bluuebunny/crossref_metadata_2025 huggingface dataset:
Time to research Australian physician‐researchers
Authors: Traill C. L. , Januszewski A. S. , Larkins R. , Keech A. C. , Jenkins A. J.
Published: February 2016

Background

Concerns have been expressed ‘that the physician‐researcher is a dying breed’. As yet there are few Australian data.

Aims

To compare over time: (i) research progress of Sydney Medical School (SMS) medical practitioner – PhD awardees; (ii) National Health and Medical Research Council (NHMRC) project grant success rates for physician‐researchers; and (iii) compare current NHMRC, NSW University and NSW Public Hospital pay scales for physician‐researchers.

Methods

We evaluated 303 medical practitioners awarded a University of Sydney/SMS PhD in 1989–2012 and their publications. We assessed 1990–2014 NHMRC grants to physicians and non‐physicians (nationally) and compared physician salaries from NHMRC, the University of Sydney and NSW public hospitals.

Results

SMS PhD completions by clinicians increased ≈2.4‐fold since 1989, with a recent decline, whilst non‐medical PhD awardees rose 10‐fold. The median time of PhD award after medical degree completion was stable at 13 years. A lower percentage of the more recent physician‐researchers had completed specialty training at PhD award (34% in 2011–2012 vs 71% in 1989–1990, P = 0.017). Publication rates were stable, but low. Although NHMRC funding increased >10‐fold since 1990, national project grant success rates declined (35% in 1990, 17% in 2013 and 15% in 2014, P < 0.0001), with physician‐led funded grants declining from 29% in 1989 to 21% in 2013, P = 0.002. Current NHMRC and University salaries are less than comparable‐stage public hospital salaries.

Conclusion

Since 1989, more medical graduates are completing SMS PhDs, although more often prior to completing clinical Fellowships, and many have ongoing, albeit low, research activity. Nationally NHMRC project grant success rates have declined significantly, as has the proportion of funded physician‐led projects. Medical practitioner salaries from NHMRC and from Universities are less than in public hospitals. The Australian physician‐researcher is at‐risk. Knowledge and actions are needed to protect our medical research capacity.
Efficacy and safety of once‐daily insulin degludec dosed flexibly at convenient times vs fixed dosing at the same time each day in a Japanese cohort with type 2 diabetes: A randomized, 26‐week, treat‐to‐target trial
Authors: Kadowaki Takashi , Jinnouchi Hideaki , Kaku Kohei , Hersløv Malene L , Hyllested‐Winge Jacob , Nakamura Shuji
Published: February 2016

Aims/Introduction

This trial assessed the efficacy and safety of the possibility of varying the daily injection time of once‐daily, long‐acting basal insulin degludec (IDeg) in Japanese patients with type 2 diabetes inadequately controlled with insulin glargine.

Materials and Methods

This was a 26‐week, multicenter, open‐label, randomized, treat‐to‐target trial, with a 2 × 2 factorial design comparing IDeg flexible (allowing dosing ±8 h from an agreed dosing time) with IDeg fixed dosing (at the same time each day). It was carried out in 458 adult patients who were inadequately controlled on insulin glargine with or without oral antidiabetic drugs.

Results

The majority of doses were taken within 2 h of the agreed dosing time, showing a high level of adherence among Japanese patients. After 26 weeks, IDeg flexible was non‐inferior to IDeg fixed with respect to change in glycated hemoglobin from baseline, estimated treatment difference 0.08% points (95% confidence interval −0.05; 0.22). Fasting plasma glucose decreased to a similar level with IDeg flexible and IDeg fixed, estimated treatment difference −0.18 mmol/L (95% confidence interval −0.48; 0.12). The rates of confirmed and nocturnal confirmed hypoglycemia were numerically, but not significantly, higher with IDeg flexible vs IDeg fixed dosing. The rates of adverse events with IDeg flexible and IDeg fixed dosing were similar.

Conclusions

These results showed the efficacy and safety of allowing patients to vary the time they dosed IDeg, when necessary, in Japanese patients with type 2 diabetes. Dosing of IDeg at a time convenient to the patient was non‐inferior, with respect to glycated hemoglobin, to dosing at the same time each day.
Is ultrasonographic evaluation essential for diagnosis of retained products of conception after surgical abortion?
Authors: Tohma Yusuf Aytaç , Dilbaz Berna , Evliyaoğlu Özlem , Çoşkun Bora , Çolak Eser , Dilbaz Serdar
Published: February 2016

Aim

The aim of this study was to evaluate the predictive value of symptomatic evaluation with transvaginal ultrasonographic findings for diagnosis of retained products of conception (RPOC) after voluntary pregnancy termination via manual vacuum aspiration (MVA).

Methods

A total of 466 patients with a gestational age < 10 weeks were followed up at the 7th day after MVA of unwanted pregnancies. The patients who had intense or moderate bleeding and other symptoms related to RPOC had a re‐evacuation and all the patients were followed up until the next menstruation. Ultrasonographic evaluation was repeated weekly in asymptomatic patients with abnormal ultrasonographic findings (increased endometrial thickness, presence of hyperechogenic, mixed and hypoechogenic material) until a normal endometrial cavity was visualized.

Results

Out of the 466 patients, 15 (3.2%) had symptoms of RPOC at day 7 while the remaining 451 (96.8%) were asymptomatic and 20 (57.9%) had normal ultrasonographic findings. The 15 symptomatic patients (3.2%) had a repeated MVA. Nine of these 15 patients (60%) had endometrial echogenicity with mixed patterns, two (13.3%) had endometrial echogenicity with hyperechoic patterns, and the remaining four (26.7%) had normal endometrial echogenicity at day 7. Histopathologic examination of 12 of these 15 patients (80%) showed chorionic villi while no gestational tissue was noted in the remaining three of these patients. Endometrial thickness ≥ 10 mm on day 7 had 75% sensitivity and 100% specificity for diagnosis of RPOC in symptomatic women. None of the 451 asymptomatic patients developed any symptoms or needed any further intervention.

Conclusion

As abnormal ultrasonographic findings return to normal over time in asymptomatic patients, the diagnosis of RPOC should not be based on ultrasonographic findings.
Surgical intestinal manipulation increases gene expression of TrkA, CGRP, and PAR‐2 IN dorsal root ganglia in the rat
Authors: Berdún S. , Rychter J. , Vergara P.
Published: February 2016

Background

Surgical handling of the bowel evokes degranulation of peritoneal mast cells (PMC). Nonetheless, role of PMCs in postoperative ileus (POI) is somewhat controversial. We aimed to investigate if intestinal manipulation elicits changes in afferent mediators related to MC activation and alteration of gastrointestinal (GI) motility.

Methods

Postoperative ileus was induced by intestinal manipulation in Sprague‐Dawley rats. Additionally, compound 48/80 (C48/80) and ketotifen were used to modulate MC activity. Rat mast cell protease 6 (RMCP‐6, ELISA) release was determined in peritoneal lavage 20 min after intestinal manipulation. At 24 h, GI transit was determined. Gene expression of calcitonin gene‐related peptide (CGRP), protease‐activated receptor‐2 (PAR‐2), nerve growth factor (NGF), and TrkA receptor was determined (PCR) in dorsal root ganglia (DRG). Ileal wall inflammation was assessed by myeloperoxidase (MPO) activity, interleukin‐6 expression (IL‐6).

Key Results

Intestinal manipulation and exposure to C48/80‐induced degranulation of PMCs delayed GI transit and up‐regulated IL‐6 and MPO activity. Intestinal manipulation, but not C48/80, up‐regulated CGRP, PAR‐2, and NGF/TrkA in DRGs. Ketotifen only improved gastric emptying and fecal output. Up‐regulation of CGRP and TrkA expression in DRG was not prevented by ketotifen.

Conclusions & Inferences

Postoperative ileus is accompanied by activation of CGRP, NGF‐TrkA, and PAR‐2 in DRGs. Our results suggest that these mediators could be a target in further POI studies in order to find new therapeutic targets for this medical condition.
Improvement in the airway after mandibular distraction osteogenesis surgery in children with temporomandibular joint ankylosis and mandibular hypoplasia
Authors: Zanaty Ola , El Metainy Shahira , Abo Alia Doaa , Medra Ahmed
Published: February 2016

Background

Temporomandibular joint (TMJ) ankylosis accompanied by mandibular micrognathia can severely obstruct a patient's upper airway. The obstructive sleep apnea and hypopnea syndrome (OSAHS) resulting from TMJ ankylosis and accompanied by mandibular micrognathia, can severely influence the patient's life.

Aim

The aim of this study was to determine if there is a difference in Cormack and Lehane score before and after distraction osteogenesis in such patients, and to evaluate the airway changes and the respiratory outcome using polysomnography after mandibular distraction osteogenesis.

Methods

This observational prospective study was carried out on 30 ASA II patients with micrognathia and TMJ ankylosis undergoing internal distraction osteogenesis. All patients were assessed with polysomnography before surgery and 6 month after surgery. Nasal intubation was done using a fiberoptic bronchoscope, then patients were subjected to the same anesthetic protocol. Direct laryngoscopy was attempted for the Cormack and Lehane grading after induction. The Cormack and Lehane grade was reassessed after facial symmetry was obtained on removal of the distractor.

Results

Mouth opening and Cormack and Lehane score improved significantly between the initial presentation for placement of mandibular distraction osteogenesis devices and on removal of the destructor under general anesthesia. Polysomnographic studies conducted after distraction confirmed the correction of airway obstruction in all patients: Improvement in Apnea–Hypopnea Index, mean difference (95% CI), 39.8 (38.8–40.9); the number of apneas per hour, mean difference, (95% CI) 41.1 (42.1–40.1); and oxygen‐desaturation‐index mean difference (95% CI) 27.6 (28.3–26.8).

Conclusion

Mandibular distraction osteogenesis improved laryngeal view. Distraction osteogenesis can be successfully used for the treatment of obstructive sleep apnea in mandibular hypoplasia patients.
Privileging Policy Change? Sustaining Automatic Stabilizing Mechanisms in Public Pensions
Authors: Weaver R. Kent
Published: February 2016

Automatic stabilizing mechanisms (ASMs) in pension systems change the policy default so that benefits or contributions adjust automatically to adverse demographic and economic conditions without direct intervention by politicians. This is politically attractive to politicians because it facilitates blame avoiding. But it only works if politicians can refrain from ad hoc interventions when an ASM is triggered. Evidence from Canada, Sweden and Germany suggests a mixed record about their sustainability. Politicians may seek to evade or manipulate the trigger mechanism to avoid blame. A cartel of major parties that insulates pension policy‐making from electoral competition can help to sustain ASMs.
Reforming a Health Care System in a Big Way? The Case of Change in the British NHS
Authors: Powell Martin
Published: February 2016

There is a significant literature on change in health care systems, but much of this has little explicit discussion of conceptual approaches, measures or explanations of change. This article examines studies of the British National Health Service (NHS) focusing on the what, how much and why of change. It sets out the main approaches to studying continuity and change: institutional continuity and path dependency (PD); incremental change; punctuated equilibrium; gradual institutional change; ideational analysis; paradigm change; and institutional logics. It briefly critically discusses each of these approaches, and then examines the main studies in chronological order. With reference to the three main questions of this article, the ‘what’ of change suggests that, in terms of the number of studies, PD and ideational approaches appear to be dominant. The ‘how much’ of change question remains problematic due to unclear dependent variables and conflicting conclusions. Lastly, the ‘why’ of change remains unresolved. In short, studies of change in the British NHS tend to be overly descriptive and under‐theorized, and do not fully address issues of theories and concepts, measures and explanations; or the what, how much and why of change.
Reassessing Policy Drift: Social Policy Change in the United States
Authors: Béland Daniel , Rocco Philip , Waddan Alex
Published: February 2016

As formulated by Jacob Hacker, the concept of policy drift turned institutional theories of public policy on their heads by suggesting that consequential policy changes often happen in the absence of reform. Especially prevalent in times of political gridlock or stasis, policy drift is a useful concept for capturing how inaction can gradually diminish the effectiveness of social programmes over time. By highlighting cases of difficult‐to‐see policy inaction, however, Hacker's concept sets a high bar for empirical scholarship. In this article, we suggest that analyzing policy drift requires attention to comparative policy outcomes, the implementation of reforms intended to alleviate drift, and the time frame of the study. With these insights in mind, we analyze the impact of drift on US retirement security and health care coverage to reflect policy changes that have occurred since Hacker's original analysis was published.
Corticosteroid use as adjunct therapy for respiratory syncytial virus infection in adult allogeneic stem cell transplant recipients
Authors: Damlaj M. , Bartoo G. , Cartin‐Ceba R. , Gijima D. , Alkhateeb H.B. , Merten J. , Hashmi S. , Litzow M. , Gastineau D. , Hogan W. , Patnaik M.M.
Published: February 2016

Background

Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in allogeneic stem cell transplant (allo‐SCT) recipients. Although ribavirin and immunoglobulins are common components of therapy, the role of adjunct corticosteroids is not established.

Objectives

We sought to evaluate corticosteroid utilization in the setting of post‐allo‐SCT RSV infection in our center and assess post‐transplant outcomes including pulmonary function decline.

Methods

Patients with a history of RSV infection from 2008 to 2014 seen at our institution were identified. Treatment and outcome data were retrospectively collected. Forced expiratory volume at 1 s (FEV1) and carbon monoxide diffusion capacity (DLCO) were collected pre‐ and post‐RSV infection.

Results

During the observation period, RSV was isolated in 53 of 552 patients undergoing allo‐SCT (10%) and 45 had evaluable therapy data. RSV‐related mortality in this cohort was 4/45 (9%). Twenty‐one (47%) were on corticosteroids prior to RSV diagnosis, of whom 11 (24%) had a dose increase post symptom onset. Eight (18%) patients were started on corticosteroids at the time of RSV infection. Corticosteroid therapy at symptom onset was associated with a higher rate of upper respiratory infection (URTI) to lower respiratory infection (LRTI) progression risk ratio (RR) 2.49 (1.21–5.13; P = 0.016), hospital admission RR 2.05 (1.24–3.37; P = 0.005), or intensive care unit admission RR 2.91 (1.89–5.01; P = 0.002). No significant difference was seen with FEV1 and DLCO decline (P = 0.3 and 0.24, respectively) or mortality (P = 0.26).

Conclusion

Adjunct corticosteroid use in the setting of RSV infection did not improve RSV‐related outcomes including long‐term pulmonary function. Our results do not support the routine use of corticosteroids; however, this finding does need to be verified in a larger cohort of patients.
L‐type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes
Authors: Kabir Z. D. , Lee A. S. , Rajadhyaksha A. M.
Published: February 2016

Brain Cav1.2 and Cav1.3 L‐type Ca2+ channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Cav1.2 and Cav1.3 Ca2+ signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour‐based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice.

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Intelligent Classifier Approach for Prediction and Sensitivity Analysis of Differential Pipe Sticking: A Comparative Study
Authors: Jahanbakhshi Reza , Keshavarzi Reza
Published: February 2016

Prediction of differential pipe sticking (DPS) prior to occurrence, and taking preventive measures, is one of the best approaches to minimize the risk of DPS. In this paper, probabilistic artificial neural network (ANN) has been introduced. Moreover, conventional ANNs through multilayer perceptron (MLP) and radial basis function (RBF) have been used to compare with probabilistic ANN. Furthermore, to determine the most important parameters, forward selection sensitivity analysis has been applied. By predicting DPS and performing sensitivity analysis, it is possible to improve well planning process. The results from the analyses have shown the better potentiality of the probabilistic ANN in this area.
Modeling Sliding Contact Temperatures, Including Effects of Surface Roughness and Convection
Authors: Kennedy F. E. , Tian X.
Published: February 2016

The ability to predict contact surface temperatures in rolling/sliding contacting bodies is important if failure of tribological components is to be avoided. Many works on surface temperature analysis and prediction have been published over the past 75 years or so, but most of the analytical solutions that are readily available do not include such important factors as finite body geometry, surface roughness, or convective cooling. Approaches for addressing these deficiencies are presented in this paper. This paper builds on previous analytical work by the authors and others, and presents models that are based on experimental observations of contact temperatures and factors that affect them. It is shown that the total surface temperature rise above ambient temperature is the sum of nominal temperature rise and flash temperature rise. Models are developed for calculating nominal surface temperature rise for sliding bodies of finite size, including effects of both convection and conduction. Flash temperature models are developed for both single and multiple contacts, as would be found with rough surfaces. Methods are presented that are valid for a variety of geometries and kinematic operating conditions, and techniques are also presented for partitioning the frictional heat between the two contacting surfaces. Examples of the use of the methodology are presented, along with experimental verification of the predictions.
A Monte Carlo study on the collimation of pencil beam scanning proton therapy beams
Authors: Charlwood Frances C. , Aitkenhead Adam H. , Mackay Ranald I.
Published: February 2016

Purpose:

The lateral edge of a proton therapy beam is commonly used to achieve conformality to the treatment volume where critical structures reside close to the target. However, when treating shallow depths, the lateral edge of a pencil beam scanning (PBS) system may be broader than that of a double scattered (DS) system. Use of a range‐shifter to degrade the beam and allow treatment of very shallow depths further blurs the lateral edge. The authors investigate the potential use of a collimator with a PBS system for delivery of 3D uniform dose–volumes to a water‐tank phantom, identifying the key factors controlling the width of the lateral edge.

Methods:

The geant4 application for tomographic emission (gate) Monte Carlo (MC) environment was used, following validation against previously published data. Key parameters for PBS beams were investigated to assess their impact on the lateral edge of both monoenergetic beams and uniform dose–volumes. These parameters included nozzle‐to‐surface distance (NSD), vacuum window‐to‐surface distance (VSD), use of a range‐shifter, and spot optimization parameters.

Results:

The lateral edge of an uncollimated PBS beam is particularly sensitive to VSD and NSD. While use of a range‐shifter blurs the lateral edge, collimation allows the edge to be sharpened to between 2 and 4 mm depending on the depth of the target. Optimization of the spot weightings alone can provide a penumbral width close to that of a single spot, but also leads to poorer uniformity near the edge of the target volume.

Conclusions:

Collimation of PBS beams should be considered for superficial targets particularly for beams delivered through a range‐shifter, since the resultant sharpening of the lateral edge will allow improved sparing of adjacent normal tissues. Further work is needed to develop collimators which are integrated into both nozzle designs and planning system optimization algorithms.
Technical Note: Relationships between gamma criteria and action levels: Results of a multicenter audit of gamma agreement index results
Authors: Crowe Scott B. , Sutherland Bess , Wilks Rachael , Seshadri Venkatakrishnan , Sylvander Steven , Trapp Jamie V. , Kairn Tanya
Published: February 2016

Purpose:

The aim of this work was to use a multicenter audit of modulated radiotherapy quality assurance (QA) data to provide a practical examination of gamma evaluation criteria and action level selection. The use of the gamma evaluation method for patient‐specific pretreatment QA is widespread, with most commercial solutions implementing the method.

Methods:

Gamma agreement indices were calculated using the criteria 1%/1 mm, 2%/2 mm, 2%/3 mm, 3%/2 mm, 3%/3 mm, and 5%/3 mm for 1265 pretreatment QA measurements, planned at seven treatment centers, using four different treatment planning systems, delivered using three different delivery systems (intensity‐modulated radiation therapy, volumetric‐modulated arc therapy, and helical tomotherapy) and measured using three different dose measurement systems. The sensitivity of each pair of gamma criteria was evaluated relative to the gamma agreement indices calculated using 3%/3 mm.

Results:

A linear relationship was observed for 2%/2 mm, 2%/3 mm, and 3%/2 mm. This result implies that most beams failing at 3%/3 mm would also fail for those criteria, if the action level was adjusted appropriately. Some borderline plans might be passed or failed depending on the relative priority (tighter tolerance) used for dose difference or distance to agreement evaluation. Dosimeter resolution and treatment modality were found to have a smaller effect on the results of QA measurements than the number of dimensions (2D or 3D) over which the gamma evaluation was calculated.

Conclusions:

This work provides a method (and a large sample of results) for calculating equivalent action levels for different gamma evaluation criteria. This work constitutes a valuable guide for clinical decision making and a means to compare published gamma evaluation results from studies using different evaluation criteria. More generally, the data provided by this work support the recommendation that gamma criteria that specifically prioritize the property of greatest clinical importance for each treatment modality of anatomical site should be selected when using gamma evaluations for modulated radiotherapy QA. It is therefore suggested that departments using the gamma evaluation as a QA analysis tool should consider the relative importance of dose difference and distance to agreement, when selecting gamma evaluation criteria.
Nature from nurture
Authors: Normile Dennis
Published: February 2016

As Japan's rice paddies go fallow, biodiversity suffers—raising questions about rewilding strategies the world over.
Mechanistic Analysis of the Effect of Deamidation on the Immunogenicity of Anthrax Protective Antigen
Authors: Verma Anita , Ngundi Miriam M. , Burns Drusilla L.
Published: February 2016

The spontaneous modification of proteins, such as deamidation of asparagine residues, can significantly affect the immunogenicity of protein-based vaccines. Using a “genetically deamidated” form of recombinant protective antigen (rPA), we have previously shown that deamidation can decrease the immunogenicity of rPA, the primary component of new-generation anthrax vaccines. In this study, we investigated the biochemical and immunological mechanisms by which deamidation of rPA might decrease the immunogenicity of the protein. We found that loss of the immunogenicity of rPA vaccine was independent of the presence of adjuvant. We assessed the effect of deamidation on the immunodominant neutralizing B-cell epitopes of rPA and found that these epitopes were not significantly affected by deamidation. In order to assess the effect of deamidation on T-cell help for antibody production elicited by rPA vaccine, we examined the ability of the wild-type and genetically deamidated forms of rPA to serve as hapten carriers. We found that when wild-type and genetically deamidated rPA were modified to similar extents with 2,4-dinitrophenyl hapten (DNP) and then used to immunize mice, higher levels of anti-DNP antibodies were elicited by wild-type DNP-rPA than those elicited by the genetically deamidated DNP-rPA, indicating that wild-type rPA elicits more T-cell help than the genetically deamidated form of the protein. These results suggest that a decrease in the ability of deamidated rPA to elicit T-cell help for antibody production is a possible contributor to its lower immunogenicity.
Evaluation of an IgG Enzyme-Linked Immunosorbent Assay as a Serological Assay for Detection of Mycoplasma bovis Infection in Feedlot Cattle
Authors: Wawegama Nadeeka K. , Markham Philip F. , Kanci Anna , Schibrowski Meghan , Oswin Sally , Barnes Tamsin S. , Firestone Simon M. , Mahony Timothy J. , Browning Glenn F.
Published: February 2016

Mycoplasma bovisis a pathogen of emerging significance in cattle throughout the world that is causing a range of diseases, including mastitis, arthritis, and pneumonia. The limited availability and efficacy of current diagnostic and prophylactic tools for its control and its increasing antimicrobial resistance are contributing to its increasing importance in beef and dairy cattle. We have developed an indirect IgG enzyme-linked immunosorbent assay (ELISA) based on a recombinant fragment of the MilA protein and have shown its potential as an effective diagnostic tool. To more comprehensively estimate the diagnostic sensitivity and specificity of this IgG ELISA for detection of infection withM. bovisin cattle and to define a suitable cutoff for use in the field, we further assessed its performance in experimentally infected calves in a closed beef herd and by applying Bayesian latent class modeling to laboratory testing results from 7,448 cattle entering Australian feedlots. The most effective cutoff points were estimated to be 68.6 antibody units (AU) for experimentally infected calves and to be 58.7 AU for a closed adult herd. Under field conditions, in feedlot cattle the globally optimal cutoff was estimated to be 105 AU. At this cutoff, the diagnostic sensitivity was 94.3% (95% probability interval [PI], 89.9% to 99.6%) with a diagnostic specificity of 94.4% (95% PI, 90.3% to 99.6%). Applying this 105 AU cutoff, 13.1% of cattle were seropositive for infection withM. bovison entry into feedlots, and 73.5% were seropositive when followed up approximately 6 weeks later suggesting a high risk of infection shortly after entry into feedlots.
Development of Rapid Enzyme-Linked Immunosorbent Assays for Detection of Antibodies to Burkholderia pseudomallei
Authors: Suttisunhakul Vichaya , Wuthiekanun Vanaporn , Brett Paul J. , Khusmith Srisin , Day Nicholas P. J. , Burtnick Mary N. , Limmathurotsakul Direk , Chantratita Narisara
Published: February 2016

Burkholderia pseudomallei
, the causative agent of melioidosis, is an environmental bacillus found in northeast Thailand. The mortality rate of melioidosis is ∼40%. An indirect hemagglutination assay (IHA) is used as a reference serodiagnostic test; however, it has low specificity in areas where the background seropositivity of healthy people is high. To improve assay specificity and reduce the time for diagnosis, four rapid enzyme-linked immunosorbent assays (ELISAs) were developed using two purified polysaccharide antigens (O-polysaccharide [OPS] and 6-deoxyheptan capsular polysaccharide [CPS]) and two crude antigens (whole-cell [WC] antigen and culture filtrate [CF] antigen) of
B. pseudomallei
. The ELISAs were evaluated using serum samples from 141 culture-confirmed melioidosis patients from Thailand along with 188 healthy donors from Thailand and 90 healthy donors from the United States as controls. The areas under receiver operator characteristic curves (AUROCC) using Thai controls were high for the OPS-ELISA (0.91), CF-ELISA (0.91), and WC-ELISA (0.90), while those of CPS-ELISA (0.84) and IHA (0.72) were lower. AUROCC values using U.S. controls were comparable to those of the Thai controls for all ELISAs except IHA (0.93). Using a cutoff optical density (OD) of 0.87, the OPS-ELISA had a sensitivity of 71.6% and a specificity of 95.7% for Thai controls; for U.S. controls, specificity was 96.7%. An additional 120 serum samples from tuberculosis, scrub typhus, or leptospirosis patients were evaluated in all ELISAs and resulted in comparable or higher specificities than using Thai healthy donors. Our findings suggest that antigen-specific ELISAs, particularly the OPS-ELISA, may be useful for serodiagnosis of melioidosis in areas where it is endemic and nonendemic.
Multicenter Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Study for Identification of Clinically Relevant Nocardia spp
Authors: Blosser Sara J. , Drake Steven K. , Andrasko Jennifer L. , Henderson Christina M. , Kamboj Kamal , Antonara Stella , Mijares Lilia , Conville Patricia , Frank Karen M. , Harrington Susan M. , Balada-Llasat Joan-Miquel , Zelazny Adrian M.
Published: February 2016

This multicenter study analyzed
Nocardia
spp., including extraction, spectral acquisition, Bruker matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identification, and score interpretation, using three
Nocardia
libraries, the Bruker, National Institutes of Health (NIH), and The Ohio State University (OSU) libraries, and compared the results obtained by each center. A standardized study protocol, 150
Nocardia
isolates, and NIH and OSU
Nocardia
MALDI-TOF MS libraries were distributed to three centers. Following standardized culture, extraction, and MALDI-TOF MS analysis, isolates were identified using score cutoffs of ≥2.0 for species/species complex-level identification and ≥1.8 for genus-level identification. Isolates yielding a score of <2.0 underwent a single repeat extraction and analysis. The overall score range for all centers was 1.3 to 2.7 (average, 2.2 ± 0.3), with common species generally producing higher average scores than less common ones. Score categorization and isolate identification demonstrated 86% agreement between centers; 118 of 150 isolates were correctly identified to the species/species complex level by all centers. Nine strains (6.0%) were not identified by any center, and six (4.0%) of these were uncommon species with limited library representation. A categorical score discrepancy among centers occurred for 21 isolates (14.0%). There was an overall benefit of 21.2% from repeat extraction of low-scoring isolates and a center-dependent benefit for duplicate spotting (range, 2 to 8.7%). Finally, supplementation of the Bruker
Nocardia
MALDI-TOF MS library with both the OSU and NIH libraries increased the genus-level and species-level identification by 18.2% and 36.9%, respectively. Overall, this study demonstrates the ability of diverse clinical microbiology laboratories to utilize MALDI-TOF MS for the rapid identification of clinically relevant
Nocardia
spp. and to implement MALDI-TOF MS libraries developed by single laboratories across institutions.
Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Accelerates Pathogen Identification and May Confer Benefit in the Outcome of Peritoneal Dialysis-Related Peritonitis
Authors: Lin Wei-Hung , Hwang Jyh-Chang , Tseng Chin-Chung , Chang Yu-Tzu , Wu An-Bang , Yan Jing-Jou , Wu Jiunn-Jong , Wang Ming-Cheng
Published: February 2016

Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and conventional standard methods were compared for time to pathogen identification and impact on clinical outcomes in peritoneal dialysis-related peritonitis patients. The MALDI-TOF MS method identified the causative microorganisms earlier (average time saved, 64 h for all pathogens), and patients had a shorter hospital stay (mean ± standard deviation, 5.2 ± 4.8 days versus 8.2 ± 4.5 days,
P
= 0.001).
Domain Organization of Vaccinia Virus Helicase-Primase D5
Authors: Hutin Stephanie , Ling Wai Li , Round Adam , Effantin Gregory , Reich Stefan , Iseni Frédéric , Tarbouriech Nicolas , Schoehn Guy , Burmeister Wim Pascal
Published: February 2016

Poxviridae
are viruses with a large linear double-stranded DNA genome coding for up to 250 open reading frames and a fully cytoplasmic replication. The double-stranded DNA genome is covalently circularized at both ends. Similar structures of covalently linked extremities of the linear DNA genome are found in the African swine fever virus (asfarvirus) and in the
Phycodnaviridae
. We are studying the machinery which replicates this peculiar genome structure. From our work with vaccinia virus, we give first insights into the overall structure and function of the essential poxvirus virus helicase-primase D5 and show that the active helicase domain of D5 builds a hexameric ring structure. This hexamer has ATPase and, more generally, nucleoside triphosphatase activities that are indistinguishable from the activities of full-length D5 and that are independent of the nature of the base. In addition, hexameric helicase domains bind tightly to single- and double-stranded DNA. Still, the monomeric D5 helicase construct truncated within the D5N domain leads to a well-defined structure, but it does not have ATPase or DNA-binding activity. This shows that the full D5N domain has to be present for hexamerization. This allowed us to assign a function to the D5N domain which is present not only in D5 but also in other viruses of the nucleocytoplasmic large DNA virus (NCLDV) clade. The primase domain and the helicase domain were structurally analyzed via a combination of small-angle X-ray scattering and, when appropriate, electron microscopy, leading to consistent low-resolution models of the different proteins.

IMPORTANCE
Since the beginning of the 1980s, research on the vaccinia virus replication mechanism has basically stalled due to the absence of structural information. As a result, this important class of pathogens is less well understood than most other viruses. This lack of information concerns in general viruses of the NCLDV clade, which use a superfamily 3 helicase for replication, as do poxviruses. Here we provide for the first time information about the domain structure and DNA-binding activity of D5, the poxvirus helicase-primase. This result not only refines the current model of the poxvirus replication fork but also will lead in the long run to a structural basis for antiviral drug design.
Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells
Authors: Nagesh Prashanth Thevkar , Husain Matloob
Published: February 2016

Viruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response.

IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response.
Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection
Authors: Swann Rachael E. , Cowton Vanessa M. , Robinson Mark W. , Cole Sarah J. , Barclay Stephen T. , Mills Peter R. , Thomson Emma C. , McLauchlan John , Patel Arvind H.
Published: February 2016

During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (
P
= 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (
n
= 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (
P
= 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the
HLA-DQB1
gene (
P
= 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses.

IMPORTANCE
Globally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies.
Uncommon mycosis in a patient with diabetes
Authors: Prasad Kuruswamy Thurai , Sehgal Inderpaul Singh , Shivaprakash M R , Dhooria Sahajal
Published: February 2016

Cryptococcosis is a fungal infection that usually occurs in immunocompromised individuals. Meningitis is the most frequent presentation; uncommonly, a disseminated form occurs. Cryptococcosis can sometimes occur in immunocompetent individuals with certain predisposing conditions such as diabetes mellitus. However, disseminated cryptococcosis is exceedingly rare in these individuals. A 48-year-old man presented with a lung mass and was initially suspected to have bronchogenic carcinoma. However, on further evaluation, it turned out to be disseminated cryptococcosis due toCryptococcus gattii, with pulmonary, pleural and meningeal involvement.
Mobile revolution: a requiem for bleeps?
Authors: Martin Guy , Janardhanan Pradeep , Withers Tristan , Gupta Sanjay
Published: February 2016

Objectives

Effective communication is a vital part of good clinical care. Traditionally bleep systems have been used as the mainstay of communication. Mobile technology is increasingly seen as a quicker, easier and more reliable method of communication. Our objective was to assess the use of mobile devices within a typical National Health Service (NHS) hospital, discuss potential benefits and pitfalls, and develop suggestions for future improvements.

Methods

A survey of 600 hospital doctors was conducted in a large NHS district general hospital between 1 May and 30 June 2015. The questionnaire explored the patterns of use, attitudes and impact of mobile communication, and identified potential risks and benefits of its wider adoption within the NHS.

Results

92% of doctors use their personal mobile for hospital-related work. 95% share their personal number with colleagues, and 64% have it available through hospital switchboard. 77% use their personal mobile to discuss patient matters, and 48% are prevented from communicating effectively due to poor signal within the hospital. 90% are contacted when not at work on a weekly or daily basis regarding patients. 73% feel that traditional bleeps should be replaced with new mobile technologies.

Conclusions

Mobile phone usage is very common among doctors, and is the preferred method of communication within the hospital. Mobile technology has the potential to revolutionise communication and clinical care and should be embraced. The introduction of new technology will inevitably change existing hospital dynamics, and consequently may create a new set of challenges that will require further work to explore in the future.
Characterizing phosphorus removal in passive waste stabilization ponds in Arctic communities
Authors: Schmidt Jordan J. , Ragush Colin M. , Krkosek Wendy H. , Gagnon Graham A. , Jamieson Rob C.
Published: February 2016

A majority of communities in the Canadian territory of Nunavut rely on passive waste stabilization ponds (WSPs) for domestic wastewater treatment. Little research has been conducted on the treatment performance of these systems. Therefore, in response to impending federal wastewater regulations, a research program was conducted in order to characterize contaminant removal, with phosphorus a contaminant of particular concern. The performance of WSPs in the Arctic communities of Kugaaruk, Pond Inlet, Grise Fiord, and Clyde River was evaluated from 2011 to 2014. Removal of total phosphorus was highly variable, ranging from 24% (Pond Inlet, 2014) to 76% (Grise Fiord, 2011). The average removal efficiency was 44%. Effluent total phosphorus concentrations generally exceeded 7 mg P/L, partly due to elevated raw wastewater concentrations. Over the course of the treatment season (defined as June to September, when the WSP is thawed), limited additional total phosphorus removal was observed. A fractionation analysis of WSP sediments showed that organic phosphorus and phosphorus bound to aluminum and iron were the predominant forms, which provided insight into primary treatment mechanisms. Further studies on these mechanisms are needed in order to optimize Arctic WSP treatment.
Mass chains of light hypernuclei and separation energies of mirror hypernuclei from BWMH mass formula
Authors: Armat Aida , Hassanabadi Hassan
Published: February 2016

In this work, by using generalized semi-empirical mass formula, decay chains of light hypernuclei for odd-A and even-A are calculated and the unstable hypernuclei of mass chains are presented. The separation energy per baryon of the mirror hypernuclei is obtained.
Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines
Authors: Zhao Yan , Wang Xinyu , Li Lei , Li Changzhong
Published: February 2016

The clinical management of cervical cancer remains a challenge and the development of new treatment strategies merits attention. However, the discovery and development of novel compounds can be a long and labourious process. Drug repositioning may circumvent this process and facilitate the rapid translation of hypothesis-driven science into the clinics. In this work, we show that a FDA-approved antibiotic, doxycycline, effectively targets human papillomavirus (HPV) positive and negative cervical cancer cells in vitro and in vivo. Doxycycline significantly inhibits proliferation of a panel of cervical cancer cell lines. It also induces apoptosis of cervical cancer cells in a time- and dose-dependent manner. In addition, the apoptosis induced by doxycycline is through caspase-dependent pathway. Mechanism studies demonstrate that doxycycline affects oxygen consumption rate, glycolysis, and reduces ATP levels in cervical cancer cells. In HeLa xenograft mouse model, doxycycline significantly inhibits growth of tumour. Our in vitro and in vivo data clearly demonstrate the inhibitory effects of doxycycline on the growth and survival of cervical cancer cells. Our work provides the evidence that doxycycline can be repurposed for the treatment of cervical cancer and targeting energy metabolism may represent a potential therapeutic strategy for cervical cancer.