bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and Metabolic Adaptations of Lactococcus lactis at Near-Zero Growth Rates
Authors: Ercan Onur , Wels Michiel , Smid Eddy J. , Kleerebezem Michiel
Published: October 2014

This paper describes the molecular and metabolic adaptations of
Lactococcus lactis
during the transition from a growing to a near-zero growth state by using carbon-limited retentostat cultivation. Transcriptomic analyses revealed that metabolic patterns shifted between lactic- and mixed-acid fermentations during retentostat cultivation, which appeared to be controlled at the level of transcription of the corresponding pyruvate dissipation-encoding genes. During retentostat cultivation, cells continued to consume several amino acids but also produced specific amino acids, which may derive from the conversion of glycolytic intermediates. We identify a novel motif containing CTGTCAG in the upstream regions of several genes related to amino acid conversion, which we propose to be the target site for CodY in
L. lactis
KF147. Finally, under extremely low carbon availability, carbon catabolite repression was progressively relieved and alternative catabolic functions were found to be highly expressed, which was confirmed by enhanced initial acidification rates on various sugars in cells obtained from near-zero-growth cultures. The present integrated transcriptome and metabolite (amino acids and previously reported fermentation end products) study provides molecular understanding of the adaptation of
L. lactis
to conditions supporting low growth rates and expands our earlier analysis of the quantitative physiology of this bacterium at near-zero growth rates toward gene regulation patterns involved in zero-growth adaptation.
Inactivation of a
GAL4
-Like Transcription Factor Improves Cell Fitness and Product Yield in Glycoengineered Pichia pastoris Strains
Authors: Jiang Bo , Argyros Rebecca , Bukowski John , Nelson Stephanie , Sharkey Nathan , Kim Sehoon , Copeland Victoria , Davidson Robert C. , Chen Ronghua , Zhuang Jun , Sethuraman Natarajan , Stadheim Terrance A.
Published: October 2014

With a completely reengineered and humanized glycosylation pathway, glycoengineered
Pichia pastoris
has emerged as a promising production host for the manufacture of therapeutic glycoproteins. However, the extensive genetic modifications have also negatively affected the overall fitness levels of the glycoengineered host cells. To make glycoengineered
Pichia
strains more compatible with a scalable industrial fermentation process, we sought to identify genetic solutions to broadly improve cell robustness during fermentation. In this study, we report that mutations within the
Pichia pastoris
ATT1
(
PpATT1
) gene (a homolog of the
Saccharomyces cerevisiae
GAL4
[
ScGAL4
] transcriptional activator) dramatically increased the cellular fitness levels of glycoengineered
Pichia
strains. We demonstrate that deletion of the
PpATT1
gene enabled glycoengineered
Pichia
strains to improve their thermal tolerance levels, reduce their cell lysis defects, and greatly improve fermentation robustness. The extension of the duration of fermentation enabled the
PpATT1
-modified glycoengineered
Pichia
strains to increase their product yields significantly without any sacrifice in product quality. Because the
ATT1
gene could be deleted from any
Pichia
strains, including empty hosts and protein-expressing production strains alike, we suggest that the findings described in this study are broadly applicable to any
Pichia
strains used for the production of therapeutic proteins, including monoclonal antibodies, Fc fusions, peptides, hormones, and growth factors.
Rotavirus Genotypes in Sewage Treatment Plants and in Children Hospitalized with Acute Diarrhea in Italy in 2010 and 2011
Authors: Ruggeri Franco M. , Bonomo Paolo , Ianiro Giovanni , Battistone Andrea , Delogu Roberto , Germinario Cinzia , Chironna Maria , Triassi Maria , Campagnuolo Rosalba , Cicala Antonella , Giammanco Giovanni M. , Castiglia Paolo , Serra Caterina , Gaggioli Andrea , Fiore Lucia
Published: October 2014

Although the molecular surveillance network RotaNet-Italy provides useful nationwide data on rotaviruses causing severe acute gastroenteritis in children in Italy, scarce information is available on rotavirus circulation in the general Italian population, including adults with mild or asymptomatic infection. We investigated the genotypes of rotaviruses present in urban wastewaters and compared them with those of viral strains from clinical pediatric cases. During 2010 and 2011, 285 sewage samples from 4 Italian cities were tested by reverse transcription-PCRs (RT-PCRs) specific for rotavirus VP7 and VP4 genes. Rotavirus was detected in 172 (60.4%) samples, 26 of which contained multiple rotavirus G (VP7 gene) genotypes, for a total of 198 G types. Thirty-two samples also contained multiple P (VP4 gene) genotypes, yielding 204 P types in 172 samples. Genotype G1 accounted for 65.6% of rotaviruses typed, followed by genotypes G2 (20.2%), G9 (7.6%), G4 (4.6%), G6 (1.0%), G3 (0.5%), and G26 (0.5%). VP4 genotype P[8] accounted for 75.0% of strains, genotype P[4] accounted for 23.0% of strains, and the uncommon genotypes P[6], P[9], P[14], and P[19] accounted for 2.0% of strains altogether. These rotavirus genotypes were also found in pediatric patients hospitalized in the same areas and years but in different proportions. Specifically, genotypes G2, G9, and P[4] were more prevalent in sewage samples than among samples from patients, which suggests either a larger circulation of the latter strains through the general population not requiring medical care or their greater survival in wastewaters. A high level of nucleotide identity in the G1, G2, and G6 VP7 sequences was observed between strains from the environment and those from patients.
Uptake of Amino Acids and Their Metabolic Conversion into the Compatible Solute Proline Confers Osmoprotection to Bacillus subtilis
Authors: Zaprasis Adrienne , Bleisteiner Monika , Kerres Anne , Hoffmann Tamara , Bremer Erhard
Published: October 2014

The data presented here reveal a new facet of the physiological adjustment processes through which
Bacillus subtilis
can derive osmostress protection. We found that the import of proteogenic (Glu, Gln, Asp, Asn, and Arg) and of nonproteogenic (Orn and Cit) amino acids and their metabolic conversion into proline enhances growth under otherwise osmotically unfavorable conditions. Osmoprotection by amino acids depends on the functioning of the ProJ-ProA-ProH enzymes, but different entry points into this biosynthetic route are used by different amino acids to finally yield the compatible solute proline. Glu, Gln, Asp, and Asn are used to replenish the cellular pool of glutamate, the precursor for proline production, whereas Arg, Orn, and Cit are converted into γ-glutamic semialdehyde/Δ
1
-pyrroline-5-carboxylate, an intermediate in proline biosynthesis. The import of Glu, Gln, Asp, Asn, Arg, Orn, and Cit did not lead to a further increase in the size of the proline pool that is already present in osmotically stressed cells. Hence, our data suggest that osmoprotection of
B. subtilis
by this group of amino acids rests on the savings in biosynthetic building blocks and energy that would otherwise have to be devoted either to the synthesis of the proline precursor glutamate or of proline itself. Since glutamate is the direct biosynthetic precursor for proline, we studied its uptake and found that GltT, an Na
+
-coupled symporter, is the main uptake system for both glutamate and aspartate in
B. subtilis
. Collectively, our data show how effectively
B. subtilis
can exploit environmental resources to derive osmotic-stress protection through physiological means.
A Novel DNA-Binding Protein, PhaR, Plays a Central Role in the Regulation of Polyhydroxyalkanoate Accumulation and Granule Formation in the Haloarchaeon Haloferax mediterranei
Authors: Cai Shuangfeng , Cai Lei , Zhao Dahe , Liu Guiming , Han Jing , Zhou Jian , Xiang Hua
Published: October 2014

Polyhydroxyalkanoates (PHAs) are synthesized and assembled as PHA granules that undergo well-regulated formation in many microorganisms. However, this regulation remains unclear in haloarchaea. In this study, we identified a PHA granule-associated regulator (PhaR) that negatively regulates the expression of both its own gene and the granule structural gene
phaP
in the same operon (
phaRP
) in
Haloferax mediterranei
. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assays demonstrated a significant interaction between PhaR and the
phaRP
promoter
in vivo
. Scanning mutagenesis of the
phaRP
promoter revealed a specific
cis
-element as the possible binding position of the PhaR. The haloarchaeal homologs of the PhaR contain a novel conserved domain that belongs to a swapped-hairpin barrel fold family found in AbrB-like proteins. Amino acid substitution indicated that this AbrB-like domain is critical for the repression activity of PhaR. In addition, the
phaRP
promoter had a weaker activity in the PHA-negative strains, implying a function of the PHA granules in titration of the PhaR. Moreover, the
H. mediterranei
strain lacking
phaR
was deficient in PHA accumulation and produced granules with irregular shapes. Interestingly, the PhaR itself can promote PHA synthesis and granule formation in a PhaP-independent manner. Collectively, our results demonstrated that the haloarchaeal PhaR is a novel bifunctional protein that plays the central role in the regulation of PHA accumulation and granule formation in
H. mediterranei
.
Effects of Actin-Like Proteins Encoded by Two Bacillus pumilus Phages on Unstable Lysogeny, Revealed by Genomic Analysis
Authors: Yuan Yihui , Peng Qin , Wu Dandan , Kou Zheng , Wu Yan , Liu Pengming , Gao Meiying
Published: October 2014

We characterized two newly isolated myoviruses, Bp8p-C and Bp8p-T, infecting the ginger rhizome rot disease pathogen
Bacillus pumilus
GR8. The plaque of Bp8p-T exhibited a clear center with a turbid rim, suggesting that Bp8p-T could transform into latent phage. Lysogeny assays showed that both the two phages could form latent states, while Bp8p-T could form latent phage at a higher frequency and stability than Bp8p-C. The genomes of Bp8p-C and Bp8p-T were 151,417 and 151,419 bp, respectively; both encoded 212 putative proteins, and only differed by three nucleotides. Moreover, owing to this difference, Bp8p-C encoded a truncated, putative actin-like plasmid segregation protein Gp27-C. Functional analysis of protein Gp27 showed that Gp27-T encoded by Bp8p-T exhibited higher ATPase activity and assembly ability than Gp27-C. The results indicate that the difference in Gp27 affected the phage lysogenic ability. Structural proteome analysis of Bp8p-C virion resulted in the identification of 14 structural proteins, among which a pectin lyase-like protein, a putative poly-gamma-glutamate hydrolase, and three proteins with unknown function, were firstly identified as components of the phage virion. Both phages exhibited specific lytic ability to the host strain GR8. Bp8p-C showed better control effect on the pathogen in ginger rhizome slices than Bp8p-T, suggesting that Bp8p-C has a potential application in bio-control of ginger rhizome rot disease.
Mortalities of Eastern and Pacific Oyster Larvae Caused by the Pathogens Vibrio coralliilyticus and Vibrio tubiashii
Authors: Richards Gary P. , Watson Michael A. , Needleman David S. , Church Karlee M. , Häse Claudia C.
Published: October 2014

Vibrio tubiashii
is reported to be a bacterial pathogen of larval Eastern oysters (
Crassostrea virginica
) and Pacific oysters (
Crassostrea gigas
) and has been associated with major hatchery crashes, causing shortages in seed oysters for commercial shellfish producers. Another bacterium,
Vibrio coralliilyticus
, a well-known coral pathogen, has recently been shown to elicit mortality in fish and shellfish. Several strains of
V. coralliilyticus
, such as ATCC 19105 and Pacific isolates RE22 and RE98, were misidentified as
V. tubiashii
until recently. We compared the mortalities caused by two
V. tubiashii
and four
V. coralliilyticus
strains in Eastern and Pacific oyster larvae. The 50% lethal dose (LD
50
) of
V. coralliilyticus
in Eastern oysters (defined here as the dose required to kill 50% of the population in 6 days) ranged from 1.1 × 10
4
to 3.0 × 10
4
CFU/ml seawater; strains RE98 and RE22 were the most virulent. This study shows that
V. coralliilyticus
causes mortality in Eastern oyster larvae. Results for Pacific oysters were similar, with LD
50
s between 1.2 × 10
4
and 4.0 × 10
4
CFU/ml.
Vibrio tubiashii
ATCC 19106 and ATCC 19109 were highly infectious toward Eastern oyster larvae but were essentially nonpathogenic toward healthy Pacific oyster larvae at dosages of ≥1.1 × 10
4
CFU/ml. These data, coupled with the fact that several isolates originally thought to be
V. tubiashii
are actually
V. coralliilyticus
, suggest that
V. coralliilyticus
has been a more significant pathogen for larval bivalve shellfish than
V. tubiashii
, particularly on the U.S. West Coast, contributing to substantial hatchery-associated morbidity and mortality in recent years.
High Incidence of Preharvest Colonization of Huanglongbing-Symptomatic Citrus sinensis Fruit by Lasiodiplodia theobromae (Diplodia natalensis) and Exacerbation of Postharvest Fruit Decay by That Fungus
Authors: Zhao Wei , Bai Jinhe , McCollum Greg , Baldwin Elizabeth
Published: October 2014

Huanglongbing (HLB), presumably caused by the bacterium “CandidatusLiberibacter asiaticus,” is a devastating citrus disease associated with excessive preharvest fruit drop.Lasiodiplodia theobromae(diplodia) is the causal organism of citrus stem end rot (SER). The pathogen infects citrus fruit under the calyx abscission zone (AZ-C) and is associated with cell wall hydrolytic enzymes similar to plant enzymes involved in abscission. By means of DNA sequencing, diplodia was found in “Ca. Liberibacter asiaticus”-positive juice from HLB-symptomatic fruit (S) but not in “Ca. Liberibacter asiaticus”-negative juice. Therefore, the incidence of diplodia in fruit tissues, the impact on HLB-related postharvest decay, and the implications for HLB-related preharvest fruit drop were investigated in Hamlin and Valencia oranges. Quantitative PCR results (qPCR) revealed a significantly (P< 0.001) greater incidence of diplodia in the AZ-C of HLB-symptomatic (S; “Ca. Liberibacter asiaticus” threshold cycle [CT] of <30) than in the AZ-C of in asymptomatic (AS; “Ca. Liberibacter asiaticus”CTof ≥30) fruit. In agreement with the qPCR results, 2 weeks after exposure to ethylene, the incidences of SER in S fruit were 66.7% (Hamlin) and 58.7% (Valencia), whereas for AS fruit the decay rates were 6.7% (Hamlin) and 5.3% (Valencia). Diplodia colonization of S fruit AZ-C was observed by scanning electron microscopy and confirmed by PCR test and morphology of conidia in isolates from the AZ-C after surface sterilization. DiplodiaCTvalues were negatively correlated with ethylene production (R= −0.838 for Hamlin;R= −0.858 for Valencia) in S fruit, and positively correlated with fruit detachment force (R= 0.855 for Hamlin;R= 0.850 for Valencia), suggesting that diplodia colonization in AZ-C may exacerbate HLB-associated preharvest fruit drop.
A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans
Authors: Liang Shen-Huan , Cheng Jen-Hua , Deng Fu-Sheng , Tsai Pei-An , Lin Ching-Hsuan
Published: October 2014

Candida albicans
is a commensal in heathy people but has the potential to become an opportunistic pathogen and is responsible for half of all clinical infections in immunocompromised patients. Central to understanding
C. albicans
behavior is the white-opaque phenotypic switch, in which cells can undergo an epigenetic transition between the white state and the opaque state. The phenotypic switch regulates multiple properties, including biofilm formation, virulence, mating, and fungus-host interactions. Switching between the white and opaque states is associated with many external stimuli, such as oxidative stress, pH, and
N
-acetylglucosamine, and is directly regulated by the Wor1 transcriptional circuit. The Hog1 stress-activated protein kinase (SAPK) pathway is recognized as the main pathway for adapting to environmental stress in
C. albicans
. In this work, we first show that loss of the
HOG1
gene in
a
/
a
and α/α cells, but not
a
/α cells, results in 100% white-to-opaque switching when cells are grown on synthetic medium, indicating that switching is repressed by the
a1
/α2 heterodimer that represses
WOR1
gene expression. Indeed, switching in the
hog1
Δ strain was dependent on the presence of
WOR1
, as a
hog1
Δ
wor1
Δ strain did not show switching to the opaque state. Deletion of
PBS2
and
SSK2
also resulted in
C. albicans
cells switching from white to opaque with 100% efficiency, indicating that the entire Hog1 SAPK pathway is involved in regulating this unique phenotypic transition. Interestingly, all Hog1 pathway mutants also caused defects in shmoo formation and mating efficiencies. Overall, this work reveals a novel role for the Hog1 SAPK pathway in regulating white-opaque switching and sexual behavior in
C. albicans
.
Organisational participation and health among smallholder farmers: a longitudinal study in a Latin American context
Authors: Orozco Fadya , Mota Eduardo , Cole Donald C
Published: October 2014

Objective

To understand the impact of social organisation affiliation and farmers’ agricultural production practices on farmer health. Organisations facilitate the acquisition and exchange of forms of social capital which can influence the adoption of practices with potential health impacts. In countries such as Ecuador, smallholder agriculture is practised by socially vulnerable populations. Agricultural production often involves the use of extremely hazardous pesticides, while practices that reduce the use of chemicals through integrated pest management (IPM) remain uncommon.

Design

Longitudinal study (2007–2010).

Setting

12 Ecuadorian communities, previously part of a participatory action research study.

Participants

208 small-scale farmers. Inclusion criteria were: age between 18 and 65 years, literate and resident in the community for the previous 3 years.

Primary outcomes

The differential effects of the membership in social organisations (as aneffect modifier), on the relationship between the implementation of IPM practices (main independent variable) and farmers’ health, measured by neurocognitive performance scores (better higher value;dependent variable).

Results

Among organisational participants, the coefficient of association between the implementation of IPM practices for the category good/very good (vs no use) and neurocognitive performance, when farmers were involved in organisations, was negative and moderate (β=−0.17, SE 0.21) though not significant (p>0.1); for the category little/moderate use, the coefficient was positive (β=0.34, SE 0.19) and significant. Among those who did not participate in organisations, both little/moderate use and good/very good use of IPM practices were associated with an increase in neurocognitive performance.

Conclusions

The effect of agricultural production practices on farmers’ health, transmitted through organisations, can be differentiated. Organisations as structures of social capital seem to be functional in the social reproduction process of the communities studied. Results highlight the need to redirect the analysis of social capital to a more integrated study of social determination of health.
Economic inequalities in burden of illness, diagnosis and treatment of five long-term conditions in England: panel study
Authors: Steel N , Hardcastle A C , Bachmann M O , Richards S H , Mounce L T A , Clark A , Lang I , Melzer D , Campbell J
Published: October 2014

Objective

We compared the distribution by wealth of self-reported illness burden (estimated from validated scales, biomarker and reported symptoms) for angina, cataract, depression, diabetes and osteoarthritis, with the distribution of self-reported medical diagnosis and treatment. We aimed to determine if the greater illness burden borne by poorer participants was matched by appropriately higher levels of diagnosis and treatment.

Design

The English Longitudinal Study of Ageing, a panel study of 12 765 participants aged 50 years and older in four waves from 2004 to 2011, selected using a stratified random sample of households in England. Distribution of illness burden, diagnosis and treatment by wealth was estimated using regression analysis.

Outcome measures

The main outcome measures were ORs for the illness burden, diagnosis and treatment, respectively, adjusted for age, sex and wealth. We estimated the illness burden for angina with the Rose Angina scale, diabetes with fasting glycosylated haemoglobin, depression with the Centre for Epidemiologic Studies Depression Scale, osteoarthritis with self-reported pain and disability and cataract with self-reported poor vision. Medical diagnoses were self-reported for all conditions. Treatment was defined as β-blocker prescription for angina, surgery for osteoarthritis and cataract, and receipt of predefined effective interventions for diabetes and depression.

Results

Compared with the wealthiest, the least wealthy participant had substantially higher odds for illness burden from any of the five conditions at all four time points, with ORs ranging from 4.2 (95% CI 2.6 to 6.8) for diabetes to 15.1 (11.4 to 20.0) for osteoarthritis. The ORs for diagnosis and treatment were smaller in all five conditions, and ranged from 0.9 (0.5 to 1.4) for diabetes treatment to 4.5 (3.3 to 6.0) for angina diagnosis.

Conclusions

The substantially higher illness burden in less wealthy participants was not matched by appropriately higher levels of diagnosis and treatment.
Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses
Authors: Simonsen Bjoerg O , Daehlin Gro K , Johansson Inger , Farup Per G
Published: October 2014

Introduction

Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods.

Methods

In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0–14), and a statement regarding the certainty of each answer (score 0–3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD).

Results

16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77).

Conclusions

The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching.
The General Weakness Syndrome Therapy (GymNAST) study: protocol for a cohort study on recovery on walking function
Authors: Mehrholz Jan , Mückel Simone , Oehmichen Frank , Pohl Marcus
Published: October 2014

Introduction

Critical illness myopathy (CIM) and polyneuropathy (CIP) are common complications of critical illness that frequently occur together. Both cause so called intensive care unit (ICU)-acquired muscle weakness. This weakness of limb muscles increases morbidity and delay rehabilitation and recovery of walking ability. Although full recovery has been reported people with severe weakness may take months to improve walking. Focused physical rehabilitation of people with ICU-acquired muscle weakness is therefore of great importance. However, although physical rehabilitation is common, detailed knowledge about the pattern and the time course of recovery of walking function are not well understood. Therefore, the aim of the General Weakness Syndrome Therapy (GymNAST) study is to describe the time course of recovery of walking function and other activities of daily living in these patients.

Methods and analysis

We conduct a prospective cohort study of people with ICU-acquired muscle weakness with defined diagnosis of CIM or CIP. Based on our sample size calculation, approximately 150 patients will be recruited from the ICU of our hospital in Germany. Amount and content of physical rehabilitation, clinical tests for example, muscle strength and motor function and neuropsychological assessments will be used as independent variables. The primary outcomes will include recovery of walking function and mobility. Secondary outcomes will include global motor function, activities in daily life and participation.

Ethics and dissemination

The study is being carried out in agreement with the Declaration of Helsinki and conducted with the approval of the local medical Ethics Committee (Landesärztekammer Sachsen, Germany, reference number EK-BR-32/13-1) and with the understanding and written consent of each patient's guardian. The results of this study will be published in peer-reviewed journals and disseminated to the medical society and general public.
How innovative are new drugs launched in the UK? A retrospective study of new drugs listed in the British National Formulary (BNF) 2001–2012
Authors: Ward Derek J , Slade Angharad , Genus Tracey , Martino Orsolina I , Stevens Andrew J
Published: October 2014

Objectives

Innovative new drugs offer potential benefits to patients, healthcare systems, governments and the pharmaceutical industry. Recent data suggest annual numbers of new drugs launched in the UK have increased in recent years, and we sought to understand whether this represents increasing numbers of highly innovative drugs being made available or the introduction of increasing numbers of drugs with limited additional therapeutic value.

Design and setting

Retrospective observational study of new drug entries in the British National Formulary (BNF).

Primary and secondary outcome measures

Number of new drugs launched in the UK each year (based on first appearance in the BNF) from 2001 to 2012, including new chemical entities and new biological drugs, categorised by degree of innovativeness according to published criteria that incorporate both clinical usefulness and the nature of the innovation.

Results

Highly innovative, moderately innovative and slightly innovative drugs made up 26%, 18% and 56% of all newly launched drugs, respectively, for the study period (n=290). There was an upward trend in annual numbers of slightly innovative drugs from 2004 onwards (R2=0.44), which aligned closely with the recovery in total numbers of new drugs launched each year since that time. There were no discernible time trends in the highly or moderately innovative categories. New drugs for malignancy and skin disease were most likely to be characterised as highly innovative (44% and 57%, respectively).

Conclusions

Highly innovative new drugs comprise only around a quarter of all new drug launches in the UK. In contrast, drugs categorised as only slightly innovative comprised well over half of all new drugs and annual numbers in this category are increasing. Current policy initiatives that seek to increase the supply of innovative new drugs have long-lead times to impact, and will need careful assessment to ensure they deliver their aims without unintended consequences.
Atrial fibrillation in Indigenous and non-Indigenous Australians: a cross-sectional study
Authors: Wong Christopher X , Brooks Anthony G , Cheng Yi-Han , Lau Dennis H , Rangnekar Geetanjali , Roberts-Thomson Kurt C , Kalman Jonathan M , Brown Alex , Sanders Prashanthan
Published: October 2014

Objective

To examine the prevalence of atrial fibrillation (AF) and cardiac structural characteristics in Indigenous and non-Indigenous Australians.

Design

Retrospective cross-sectional study linking clinical, echocardiography and administrative databases over a 10-year period.

Setting

A tertiary, university teaching hospital in Adelaide, Australia.

Participants

Indigenous and non-Indigenous Australians.

Main outcome measures

AF prevalence and echocardiographic characteristics.

Results

Indigenous Australians with AF were significantly younger compared to non-Indigenous Australians (55±13 vs 75±13 years, p<0.001). As a result, racial differences in AF prevalence and left atrial diameter varied according to age. In those under 60 years of age, Indigenous Australians had a significantly greater AF prevalence (2.57 vs1.73%, p<0.001) and left atrial diameters (39±7 vs 37±7 mm, p<0.001) compared to non-Indigenous Australians. In those aged 60 years and above, however, non-Indigenous Australians had significantly greater AF prevalence (9.26 vs 4.61%, p<0.001) and left atrial diameters (39±7 vs 37±7 mm, p<0.001). Left ventricular ejection fractions were less in Indigenous Australians under 60 years of age (49±14 vs 55±11%, p<0.001) and not statistically different in those aged 60 years and above (47±11 vs 52±13, p=0.074) compared to non-Indigenous Australians. Despite their younger age, Indigenous Australians with AF had similar or greater rates of cardiovascular comorbidities than non-Indigenous Australians with AF.

Conclusions

Young Indigenous Australians have a significantly greater prevalence of AF than their non-Indigenous counterparts. In contrast, older non-Indigenous Australians have a greater prevalence of AF compared to their Indigenous counterparts. These observations may be mediated by age-based differences in comorbid cardiovascular conditions, left atrial diameter and left ventricular ejection fraction. Our findings suggest that AF is likely to be contributing to the greater burden of morbidity and mortality experienced by young Indigenous Australians. Further study is required to elucidate whether strategies to prevent and better manage AF in Indigenous Australians may reduce this burden.
Protocol for developing the evidence base for a national salt reduction programme for India
Authors: Johnson Claire , Mohan Sailesh , Praveen Deversetty , Woodward Mark , Maulik Pallab K , Shivashankar Roopa , Amarchand Ritvik , Webster Jacqui , Dunford Elizabeth , Thout Sudhir Raj , MacGregor Graham , He Feng , Reddy K Srinath , Krishnan Anand , Prabhakaran Dorairaj , Neal Bruce
Published: October 2014

Introduction

The scientific evidence base in support of salt reduction is strong but the data required to translate these insights into reduced population salt intake are mostly absent. The aim of this research project is to develop the evidence base required to formulate and implement a national salt reduction programme for India.

Methods and analysis

The research will comprise three components: a stakeholder analysis involving government, industry, consumers and civil society organisations; a population survey using an age-stratified and sex-stratified random samples drawn from urban (slum and non-slum) and rural areas of North and South India; and a systematic quantitative evaluation of the nutritional components of processed and restaurant foods. The stakeholder interviews will be analysed using qualitative methods to summarise the main themes and define the broad range of factors influencing the food environment in India. The population survey will estimate the mean daily salt consumption through the collection of 24 h urine samples with concurrent dietary surveys identifying the main sources of dietary sodium/salt. The survey of foods will record the nutritional composition of the chief elements of food supply. The findings from this research will be synthesised and proposals for a national salt reduction strategy for India will be developed in collaboration with key stakeholders.

Ethics and dissemination

This study has been approved by the Human Research Ethics Committees of the University of Sydney and the Centre for Chronic Disease Control in New Delhi, and also by the Indian Health Ministry's Screening Committee. The project began fieldwork in February 2014 and will report the main results in 2016. The ﬁndings will be targeted primarily at public health policymakers and advocates, but will be disseminated widely through other mechanisms including conference presentations and peer-reviewed publications, as well as to the participating communities.
A protocol for a discrete choice experiment: understanding preferences of patients with cancer towards their cancer care across metropolitan and rural regions in Australia
Authors: Wong Shu Fen , Norman Richard , Dunning Trisha L , Ashley David M , Lorgelly Paula K
Published: October 2014

Introduction

Medical decision-making in oncology is a complicated process and to date there are few studies examining how patients with cancer make choices with respect to different features of their care. It is also unknown whether patient choices vary by geographical location and how location could account for observed rural and metropolitan cancer differences. This paper describes an ongoing study that aims to (1) examine patient and healthcare-related factors that influence choices of patients with cancer; (2) measure and quantify preferences of patients with cancer towards cancer care using a discrete choice experiment (DCE) and (3) explore preference heterogeneity between metropolitan and rural locations.

Methods and analysis

A DCE is being conducted to understand how patients with cancer choose between two clinical scenarios accounting for different patient and healthcare-related factors (and levels). Preliminary qualitative research was undertaken to guide the development of an appropriate DCE design including characteristics that are important and relevant to patients with cancer. A fractional factorial design using the D-efficiency criteria was used to estimate interactions among attributes. Multinomial logistic regression will be used for the primary DCE analysis and to control for sociodemographic and clinical characteristics.

Ethics and dissemination

The Barwon Health Human Research Ethics Committee approved the study. Findings from the study will be presented in national/international conferences and peer-reviewed journals. Our results will form the basis of a feasibility study to inform the development of a larger scale study into preferences of patients with cancer and their association with cancer outcomes.
Simulation-based training and assessment of non-technical skills in the Norwegian Helicopter Emergency Medical Services: a cross-sectional survey
Authors: Abrahamsen Håkon B , Sollid Stephen J M , Öhlund Lennart S , Røislien Jo , Bondevik Gunnar Tschudi
Published: October 2014

Background

Human error and deficient non-technical skills (NTSs) among providers of ALS in helicopter emergency medical services (HEMS) is a threat to patient and operational safety. Skills can be improved through simulation-based training and assessment.

Objective

To document the current level of simulation-based training and assessment of seven generic NTSs in crew members in the Norwegian HEMS.

Methods

A cross-sectional survey, either electronic or paper-based, of all 207 physicians, HEMS crew members (HCMs) and pilots working in the civilian Norwegian HEMS (11 bases), between 8 May and 25 July 2012.

Results

The response rate was 82% (n=193). A large proportion of each of the professional groups lacked simulation-based training and assessment of their NTSs. Compared with pilots and HCMs, physicians undergo statistically significantly less frequent simulation-based training and assessment of their NTSs. Fifty out of 82 (61%) physicians were on call for more than 72 consecutive hours on a regular basis. Of these, 79% did not have any training in coping with fatigue. In contrast, 72 out of 73 (99%) pilots and HCMs were on call for more than 3 days in a row. Of these, 54% did not have any training in coping with fatigue.

Conclusions

Our study indicates a lack of simulation-based training and assessment. Pilots and HCMs train and are assessed more frequently than physicians. All professional groups are on call for extended hours, but receive limited training in how to cope with fatigue.
Admission glycaemia and its association with acute coronary syndrome in Emergency Department patients with chest pain
Authors: Gardner Logan S , Nguyen-Pham Sallyanne , Greenslade Jaimi H , Parsonage William , D'Emden Michael , Than Martin , Aldous Sally , Brown Anthony , Cullen Louise
Published: October 2014

Background

This study aims to evaluate admission blood glucose level (BGL) in patients presenting to the emergency department (ED) as a risk factor for a major adverse cardiac event (MACE) on presentation and up to 30 days post discharge. Admission BGL is a prognostic indicator in patients with confirmed acute coronary syndrome (ACS). It is unclear if admission BGL improves the diagnosis and stratification of patients presenting to the ED with suspected ACS.

Methods

This study is an analysis of data collected from a prospective observational study. The study population consisted of ED patients from Brisbane, Australia and Christchurch, New Zealand. Patients were enrolled between November 2007 and February 2011. Admission BGL was taken as part of routine admission blood with fasting status unknown. The primary end point for this study was a MACE at presentation and up to 30 days post discharge. Logistic regression analyses examined the relationship between admission hyperglycaemia and MACE. A hyperglycaemic threshold of 7 mmol/L was chosen based on WHO standards.

Results

A total of 1708 patients were eligible. A MACE was identified in 336 patients (19.7%) within 30 days. Of these 98 had confirmed unstable angina and 232 had non-ST elevation myocardial infarction. Hyperglycaemia was identified in 476 (27.9%) patients with 147 (30.9%) having a MACE. Admission BGL >7 mmol/L was demonstrated as an independent predictor of a MACE (OR1.51 CI 1.06 to 2.14). Gender, age, hypertension, dyslipidaemia, family history, ischaemic ECG and positive troponin remained important factors.

Conclusions

Admission BGL is an independent risk factor for a MACE in patients with suspected ACS. Hyperglycaemia should be considered a risk factor for MACEs and consideration be given to its inclusion in existing diagnostic tools.
The effect of the transition from the ninth to the tenth revision of the International Classification of Diseases on external cause registration of injury morbidity in Sweden
Authors: Nilson Finn , Bonander Carl , Andersson Ragnar
Published: October 2014

Background

Revisions of the International Classification of Diseases (ICD) have previously been shown to cause dramatic effects with regard to injury mortality data when implemented. However, limited knowledge exists on the effects on the coding of external causes of injury morbidity, despite this being an important aspect with regard to injury prevention.

Method

Hospitalised injuries in Sweden were studied using time series intervention analysis to observe the effect of the ICD change from ICD-9 to ICD-10 in 1997 on external cause coding.

Results

The results would suggest considerable coding issues with a large spike in the proportion of injury admissions registered without an external cause code in 1997, with continuing, although gradually diminishing, problems up to 2002. The coding change seems to have had an immediate effect on all external cause of injury categories, although the categories that were not directly convertible from ICD-9 to ICD-10 were seemingly more greatly affected.

Discussion

The study illustrates the potential issues associated with changes between ICD revisions and the importance of data quality control both during surveillance and collection of data, but also when presenting injury trends across ICD versions.
The Cataract Extraction and Driving Ability Research Study Protocol: characterisation of deficits in driving performance and self-regulation among older drivers with bilateral cataract
Authors: Meuleners Lynn B , Agramunt Seraina , Ng Jonathon Q , Morlet Nigel , Keay Lisa , McCluskey Peter , Young Mark
Published: October 2014

Purpose

Cataract is one of the leading causes of visual impairment in Australia. As more older adults are driving, the number of people with cataract on the roads will increase. A greater understanding of the effects of cataract and cataract surgery on driving performance and driver self-regulation is essential to improve road safety. This proposed study will examine the effects of bilateral cataract surgery on driving outcomes including driving performance and driver self-regulation.

Methods

A 3-year prospective study will be undertaken in Western Australia (WA) and New South Wales (NSW). Three hundred participants (n=150 from WA and n=150 from NSW) aged >60 years with bilateral cataract will be assessed at three time points: the month before first-eye cataract surgery, 1–3 months after first-eye cataract surgery and 3 months after second-eye cataract surgery. Driving performance will be assessed using a driving simulator and driver self-regulation patterns measured using in-vehicle driver-monitoring devices. Objective visual measures, quality of life and self-reported driving difficulties will also be collected at the three assessments.

Conclusions

The study results may impact on ophthalmology, optometry and general medical practices in terms of the driving advice provided to patients with bilateral cataract and those undergoing cataract surgery. The information gained from this study will allow these professionals to advise patients about specific driving difficulties they may face at different stages of cataract surgery and appropriate self-regulation practices. The results will be of use to licensing authorities in the assessment of ‘fitness to drive’.
Low cardiorespiratory fitness in young adulthood and future risk of disability pension: a follow-up study until 59 years of age in Swedish men
Authors: Rabiee Rynaz , Agardh Emilie , Kjellberg Katarina , Falkstedt Daniel
Published: October 2014

Background

There is a strong belief in the potential of increased physical activity to improve the health of populations. The objective of the present study was to estimate the association between low cardiorespiratory fitness in young adulthood and subsequent health impairment until middle age, measured by disability pension.

Methods

The study utilised data on cardiorespiratory fitness and a number of covariates (social background, health behaviours and psychological characteristics) from the Swedish Conscription Cohort of 1969/1970 including 49 321 men born in 1949–1951, and data on disability pension from 1971 to 2008 (20–59 years of age) through record linkage with two national insurance databases. Cox proportional-hazards regressions yielded hazard ratios (HR) with 95% confidence intervals (CI).

Results

Having low-level or mid-level cardiorespiratory fitness in late adolescence was associated with an increased HR of disability pension across the follow-up (HR for low fitness: 1.85, CI 1.71 to 2.00; HR for mid-level fitness: 1.40, CI 1.31 to 1.50). The association was stronger with earlier disability pensions than with later disability pensions, which was also seen after multiple confounding adjustments. At the same time, these adjustments revealed considerable confounding of the association by individual differences in psychological characteristics in particular.

Conclusions

Lower levels of cardiorespiratory fitness in young adulthood were found to be associated with an increased HR of disability pension throughout the follow-up until 59 years of age, even after adjustment for important confounding factors measured in late adolescence. Increased physical fitness may thus have a lowering effect on the risk of disability pension.
Caprine arthritis encephalitis and caseous lymphadenitis in goats: use of bulk tank milk ELISAs for herd‐level surveillance
Authors: Nagel‐Alne G. E. , Valle P. S. , Krontveit R. , Sølverød L. S.
Published: October 2014

The objective of this study was to evaluate the diagnostic performance of two ELISA tests applied to bulk tank milk (BTM) as the first part of a two‐step test scheme for the surveillance of caprine arthritis encephalitis (CAE) and caseous lymphadenitis (CLA) infections in goats. The herd‐level BTM tests were assessed by comparing them to the test results of individual serological samples. The potential for refining the cut‐off levels for BTM tests used as surveillance tools in a population recently cleared of infection was also investigated. Data was gathered on serum (nCAE =9702 and nCLA =13426) and corresponding BTM (nCAE =78 and nCLA =123) samples from dairy goat herds enrolled in the Norwegian disease control and eradication programme ‘Healthier Goats’. The results showed that the sensitivity and specificity of the CAE ELISA BTM test with respect to detecting ≥2 per cent within‐herd prevalence were 72.7 per cent and 86.6 per cent, respectively. For the CLA ELISA BTM the sensitivity and specificity were 41.4 per cent and 81.7 per cent, respectively, for the same goal of detection. The results suggest that BTM testing can be applied as a cost‐effective first step for early detection of CAE and CLA infection.
Vessel sealing versus suture ligation for canine ovarian pedicle haemostasis: a randomised clinical trial
Authors: Schwarzkopf I. , Van Goethem B. , Vandekerckhove P. M. , de Rooster H.
Published: October 2014

Vessel sealing (VS) is well established in laparoscopic ovariectomy (OVE) in dogs. The objectives of this study were to evaluate the efficacy of ovarian pedicle haemostasis by VS using a commercially available VS tool in open OVE and compare it with suture ligation (SL). A prospective, randomised clinical trial including 20 female dogs was designed. Open OVE was performed via a standard mid‐line celiotomy by a single surgeon using a standardised protocol. At random, the right ovarian pedicle was sealed (VS) or ligated (SL) whereas the left pedicle was treated by the alternative technique. Surgical times for procedural stages and intra‐operative complications were recorded and statistically evaluated. Total surgical time was 29.28±11.13 minutes (range 12.50–62.13 minutes) and time from identification to removal of the ovary was significantly less when sealing (VS 2.22±0.58 minutes) than when ligating (SL 4.10±1.13 minutes P=0.0001). Intra‐operative complications were rare for both techniques (failure of the electrode of the VS device (n=3); ovarian pedicle haemorrhage due to ligature slippage (n=1)). The results of the current study indicate that ovarian pedicle haemostasis achieved by VS is significantly faster than by placement of ligatures without appearing to compromise safety.
Solid-phase lanthanum catalysis of monoacylation of diols in water by acyl phosphate monoesters
Authors: Dhiman Raj S. , Wang Aizhou , Kluger Ronald
Published: October 2014

Lanthanide ions are readily bound to ion-exchange resins. The lanthanide-containing resins serve as immobilized catalysts for the biomimetic monoacylation of diols in water using acyl phosphate monoesters as acylation agents. This method provides an efficient route for recovering the catalyst in the process of modifying RNA derivatives and carbohydrates.