of the extended evolutionary synthesis. Here, we propose a framework for an extended view of inheritance and introduce some conceptual distinctions that we believe are important to this issue. In this framework, the phenotype is conceived of as a dynamic entity, its state at any point in time resulting from intertwined effects of previous phenotypic state, and of hereditary materials (DNA and otherwise) and environment. We contrast our framework with the standard gene-based view of inheritance, and also discuss our framework in the specific context of recent attempts to accommodate non-genetic inheritance within the framework of classical quantitative genetics and the Price equation. In particular, we believe that the extended view of inheritance and effects on the phenotype developed here is particularly well-suited to individual-based simulation studies of evolutionary dynamics. The results of such simulations, in turn, could be useful for assessing how well extended models based on quantitative genetics or the Price equation perform at capturing complex evolutionary dynamics.
TYPE-ONE PROTEIN PHOSPHATASE4 Regulates Pavement Cell Interdigitation by Modulating PIN-FORMED1 Polarity and Trafficking in Arabidopsis
Authors: Guo Xiaola , Qin Qianqian , Yan Jia , Niu Yali , Huang Bingyao , Guan Liping , Li Yuan , Ren Dongtao , Li Jia , Hou Suiwen
Published: January 2015

In plants, cell morphogenesis is dependent on intercellular auxin accumulation. The polar subcellular localization of the PIN-FORMED (PIN) protein is crucial for this process. Previous studies have shown that the protein kinase PINOID (PID) and protein phosphatase6-type phosphatase holoenzyme regulate the phosphorylation status of PIN1 in root tips and shoot apices. Here, we show that a type-one protein phosphatase, TOPP4, is essential for the formation of interdigitated pavement cell (PC) pattern in Arabidopsis (Arabidopsis thaliana) leaf. The dominant-negative mutant topp4-1 showed severely inhibited interdigitated PC growth. Expression of topp4-1 gene in wild-type plants recapitulated the PC defects in the mutant. Genetic analyses suggested that TOPP4 and PIN1 likely function in the same pathway to regulate PC morphogenesis. Furthermore, colocalization, in vitro and in vivo protein interaction studies, and dephosphorylation assays revealed that TOPP4 mediated PIN1 polar localization and endocytic trafficking in PCs by acting antagonistically with PID to modulate the phosphorylation status of PIN1. In addition, TOPP4 affects the cytoskeleton pattern through the Rho of Plant GTPase-dependent auxin-signaling pathway. Therefore, we conclude that TOPP4-regulated PIN1 polar targeting through direct dephosphorylation is crucial for PC morphogenesis in the Arabidopsis leaf.