bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Self‐Assessment for Organizational Capacity Instrument for Evidence‐Informed Health Policy: Preliminary Reliability and Validity of an Instrument
Authors: Catallo Cristina , Sidani Souraya 
Published: October 2013

ABSTRACTBackgroundHealth policymakers work in organizations that involve multiple competing demands and limited time to make decisions. Influential international policy organizations continue to publish guidance and recommendations without the use of high‐quality research evidence. Few studies have described the process with which governments, including health ministries, use evidence to support health policymaking decisions. Research is needed to better understand the psychometric properties of instruments that assess health policy organizations’ capacity to use research evidence.AimThe purpose of this study was to assess the preliminary psychometric properties of an instrument which assesses organizational capacity for evidence use.MethodsThe instrument was administered by telephone survey from January to June 2011 using a purposeful sample of 57 Canadian health policymakers (policy analyst and senior management levels). Reliability of the instrument was assessed with Cronbach'sαcoefficient and item‐to‐total correlation for internal consistency; interitem coefficients were used to identify particular item redundancy. Discriminant validity was assessed using the known‐group comparison approach, with the independent samplet‐test to assess subscale responses of policy analysts and senior managers.FindingsCronbach'sαindicated acceptable internal consistency across its subscales. Discriminant validity analysis revealed a statistically significant difference between policy analysts and senior managers for one subscale.Linking Evidence to ActionOur study provides a first look at the Self‐assessment for Organizational Capacity Instrument's psychometric properties and demonstrates that this instrument can be useful when evaluating government and other organizations’ use of evidence to inform decision making. Further testing of this instrument is needed using large and varied samples of policymakers, from policy analysts to senior managers, across varied policymaking contexts. This instrument can be a starting point for government and related organizations to better understand how well it supports evidence use, including its acquisition, appraisal, and use in health policy decision making.
Reevaluation of Ceftazidime Dosing Recommendations in Patients on Continuous Ambulatory Peritoneal Dialysis
Authors: Cardone Katie E. , Grabe Darren W. , Zasowski Evan J. , Lodise Thomas P. 
Published: October 2013

ABSTRACT

While intraperitoneal (i.p.) ceftazidime is commonly used to treat continuous ambulatory peritoneal dialysis (CAPD)-related infections, the ability of i.p. regimens to achieve critical pharmacodynamic targets in both blood and dialysate has not been reported. To understand the pharmacodynamic profile of ceftazidime during CAPD, data were obtained from a single-dose pharmacokinetic (PK) i.p. ceftazidime study that included 10 CAPD patients who received i.p. ceftazidime at 15 mg/kg of body weight. The probability of target attainment (concentrations maintained above the MIC for >60% of the dosing interval [60%
T
> MIC]) was determined for six simulated regimens. A 3-compartment model with each dialysis dwell modeled as a separate differential equation was fit to ceftazidime concentrations using BigNPAG. Embedded with the final PK model, serum and dialysate concentration-time profiles of ceftazidime at 1, 1.5, and 2 g i.p. every 24 h (q24h) to q48h were simulated using ADAPT 5. The mean population pharmacokinetic parameters were as follows: apparent volume of the central compartment (

V
c

), 7.57 liter; apparent volume of the peritoneal cavity (
V
pd), 2.44 liter; clearance from the central compartment (CL), 0.379 liter/h; intercompartmental transfer rate constants (first order) between the central and peripheral compartments (
k
12
and
k
21
), 4.66 and 4.88 h
−1
, respectively; and intercompartmental transfer rate constants (first order) between the central and peritoneal compartments (
k
13
and
k
31
), 0.111 and 0.227 h
−1
, respectively. In serum, the probability of target attainment for MICs of ≤8 mg/liter exceeded 90% for 1.5 to 2 g i.p. q24h to q48h. However, no tested regimen provided adequate dialysate exposure at MICs of ≥8 mg/liter on day 1 without the use of a 3-g loading dose (
post hoc
analysis). On day 2, 1.5 to 2 g i.p. q24h or 2 g i.p. q48h provided adequate exposure in the peritoneal cavity. These results should be validated in the presence of infection. Ceftazidime i.p. at 1.5 or 2 g q24h to q48h is recommended for nonperitoneal infections. For peritonitis, a 3-g load with maintenance dosing of 1 to 2 g i.p. q24h or 2 g i.p. q48h is recommended.
New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells
Authors: Salina Elena , Ryabova Olga , Kaprelyants Arseny , Makarov Vadim 
Published: October 2013

ABSTRACT

From
in vivo
observations, a majority of
M. tuberculosis
cells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequate
in vitro
models for screening of drug candidates. We propose here a novel
in vitro
model of
M. tuberculosis
dormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormant
M. tuberculosis
cells. By means of the model of
M. tuberculosis
nonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormant
M. tuberculosis
cells. The bactericidal effects of compounds against dormant
M. tuberculosis
was confirmed by using three different
in vitro
models of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latent
M. tuberculosis
infection.
KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo
Authors: Duraffour Sophie , Drillien Robert , Haraguchi Kazuhiro , Balzarini Jan , Topalis Dimitri , van den Oord Joost J. , Andrei Graciela , Snoeck Robert 
Published: October 2013

ABSTRACTThe availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1′-methyl-substituted 4′-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses.In vitro, KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK;J2R) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2′-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1′-carbon-substituted 4′-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.
Frequency of
fks
Mutations among Candida glabrata Isolates from a 10-Year Global Collection of Bloodstream Infection Isolates
Authors: Castanheira Mariana , Woosley Leah N. , Messer Shawn A. , Diekema Daniel J. , Jones Ronald N. , Pfaller Michael A. 
Published: October 2013

ABSTRACT

Among 119 echinocandin non-wild-type (non-WT)
Candida glabrata
strains from two global surveys, mutations in
fks
hot spots (HSs) were detected in 28 (from 7 countries and 8 U.S. states): 24 strains (85.7%) had non-WT MICs for micafungin, 22 (78.6%) for anidulafungin, and 25 (89.3%) for caspofungin. The most common FKS substitutions among non-WT strains were at positions F659 (
n
= 7) and S663 (
n
= 7). Three isolates displaying WT MIC results had F625Y, L630I, and D632Y substitutions or non-HS mutations. Mutations that have been reported to decrease the echinocandin binding to the 1,3-β-
d
-glucan synthase were categorized as resistant by applying the new CLSI breakpoint criteria for all three echinocandins.
Outpatient Antibiotic Use in France between 2000 and 2010: after the Nationwide Campaign, It Is Time To Focus on the Elderly
Authors: Bernier Adeline , Delarocque-Astagneau Elisabeth , Ligier Caroline , Vibet Marie-Anne , Guillemot Didier , Watier Laurence 
Published: October 2013

ABSTRACT

Antibiotic overconsumption is the main force driving the emergence of multidrug-resistant bacterial strains. To promote better antibiotic use in France, a nationwide campaign has been run every year from October to March since 2002. In 2007, it was shown that winter outpatient antibiotic consumption had decreased by 26.5% compared to the 2000-2002 baseline period. Here, we quantified outpatient antibiotic use between 2000 and 2010 as a follow-up analysis of the nationwide campaign. Reimbursed outpatient antibiotic prescriptions were extracted from computerized French National Health Insurance databases. Entire series and age group and antibiotic class analyses were computed. Time series analyses used autoregressive moving-average models with exogenous variables and intervention functions. Two periods were considered: October to March “campaign” periods and April to September “warm” periods. Compared to the precampaign (2000-2002) baseline period, the numbers of weekly antibiotic prescriptions per 1,000 inhabitants during campaign periods decreased until winter 2006 to 2007 (−30% [95% confidence interval {CI}, −36.3 to −23.8%];
P
< 0.001) and then stabilized except for individuals >60 years of age, for whom prescriptions reached the precampaign level. During the warm periods from April to September, no significant differences were estimated compared to the baseline level for the entire series, but seniors had an increasing trend that became significant as of 2005, reaching +21% (95% CI, +12.9 to +29.6%) in 2009 (
P
< 0.0001). These results highlight the need for a better understanding of antibiotic use by the elderly, requiring research with targeted and tailored public health actions for this population.
Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model
Authors: Dolton Michael J. , Perera Vidya , Pont Lisa G. , McLachlan Andrew J. 
Published: October 2013

ABSTRACTTerbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergisticin vitroantifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.
Activation of NLRP3 and AIM2 Inflammasomes by Porphyromonas gingivalis Infection
Authors: Park Eunjoo , Na Hee Sam , Song Yu-Ri , Shin Seong Yeol , Kim You-Me , Chung Jin 
Published: October 2013

ABSTRACT

Porphyromonas gingivalis
, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1β (IL-1β), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1β is linked to periodontal destruction. IL-1β synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by which
P. gingivalis
infection causes IL-1β secretion, we examined the characteristics of
P. gingivalis
-induced signaling in differentiated THP-1 cells. We found that
P. gingivalis
induces IL-1β secretion and inflammatory cell death via caspase-1 activation. We also found that
P. gingivalis
-induced IL-1β secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X
7
receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedes
P. gingivalis
-induced IL-1β release. Our study provides novel insight into the innate immune response against
P. gingivalis
infection which could potentially be used for the prevention and therapy of periodontitis.
Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea
Authors: Zhou Xiyou , Gao Xi , Broglie Peter M. , Kebaier Chahnaz , Anderson James E. , Thom Natalie , Apicella Michael A. , Sempowski Gregory D. , Duncan Joseph A. 
Published: October 2013

ABSTRACT

Neisseria gonorrhoeae
causes gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients with
N. gonorrhoeae
remain asymptomatic, without evidence of localized inflammation. Inflammatory responses to
N. gonorrhoeae
are generated by host innate immune recognition of
N. gonorrhoeae
by several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1β (IL-1β) processing complex known as the inflammasome. The lipooligosaccharide of
N. gonorrhoeae
has a hexa-acylated lipid A.
N. gonorrhoeae
strains that carry an inactivated
msbB
(also known as
lpxL1
) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show that
msbB
-deficient
N. gonorrhoeae
induces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affect
N. gonorrhoeae
-mediated activation of the inflammasome. We demonstrate that
N. gonorrhoeae
msbB
is dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection with
msbB
-deficient
N. gonorrhoeae
is associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition of
N. gonorrhoeae
LOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections.
In VitroInfection of Bovine Monocytes with Mycoplasma bovis Delays Apoptosis and Suppresses Production of Gamma Interferon and Tumor Necrosis Factor Alpha but Not Interleukin-10
Authors: Mulongo Musa , Prysliak Tracy , Scruten Erin , Napper Scott , Perez-Casal Jose 
Published: October 2013

ABSTRACTMycoplasma bovisis one of the major causative pathogens of bovine respiratory complex disease (BRD), which is characterized by enzootic pneumonia, mastitis, pleuritis, and polyarthritis.M. bovisenters and colonizes bovine respiratory epithelial cells through inhalation of aerosol from contaminated air. The nature of the interaction betweenM. bovisand the bovine innate immune system is not well understood. We hypothesized thatM. bovisinvades blood monocytes and regulates cellular function to support its persistence and systemic dissemination. We used bovine-specific peptide kinome arrays to identify cellular signaling pathways that could be relevant toM. bovis-monocyte interactionsin vitro. We validated these pathways using functional, protein, and gene expression assays. Here, we show that infection of bovine blood monocytes withM. bovisdelays spontaneous or tumor necrosis factor alpha (TNF-α)/staurosporine-driven apoptosis, activates the NF-κB p65 subunit, and inhibits caspase-9 activity. We also report thatM. bovis-infected bovine monocytes do not produce gamma interferon (IFN-γ) and TNF-α, although the level of production of interleukin-10 (IL-10) is elevated. Our findings suggest thatM. bovistakes over the cellular machinery of bovine monocytes to prolong bacterial survival and to possibly facilitate subsequent systemic distribution.
Ethanolamine and Choline Promote Expression of Putative and Characterized Fimbriae in Enterohemorrhagic Escherichia coli O157:H7
Authors: Gonyar Laura A. , Kendall Melissa M. 
Published: October 2013

ABSTRACT

Enterohemorrhagic
Escherichia coli
(EHEC) O157:H7 is an important food-borne pathogen responsible for disease outbreaks worldwide. In order to colonize the human gastrointestinal (GI) tract and cause disease, EHEC must be able to sense the host environment and promote expression of virulence genes essential for adherence. Ethanolamine (EA) is an important metabolite for EHEC in the GI tract, and EA is also a signal that EHEC uses to activate virulence traits. Here, we report that EA influenced EHEC adherence to epithelial cells and fimbrial gene expression. Quantitative reverse transcriptase PCR indicated that EA promoted the transcription of the genes in characterized and putative fimbrial operons. Moreover, putative fimbrial structures were produced by EHEC cells grown with EA but not in medium lacking EA. Additionally, we defined two previously uncharacterized EA-regulated fimbrial operons,
loc10
and
loc11
. We also tested whether choline or serine, both of which are also components of cell membranes, activated fimbrial gene expression. In addition to EA, choline activated fimbrial gene expression in EHEC. These findings describe for the first time the transcription of several putative fimbrial loci in EHEC. Importantly, the biologically relevant molecules EA and choline, which are abundant in the GI tract, promoted expression of these fimbriae.
Yersinia enterocolitica Inhibits Salmonella enterica Serovar Typhimurium and Listeria monocytogenes Cellular Uptake
Authors: Habyarimana Fabien , Swearingen Matthew C. , Young Glenn M. , Seveau Stephanie , Ahmer Brian M. M. 
Published: October 2013

ABSTRACT

Yersinia enterocolitica
biovar 1B employs two type three secretion systems (T3SS), Ysa and Ysc, which inject effector proteins into macrophages to prevent phagocytosis. Conversely,
Salmonella enterica
serovar Typhimurium uses a T3SS encoded by
Salmonella
pathogenicity island 1 (SPI1) to actively invade cells that are normally nonphagocytic and a second T3SS encoded by SPI2 to survive within macrophages. Given the distinctly different outcomes that occur with regard to host cell uptake of
S
. Typhimurium and
Y. enterocolitica
, we investigated how each pathogen influences the internalization outcome of the other.
Y. enterocolitica
reduces
S
. Typhimurium invasion of HeLa and Caco-2 cells to a level similar to that observed using an
S
. Typhimurium SPI1 mutant alone. However,
Y. enterocolitica
had no effect on
S
. Typhimurium uptake by J774.1 or RAW264.7 macrophage-like cells.
Y. enterocolitica
was also able to inhibit the invasion of epithelial and macrophage-like cells by
Listeria monocytogenes
.
Y. enterocolitica
mutants lacking either the Ysa or Ysc T3SS were partially defective, while double mutants were completely defective, in blocking
S
. Typhimurium uptake by epithelial cells.
S
. Typhimurium encodes a LuxR homolog, SdiA, which detects
N
-acylhomoserine lactones (AHLs) produced by
Y. enterocolitica
and upregulates the expression of an invasin (Rck) and a putative T3SS effector (SrgE). Two different methods of constitutively activating the
S
. Typhimurium SdiA regulon failed to reverse the uptake blockade imposed by
Y. enterocolitica
.
Secondary Lymphoid Organ Homing Phenotype of Human Myeloid Dendritic Cells Disrupted by an Intracellular Oral Pathogen
Authors: Miles Brodie , Zakhary Ibrahim , El-Awady Ahmed , Scisci Elizabeth , Carrion Julio , O'Neill John C. , Rawlings Aaron , Stern J. Kobi , Susin Cristiano , Cutler Christopher W. 
Published: October 2013

ABSTRACTSeveral intracellular pathogens, including a key etiological agent of chronic periodontitis,Porphyromonas gingivalis, infect blood myeloid dendritic cells (mDCs). This infection results in pathogen dissemination to distant inflammatory sites (i.e., pathogen trafficking). The alteration in chemokine-chemokine receptor expression that contributes to this pathogen trafficking function, particularly toward sites of neovascularization in humans, is unclear. To investigate this, we utilized human monocyte-derived DCs (MoDCs) and primary endothelial cellsin vitro, combined withex vivo-isolated blood mDCs and serum from chronic periodontitis subjects and healthy controls. Our results, using conditional fimbria mutants ofP. gingivalis, show thatP. gingivalisinfection of MoDCs induces an angiogenic migratory profile. This profile is enhanced by expression of DC-SIGN on MoDCs and minor mfa-1 fimbriae onP. gingivalisand is evidenced by robust upregulation of CXCR4, but not secondary lymphoid organ (SLO)-homing CCR7. This disruption of SLO-homing capacity in response to respective chemokines closely matches surface expression of CXCR4 and CCR7 and is consistent with directed MoDC migration through an endothelial monolayer.Ex vivo-isolated mDCs from the blood of chronic periodontitis subjects, but not healthy controls, expressed a similar migratory profile; moreover, sera from chronic periodontitis subjects expressed elevated levels of CXCL12. Overall, we conclude thatP. gingivalisactively “commandeers” DCs by reprogramming the chemokine receptor profile, thus disrupting SLO homing, while driving migration toward inflammatory vascular sites.