bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential patterns, trends and hotspots of road traffic injuries on different road networks in Vellore district, southern India
Authors: Mohan Venkata Raghava , Sarkar Rajiv , Abraham Vinod Joseph , Balraj Vinohar , Naumova Elena N 
Published: November 2014

AbstractObjectiveTo describe spatial and temporal profiles of Road Traffic Injuries (RTIs) on different road networks in Vellore district of southern India.MethodsUsing the information in the police maintained First Information Reports (FIRs), daily time series of RTI counts were created and temporal characteristics were analysed with respect to the vehicle, road types and time of the day for the period January 2005 to May 2007. Daily incidence and trend of RTIs were estimated using a Poisson regression analysis.ResultsOf the reported 3262 RTIs, 52% had occurred on the National Highway (NH). The overall RTI rate on the NH was 8.8/100 000 vehicles per day with significantly higher pedestrian involvement. The mean numbers of RTIs were significantly higher on weekends. Thirteen percentage of all RTIs were associated with fatalities. Hotspots are major town junctions, and RTI rates differ over different stretches of the NH.ConclusionIn India, FIRs form a valuable source of RTI information. Information on different vehicle profile, RTI patterns, and their spatial and temporal trends can be used by administrators to devise effective strategies for RTI prevention by concentrating on the high‐risk areas, thereby optimising the use of available personnel and resources.
Determinants Associated with Veterinary Antimicrobial Prescribing in Farm Animals in the Netherlands: A Qualitative Study
Authors: Speksnijder D. C. , Jaarsma A. D. C. , van der Gugten A. C. , Verheij T. J. M. , Wagenaar J. A. 
Published: November 2014

SummaryAntimicrobial use in farm animals might contribute to the development of antimicrobial resistance in humans and animals, and there is an urgent need to reduce antimicrobial use in farm animals. Veterinarians are typically responsible for prescribing and overseeing antimicrobial use in animals. A thorough understanding of veterinarians' current prescribing practices and their reasons to prescribe antimicrobials might offer leads for interventions to reduce antimicrobial use in farm animals. This paper presents the results of a qualitative study of factors that influence prescribing behaviour of farm animal veterinarians. Semi‐structured interviews with eleven farm animal veterinarians were conducted, which were taped, transcribed and iteratively analysed. This preliminary analysis was further discussed and refined in an expert meeting. A final conceptual model was derived from the analysis and sent to all the respondents for validation. Many conflicting interests are identifiable when it comes to antimicrobial prescribing by farm animal veterinarians. Belief in the professional obligation to alleviate animal suffering, financial dependency on clients, risk avoidance, shortcomings in advisory skills, financial barriers for structural veterinary herd health advisory services, lack of farmers' compliance to veterinary recommendations, public health interests, personal beliefs regarding the veterinary contribution to antimicrobial resistance and major economic powers are all influential determinants in antimicrobial prescribing behaviour of farm animal veterinarians. Interventions to change prescribing behaviour of farm animal veterinarians could address attitudes and advisory skills of veterinarians, as well as provide tools to deal with (perceived) pressure from farmers and advisors to prescribe antimicrobials. Additional (policy) measures could probably support farm animal veterinarians in acting as a more independent animal health consultant.
Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic
Authors: Dhar Neeraj , Dubée Vincent , Ballell Lluis , Cuinet Guillaume , Hugonnet Jean-Emmanuel , Signorino-Gelo François , Barros David , Arthur Michel , McKinney John D. 
Published: November 2014

ABSTRACT

Recent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently kills
Mycobacterium tuberculosis
even in the absence of clavulanate. The target enzymes,
l
,
d
-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.
Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections
Authors: Shorr Andrew F. , Lodise Thomas P. , Corey G. Ralph , De Anda Carisa , Fang Edward , Das Anita F. , Prokocimer Philippe 
Published: November 2014

ABSTRACT

Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by
Staphylococcus aureus
. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%;
P
= 0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm
3
at the EOT (tedizolid, 4.9%; linezolid, 10.8%;
P
= 0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%;
P
= 0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.)
Influence of Vancomycin Infusion Methods on Endothelial Cell Toxicity
Authors: Drouet Maryline , Chai Feng , Barthélémy Christine , Lebuffe Gilles , Debaene Bertrand , Décaudin Bertrand , Odou Pascal 
Published: November 2014

ABSTRACTPeripheral intravenous therapy is frequently used in routine hospital practice and, due to various factors, its most common side effect is phlebitis. The infusion of vancomycin is particularly associated with phlebitis despite its widespread use. French guidelines recommend central intravenous infusion for high concentrations of vancomycin, but peripheral intravenous therapy is often preferred in intensive care units. Methods of vancomycin infusion are either intermittent infusion or continuous infusion. A comparison of these methods underin vitroconditions simulating clinical use could result in better infusion efficacy. Human umbilical vein endothelial cells (HUVECs) were therefore challenged with clinical doses of vancomycin over a 24- to 72-h period using these infusion methods. Cell death was measured with the alamarBlue test. Concentration-dependent and time-dependent vancomycin toxicity on HUVECs was noted with a 50% lethal dose at 5 mg/ml after 24 h, reaching 2.5 mg/ml after 72 h of infusion, simulating long-term infusion. This toxicity does not seem to be induced by acidic pH. In comparing infusion methods, we observed that continuous infusion induced greater cell toxicity than intermittent infusion at doses higher than 1 g/day. The increasing use of vancomycin means that new guidelines are required to avoid phlebitis. If peripheral intravenous therapy is used to reduce infusion time, along with intermittent infusion, vein irritation and localized phlebitis may be reduced. Further studies have to be carried out to explore the causes of vancomycin endothelial toxicity.
Genetic Determinants Involved in
p
-Aminosalicylic Acid Resistance in Clinical Isolates from Tuberculosis Patients in Northern China from 2006 to 2012
Authors: Zhang Xiaobing , Liu Liguo , Zhang Yan , Dai Guangming , Huang Hairong , Jin Qi 
Published: November 2014

ABSTRACT

p
-Aminosalicylic acid (PAS) is an important compound for treating multidrug-resistant tuberculosis (TB). Previous studies showed that
thyA
mutations are often related to PAS resistance in clinical isolates. We performed a systematic analysis of isolate genotypes and detected mutations in three folate pathway genes (
folC
,
thyA
, and
ribD
) in 61.1% (127/208) of PAS-resistant isolates, including 11 double mutants. This result expands our knowledge about the distribution and frequency of mutations related to PAS resistance in mycobacterial clinical isolates.
Complete Nucleotide Sequences of Two NDM-1-Encoding Plasmids from the Same Sequence Type 11 Klebsiella pneumoniae Strain
Authors: Studentova V. , Dobiasova H. , Hedlova D. , Dolejska M. , Papagiannitsis C. C. , Hrabak J. 
Published: November 2014

ABSTRACT

The sequence type 11
Klebsiella pneumoniae
strain Kpn-3002cz was confirmed to harbor two NDM-1-encoding plasmids, pB-3002cz and pS-3002cz. pB-3002cz (97,649 bp) displayed extensive sequence similarity with the
bla
NDM-1
-carrying plasmid pKPX-1. pS-3002cz (73,581 bp) was found to consist of an IncR-related sequence (13,535 bp) and a mosaic region (60,046 bp). A 40,233-bp sequence of pS-3002cz was identical to the mosaic region of pB-3002cz, indicating the
en bloc
acquisition of the NDM-1-encoding region from one plasmid by the other.
First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity
Authors: Bruderer Shirin , Hurst Noémie , de Kanter Ruben , Miraval Tommaso , Pfeifer Thomas , Donazzolo Yves , Dingemanse Jasper 
Published: November 2014

ABSTRACT

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant
Plasmodium falciparum
strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200- and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an
ex vivo
bioassay with
P. falciparum
. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (
C
max
) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng · h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the
C
max
was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.)
Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors
Authors: Basson Adriaan E. , Rhee Soo-Yon , Parry Chris M. , El-Khatib Ziad , Charalambous Salome , De Oliveira Tulio , Pillay Deenan , Hoffmann Christopher , Katzenstein David , Shafer Robert W. , Morris Lynn 
Published: November 2014

ABSTRACTThe objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in anin vitrosingle-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.
Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans
Authors: Malmquist Nicholas A. , Sundriyal Sandeep , Caron Joachim , Chen Patty , Witkowski Benoit , Menard Didier , Suwanarusk Rossarin , Renia Laurent , Nosten Francois , Jiménez-Díaz María Belén , Angulo-Barturen Iñigo , Martínez María Santos , Ferrer Santiago , Sanz Laura M. , Gamo Francisco-Javier , Wittlin Sergio , Duffy Sandra , Avery Vicky M. , Ruecker Andrea , Delves Michael J. , Sinden Robert E. , Fuchter Matthew J. , Scherf Artur 
Published: November 2014

ABSTRACT

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising
in vitro
parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for
in vitro
and
in vivo
efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent
in vitro
activity, with 50% inhibitory concentrations (IC
50
s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory
Plasmodium falciparum
isolates. Activities against
ex vivo
clinical isolates of both
P. falciparum
and
Plasmodium vivax
were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in
in vivo
mouse models of
Plasmodium berghei
and
P. falciparum
infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Biochemical Characterization of Recombinant Enterovirus 71 3C Protease with Fluorogenic Model Peptide Substrates and Development of a Biochemical Assay
Authors: Shang Luqing , Zhang Shumei , Yang Xi , Sun Jixue , Li Linfeng , Cui Zhengjie , He Qiuhong , Guo Yu , Sun Yuna , Yin Zheng 
Published: November 2014

ABSTRACT

Enterovirus 71 (EV71), a primary pathogen of hand, foot, and mouth disease (HFMD), affects primarily infants and children. Currently, there are no effective drugs against HFMD. EV71 3C protease performs multiple tasks in the viral replication, which makes it an ideal antiviral target. We synthesized a small set of fluorogenic model peptides derived from cleavage sites of EV71 polyprotein and examined their efficiencies of cleavage by EV71 3C protease. The novel peptide P08 [(2-(
N
-methylamino)benzoyl) (NMA)-IEALFQGPPK(DNP)FR] was determined to be the most efficiently cleaved by EV71 3C protease, with a kinetic constant
k
cat
/

K
m

of 11.8 ± 0.82 mM
−1
min
−1
. Compared with literature reports, P08 gave significant improvement in the signal/background ratio, which makes it an attractive substrate for assay development. A Molecular dynamics simulation study elaborated the interactions between substrate P08 and EV71 3C protease. Arg39, which is located at the bottom of the S2 pocket of EV71 3C protease, may participate in the proteolysis process of substrates. With an aim to evaluate EV71 3C protease inhibitors, a reliable and robust biochemical assay with a
Z
′ factor of 0.87 ± 0.05 was developed. A novel compound (compound 3) (50% inhibitory concentration [IC
50
] = 1.89 ± 0.25 μM) was discovered using this assay, which effectively suppressed the proliferation of EV 71 (strain Fuyang) in rhabdomyosarcoma (RD) cells with a highly selective index (50% effective concentration [EC
50
] = 4.54 ± 0.51 μM; 50% cytotoxic concentration [CC
50
] > 100 μM). This fast and efficient assay for lead discovery and optimization provides an ideal platform for anti-EV71 drug development targeting 3C protease.
Requirement for Serratia marcescens Cytolysin in a Murine Model of Hemorrhagic Pneumonia
Authors: González-Juarbe Norberto , Mares Chris A. , Hinojosa Cecilia A. , Medina Jorge L. , Cantwell Angelene , Dube Peter H. , Orihuela Carlos J. , Bergman Molly A. 
Published: November 2014

ABSTRACT

Serratia marcescens
, a member of the carbapenem-resistant
Enterobacteriaceae
, is an important emerging pathogen that causes a wide variety of nosocomial infections, spreads rapidly within hospitals, and has a systemic mortality rate of ≤41%. Despite multiple clinical descriptions of
S. marcescens
nosocomial pneumonia, little is known regarding the mechanisms of bacterial pathogenesis and the host immune response. To address this gap, we developed an oropharyngeal aspiration model of lethal and sublethal
S. marcescens
pneumonia in BALB/c mice and extensively characterized the latter. Lethal challenge (>4.0 × 10
6
CFU) was characterized by fulminate hemorrhagic pneumonia with rapid loss of lung function and death. Mice challenged with a sublethal dose (<2.0 × 10
6
CFU) rapidly lost weight, had diminished lung compliance, experienced lung hemorrhage, and responded to the infection with extensive neutrophil infiltration and histopathological changes in tissue architecture. Neutrophil extracellular trap formation and the expression of inflammatory cytokines occurred early after infection. Mice depleted of neutrophils were exquisitely susceptible to an otherwise nonlethal inoculum, thereby demonstrating the requirement for neutrophils in host protection. Mutation of the genes encoding the cytolysin ShlA and its transporter ShlB resulted in attenuated
S. marcescens
strains that failed to cause profound weight loss, extended illness, hemorrhage, and prolonged lung pathology in mice. This study describes a model of
S. marcescens
pneumonia that mimics known clinical features of human illness, identifies neutrophils and the toxin ShlA as a key factors important for defense and infection, respectively, and provides a solid foundation for future studies of novel therapeutics for this important opportunistic pathogen.
The Environment of “Mycobacterium avium subsp. hominissuis” Microaggregates Induces Synthesis of Small Proteins Associated with Efficient Infection of Respiratory Epithelial Cells
Authors: Babrak Lmar , Danelishvili Lia , Rose Sasha J. , Kornberg Tiffany , Bermudez Luiz E. 
Published: November 2014

ABSTRACT

“
Mycobacterium avium
subsp.
hominissuis
” is an opportunistic environmental pathogen that causes respiratory illness in immunocompromised patients, such as those with cystic fibrosis as well as other chronic respiratory diseases. Currently, there is no efficient approach to prevent or treat
M. avium
subsp.
hominissuis
infection in the lungs. During initial colonization of the airways,
M. avium
subsp.
hominissuis
forms microaggregates composed of 3 to 20 bacteria on human respiratory epithelial cells, which provides an environment for phenotypic changes leading to efficient mucosal invasion
in vitro
and
in vivo
. DNA microarray analysis was employed to identify genes associated with the microaggregate phenotype. The gene encoding microaggregate-binding protein 1 (MBP-1) (MAV_3013) is highly expressed during microaggregate formation. When expressed in noninvasive
Mycobacterium smegmatis
, MBP-1 increased the ability of the bacteria to bind to HEp-2 epithelial cells. Using anti-MBP-1 immune serum, microaggregate binding to HEp-2 cells was significantly reduced. By far-Western blotting, and verified by coimmunoprecipitation, we observed that MBP-1 interacts with the host cytoskeletal protein vimentin. As visualized by confocal microscopy, microaggregates, as well as MBP-1, induced vimentin polymerization at the site of bacterium-host cell contact. Binding of microaggregates to HEp-2 cells was inhibited by treatment with an antivimentin antibody, suggesting that MBP-1 expression is important for
M. avium
subsp.
hominissuis
adherence to the host cell. MBP-1 immune serum significantly inhibited
M. avium
subsp.
hominissuis
infection throughout the respiratory tracts of mice. This study characterizes a pathogenic mechanism utilized by
M. avium
subsp.
hominissuis
to bind and invade the host respiratory epithelium, suggesting new potential targets for the development of antivirulence therapy.