bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broader Health Coverage is Good for the Nation’s Health: Evidence from Country Level Panel Data
Authors: Moreno-Serra Rodrigo , Smith Peter C. 
Published: February 2014

SummaryProgress towards universal health coverage involves providing people with access to needed health services without entailing financial hardship and is often advocated on the grounds that it improves population health. The paper offers econometric evidence on the effects of health coverage on mortality outcomes at the national level. We use a large panel data set of countries, examined by using instrumental variable specifications that explicitly allow for potential reverse causality and unobserved country-specific characteristics. We employ various proxies for the coverage level in a health system. Our results indicate that expanded health coverage, particularly through higher levels of publicly funded health spending, results in lower child and adult mortality, with the beneficial effect on child mortality being larger in poorer countries.
Likelihood Ratio Tests for Dependent Data with Applications to Longitudinal and Functional Data Analysis
Authors: Staicu Ana‐Maria , Li Yingxing , Crainiceanu Ciprian M. , Ruppert David 
Published: February 2014

ABSTRACTThis paper introduces a general framework for testing hypotheses about the structure of the mean function of complex functional processes. Important particular cases of the proposed framework are as follows: (1) testing the null hypothesis that the mean of a functional process is parametric against a general alternative modelled by penalized splines; and (2) testing the null hypothesis that the means of two possibly correlated functional processes are equal or differ by only a simple parametric function. A global pseudo‐likelihood ratio test is proposed, and its asymptotic distribution is derived. The size and power properties of the test are confirmed in realistic simulation scenarios. Finite‐sample power results indicate that the proposed test is much more powerful than competing alternatives. Methods are applied to testing the equality between the means of normalizedδ‐power of sleep electroencephalograms of subjects with sleep‐disordered breathing and matched controls.
Transfusion‐associated anaphylaxis during anaesthesia and surgery – a retrospective study
Authors: Lindsted G. , Larsen R. , Krøigaard M. , Garvey L. H. , Poulsen L. K. , Mosbech H. , Sørensen B. , Norgaard A. 
Published: February 2014

Background and ObjectivesTransfusion‐associated anaphylaxis (TAA) is a severe adverse reaction reported to occur in 1:9000–90 000 transfusions. According to the Danish Registration of Transfusion Risks (DART), the frequency is 1:300 000 transfusions, which suggests insufficient reporting of TAA in Denmark. Our aims were to identify possible cases of TAA, to characterize their symptoms and tryptase levels and to investigate the reporting of TAA to the haemovigilance systems.Material and methodsWe reviewed 245 patients with suspected allergic reactions during anaesthesia and surgery, investigated at the Danish Anaesthesia Allergy Centre (DAAC). Based on the outcome of this investigation, the patients were classified as DAAC positive (confirmed hypersensitivity to identified agent, n = 112), or DAAC negative (no confirmed hypersensitivity, n = 133). Data on case history, details of blood transfusion and results of laboratory and clinical investigations were collected. TAA cases were identified according to the recommendations of the International Society of Blood Transfusion (ISBT).ResultsTen possible TAA cases (30% of all transfused patients) were identified, all DAAC negative. The frequency of elevated serum tryptase, hypotension and male sex was significantly higher among these cases compared with the remaining DAAC negative (P < 0·05), but not different from the DAAC‐positive patients. One case had been reported to the Blood Bank haemovigilance system and none to DART.ConclusionWe identified unreported cases of possible TAA, which resembled the DAAC‐positive patients with respect to elevated tryptase and symptoms. By applying the ISBT criteria of adverse transfusion reactions, we conclude that TAA during anaesthesia and surgery is likely to be underreported in Denmark.
Dissemination of 16S rRNA Methylase ArmA-Producing Acinetobacter baumannii and Emergence of OXA-72 Carbapenemase Coproducers in Japan
Authors: Tada Tatsuya , Miyoshi-Akiyama Tohru , Shimada Kayo , Shimojima Masahiro , Kirikae Teruo 
Published: February 2014

ABSTRACT

Forty-nine clinical isolates of multidrug-resistant
Acinetobacter baumannii
were obtained from 12 hospitals in 7 prefectures throughout Japan. Molecular phylogenetic analysis revealed the clonal spread of
A. baumannii
sequence type 208 (ST208) and ST455 isolates harboring the
armA
gene and ST512 harboring the
armA
and
bla
OXA-72
genes. These findings show that
A. baumannii
isolates harboring
armA
are disseminated throughout Japan, and this is the first report to show that
A. baumannii
strains harboring
bla
OXA-72
and
armA
are emerging in hospitals in Japan.
Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs
Authors: Saïdani Nadia , Botté Cyrille Y. , Deligny Michael , Bonneau Anne-Laure , Reader Janette , Lasselin Ronald , Merer Goulven , Niepceron Alisson , Brossier Fabien , Cintrat Jean-Christophe , Rousseau Bernard , Birkholtz Lyn-Marie , Cesbron-Delauw Marie-France , Dubremetz Jean-François , Mercier Corinne , Vial Henri , Lopez Roman , Maréchal Eric 
Published: February 2014

ABSTRACTA piperidinyl-benzimidazolone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism, acting on enzymes manipulating diacylglycerol and phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolone analogs might therefore identify compounds acting against infectious parasites. We first evaluated thein vitroeffects of (S)-2-(dibenzylamino)-3-phenylpropyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate (compound 1) onToxoplasma gondiiandPlasmodium falciparum. InT. gondii, motility and apical complex integrity appeared to be unaffected, whereas cell division was inhibited at compound 1 concentrations in the micromolar range. InP. falciparum, the proliferation of erythrocytic stages was inhibited, without any delayed death phenotype. We then explored a library of 250 analogs in two steps. We selected 114 compounds with a 50% inhibitory concentration (IC50) cutoff of 2 μM for at least one species and determinedin vitroselectivity indexes (SI) based on toxicity against K-562 human cells. We identified compounds with high gains in the IC50(in the 100 nM range) and SI (up to 1,000 to 2,000) values. Isobole analyses of two of the most active compounds againstP. falciparumindicated that their interactions with artemisinin were additive. Here, we propose the use of structure-activity relationship (SAR) models, which will be useful for designing probes to identify the target compound(s) and optimizations for monotherapy or combined-therapy strategies.
Spread of NDM-1-Producing Enterobacteriaceae in a Neonatal Intensive Care Unit in Istanbul, Turkey
Authors: Poirel Laurent , Yilmaz Mesut , Istanbullu Ayse , Arslan Ferhat , Mert Ali , Bernabeu Sandrine , Nordmann Patrice 
Published: February 2014

ABSTRACT

Twenty-two consecutive carbapenem-resistant enterobacterial isolates were recovered from patients hospitalized between January and April 2013 in different units at a university hospital in Istanbul, Turkey. These were
Klebsiella pneumoniae
isolates producing the carbapenemases OXA-48, NDM-1, and KPC-2,
Enterobacter cloacae
isolates producing NDM-1, and
Escherichia coli
isolates producing OXA-48. Most of the OXA-48-producing
K. pneumoniae
and all the NDM-1-producing
E. cloacae
were clonally related. The NDM-1-producing
E. cloacae
isolates recovered from a single neonatal intensive care unit corresponded to a single cluster, highlighting the spread of that clone in that setting.
Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination
Authors: Ma H. , Le Pogam S. , Fletcher S. , Hinojosa-Kirschenbaum F. , Javanbakht H. , Yan J.-M. , Jiang W.-R. , Inocencio N. , Klumpp K. , Nájera I. 
Published: February 2014

ABSTRACT
Mericitabine (RG7128) is the prodrug of a highly selective cytidine nucleoside analog inhibitor (RO5855) of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. This study evaluated the effects of combining RO5855 and ribavirin on HCV replication in the HCV subgenomic replicon by using two drug-drug interaction models. The effects of RO5855 and ribavirin on the intracellular metabolism of each compound, on interferon-stimulated gene (ISG) expression, and on the viability of hepatocyte-derived cells were also investigated. RO5855 and ribavirin had additive inhibitory activities against HCV subgenomic replicon replication in drug-drug interaction analyses. RO5855 did not affect the uptake or phosphorylation of ribavirin in primary human hepatocytes, human peripheral blood mononuclear cells, or genotype 1b (G1b) replicon cells. Similarly, ribavirin did not affect the concentrations of intracellular species derived from RO5855 in primary human hepatocytes or the formation of the triphosphorylated metabolites of RO5855. Ribavirin at concentrations of >40 μM significantly reduced the viability of primary hepatocytes but not of Huh7, the G1b replicon, or interferon-cured Huh7 cells. RO5855 alone or with ribavirin did not significantly alter the viability of Huh7 or G1b replicon cells, and it did not significantly affect the viability of primary hepatocytes when it was administered alone. The viability of primary hepatocytes was reduced when they were incubated with RO5855 and ribavirin, similar to the effects of ribavirin alone. RO5855 alone or with ribavirin had no effect on ISG mRNA levels in any of the cells tested. In conclusion, RO5855 did not show any unfavorable interactions with ribavirin in human hepatocytes or an HCV subgenomic replicon system.
Trichomonas vaginalis Metronidazole Resistance Is Associated with Single Nucleotide Polymorphisms in the Nitroreductase Genes

ntr4
Tv

and

ntr6
Tv
Authors: Paulish-Miller Teresa E. , Augostini Peter , Schuyler Jessica A. , Smith William L. , Mordechai Eli , Adelson Martin E. , Gygax Scott E. , Secor William E. , Hilbert David W. 
Published: February 2014

ABSTRACT

Metronidazole resistance in the sexually transmitted parasite
Trichomonas vaginalis
is a problematic public health issue. We have identified single nucleotide polymorphisms (SNPs) in two nitroreductase genes (

ntr4
Tv

and

ntr6
Tv

) associated with resistance. These SNPs were associated with one of two distinct
T. vaginalis
populations identified by multilocus sequence typing, yet one SNP (

ntr6
Tv

A238T), which results in a premature stop codon, was associated with resistance independent of population structure and may be of diagnostic value.
High Activity of Fosfomycin and Rifampin against Methicillin-Resistant Staphylococcus aureus Biofilm
In Vitro
and in an Experimental Foreign-Body Infection Model
Authors: Mihailescu Raluca , Furustrand Tafin Ulrika , Corvec Stéphane , Oliva Alessandra , Betrisey Bertrand , Borens Oliver , Trampuz Andrej 
Published: February 2014

ABSTRACT

Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 μg/ml; daptomycin, 0.125 μg/ml; vancomycin, 1 μg/ml; rifampin, 0.04 μg/ml; and tigecycline, 0.125 μg/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log
10
CFU/ml at 128 × the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log
10
CFU/ml with fosfomycin and tigecycline, 1.7 log
10
with daptomycin, 2.2 log
10
with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log
10
with fosfomycin-daptomycin, and >6.0 log
10
with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cage-associated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 μg/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cage-associated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.
NADPH Oxidase Promotes Neutrophil Extracellular Trap Formation in Pulmonary Aspergillosis
Authors: Röhm Marc , Grimm Melissa J. , D'Auria Anthony C. , Almyroudis Nikolaos G. , Segal Brahm H. , Urban Constantin F. 
Published: February 2014

ABSTRACT

NADPH oxidase is a crucial enzyme in antimicrobial host defense and in regulating inflammation. Chronic granulomatous disease (CGD) is an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates.
Aspergillus
species are ubiquitous, filamentous fungi, which can cause invasive aspergillosis, a major cause of morbidity and mortality in CGD, reflecting the critical role for NADPH oxidase in antifungal host defense. Activation of NADPH oxidase in neutrophils can be coupled to the release of proteins and chromatin that comingle in neutrophil extracellular traps (NETs), which can augment extracellular antimicrobial host defense. NETosis can be driven by NADPH oxidase-dependent and -independent pathways. We therefore undertook an analysis of whether NADPH oxidase was required for NETosis in
Aspergillus fumigatus
pneumonia. Oropharyngeal instillation of live
Aspergillus
hyphae induced neutrophilic pneumonitis in both wild-type and NADPH oxidase-deficient (p47

phox−/−

) mice which had resolved in wild-type mice by day 5 but progressed in p47

phox
−/−

mice. NETs, identified by immunostaining, were observed in lungs of wild-type mice but were absent in p47

phox
−/−

mice. Using bona fide NETs and nuclear chromatin decondensation as an early NETosis marker, we found that NETosis required a functional NADPH oxidase
in vivo
and
ex vivo
. In addition, NADPH oxidase increased the proportion of apoptotic neutrophils. Together, our results show that NADPH oxidase is required for pulmonary clearance of
Aspergillus
hyphae and generation of NETs
in vivo
. We speculate that dual modulation of NETosis and apoptosis by NADPH oxidase enhances antifungal host defense and promotes resolution of inflammation upon infection clearance.
Metabolic and Bactericidal Effects of Targeted Suppression of NadD and NadE Enzymes in Mycobacteria
Authors: Rodionova Irina A. , Schuster Brian M. , Guinn Kristine M. , Sorci Leonardo , Scott David A. , Li Xiaoqing , Kheterpal Indu , Shoen Carolyn , Cynamon Michael , Locher Christopher , Rubin Eric J. , Osterman Andrei L. 
Published: February 2014

ABSTRACT

Mycobacterium tuberculosis
remains a major cause of death due to the lack of treatment accessibility, HIV coinfection, and drug resistance. Development of new drugs targeting previously unexplored pathways is essential to shorten treatment time and eliminate persistent
M. tuberculosis
. A promising biochemical pathway which may be targeted to kill both replicating and nonreplicating
M. tuberculosis
is the biosynthesis of NAD(H), an essential cofactor in multiple reactions crucial for respiration, redox balance, and biosynthesis of major building blocks. NaMN adenylyltransferase (NadD) and NAD synthetase (NadE), the key enzymes of NAD biosynthesis, were selected as promising candidate drug targets for
M. tuberculosis
. Here we report for the first time kinetic characterization of the recombinant purified NadD enzyme, setting the stage for its structural analysis and inhibitor development. A protein knockdown approach was applied to validate bothNadD and NadE as target enzymes. Induced degradation of either target enzyme showed a strong bactericidal effect which coincided with anticipated changes in relative levels of NaMN and NaAD intermediates (substrates of NadD and NadE, respectively) and ultimate depletion of the NAD(H) pool. A metabolic catastrophe predicted as a likely result of NAD(H) deprivation of cellular metabolism was confirmed by
13
C biosynthetic labeling followed by gas chromatography-mass spectrometry (GC-MS) analysis. A sharp suppression of metabolic flux was observed in multiple NAD(P)(H)-dependent pathways, including synthesis of many amino acids (serine, proline, aromatic amino acids) and fatty acids. Overall, these results provide strong validation of the essential NAD biosynthetic enzymes, NadD and NadE, as antimycobacterial drug targets.

IMPORTANCE
To address the problems of
M. tuberculosis
drug resistance and persistence of tuberculosis, new classes of drug targets need to be explored. The biogenesis of NAD cofactors was selected for target validation because of their indispensable role in driving hundreds of biochemical transformations. We hypothesized that the disruption of NAD production in the cell via genetic suppression of the essential enzymes (NadD and NadE) involved in the last two steps of NAD biogenesis would lead to cell death, even under dormancy conditions. In this study, we confirmed the hypothesis using a protein knockdown approach in the model system of
Mycobacterium smegmatis
. We showed that induced proteolytic degradation of either target enzyme leads to depletion of the NAD cofactor pool, which suppresses metabolic flux through numerous NAD(P)-dependent pathways of central metabolism of carbon and energy production. Remarkably, bactericidal effect was observed even for nondividing bacteria cultivated under carbon starvation conditions.
An evidence-driven approach to scrum law modifications in amateur rugby played in South Africa
Authors: Hendricks Sharief , Lambert Mike I , Brown James C , Readhead Clint , Viljoen Wayne 
Published: February 2014

BackgroundIn 2012, the South African Rugby Union (SARU) approved a new set of scrum laws for amateur rugby played in the country, to be implemented at the start of the 2013 rugby season. These law changes were primarily based on the relatively high proportion of scrum-related catastrophic injury data collected as part of the BokSmart National Rugby Safety Programme (BokSmart) over the preceding 4 years (2008–2011).AimTo describe the scrum-related catastrophic injury data in South Africa over the past 5 years (2008–2012), and to discuss how this evidence justifies the change in the Amateur Scrum Laws to make this aspect of the game safer in South Africa.MethodsCatastrophic injury data were collected throughBokSmartat amateur and professional levels, during training and matches over 5 years (2008–2012).ResultsThe scrum phase accounted for 33% (n=20 of 60) of all catastrophic injuries between 2008 and 2012. Eighteen of the 20 scrum injuries (90%) were confirmed as acute spinal cord injuries, with 13 of these being permanent injuries. For the scrum injury mechanisms that were provided (n=19), ‘impact on the engagement’ was the most frequently reported (n=11 of 19, 58%), followed by ‘collapsed scrum’ (n=7 of 19, 37%) and ‘popping out’ (n=1 of 19, 5%).ConclusionsBased on these scrum-related catastrophic injury data, a change in the Amateur Scrum Laws of South African Rugby was justified. The main purpose of these scrum law changes is to reduce the number of scrum-related catastrophic injuries in the country, by minimising the opportunity for impact injury and subsequent scrum collapse in amateur rugby in South Africa, thereby making this aspect of the game of rugby safer.
The smoking habit of a close friend or family member—how deep is the impact? A cross-sectional study
Authors: Saari Antti J , Kentala Jukka , Mattila Kari J 
Published: February 2014

ObjectivesTo assess the risk of becoming a smoker in adulthood associated with parental smoking as well as the smoking of siblings and close friends.DesignA cross-sectional study.Setting4 oral healthcare centres in Finland and a follow-up.ParticipantsAn age cohort born in 1979 (n=2586) and living in four Finnish towns. Of those reached by the 2008 follow-up, 46.9% (n=1020) responded.Primary and secondary outcome measuresSmoking behaviour at the age of 29. Smoking behaviour at the age of 13 and smoking behaviour of family members and close friends.ResultsSmoking of a current close friend was strongly associated with participants’ own smoking (OR 5.6, 95% CI 3.6 to 8.8). The smoking of a close friend during schooldays was similarly associated (OR 2.9, 95% CI 1.8 to 4.5). Smoking among men was associated with the smoking behaviour of mothers and siblings while that among females was not.ConclusionsThe impact of a smoker as a close friend is greater than that of a smoking parent or sibling in school age when it comes to smoking behaviour in adulthood. This should be taken into consideration when attempting to prevent smoking initiation or continuation.Trial registrationAt clinicaltrials.gov (NCT01348646).
The impact of heatwaves on mortality in Australia: a multicity study
Authors: Tong Shilu , Wang Xiao Yu , Yu Weiwei , Chen Dong , Wang Xiaoming 
Published: February 2014

ObjectivesTo assess the heterogeneity of heatwave-related impacts on mortality across different cities.DesignA multicity time series study.Setting3 largest Australian cities: Brisbane, Melbourne and Sydney.ParticipantsAll residents living in these cities.Main outcome measuresNon-external causes mortality data by gender and two age groups (ie, 0–75 and 75+) for these cities during the period 1988–2009 were obtained from relevant government agencies.ResultsTotal mortality increased mostly within the same day (lag 0) or a lag of 1 day (lag 1) during almost all heatwaves in three cities. Using the heatwave definition (HWD) as the 95th centile of mean temperature for two or more consecutive days in the summer season, the relative risk for total mortality at lag 1 in Brisbane, Melbourne and Sydney was 1.13 (95% CI 1.08 to 1.19), 1.10 (95% CI 1.06 to 1.14) and 1.06 (95% CI 1.01 to 1.10), respectively. Using the more stringent HWD—the 99th centile of mean temperature for two or more consecutive days, the relative risk of total mortality at the lags of 0–2 days in Brisbane and Melbourne was 1.40 (95% CI 1.29 to 1.51) and 1.47 (95% CI 1.36 to 1.59), respectively. Elderly, particularly females, were more vulnerable to the impact of heatwaves.ConclusionsA consistent and significant increase in mortality was observed during heatwaves in the three largest Australian cities, but the impacts of heatwave appeared to vary with age, gender, the HWD and geographical area.