bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a National Physical Activity Plan for the United States
Authors: Bornstein Daniel B. , Pate Russell R. , Buchner David M. 
Published: April 2014

Background:Efforts to increase population levels of physical activity are increasingly taking the form of strategic plans at national, state/regional, and local levels. The processes employed for developing such plans have not been described previously. The purpose of this article is to chronicle the processes employed in and lessons learned from developing the US National Physical Activity Plan (NPAP).Methods:The Coordinating Committee oversaw development of the NPAP. Key steps in the process included creating a private–public coalition based in the private sector, organizing the NPAP around 8 societal sectors, reviewing the evidence base for promotion of physical activity in each sector, conducting a national conference to initiate development of the NPAP’s core content, ensuring broad participation in developing and refining the NPAP, and launching the NPAP through a press event that attracted national attention.Results and Conclusion:The 3-year effort to develop the NPAP was guided by a private–public collaborative partnership involving private sector organizations and government agencies. Launched in May 2010, the NPAP included more than 250 evidence-based recommendations for changes to policy and practice at the national, state, and local levels across 8 societal sectors.
Heterologous Expression of Thuricin CD Immunity Genes in Listeria monocytogenes
Authors: Mathur Harsh , O'Connor Paula M. , Cotter Paul D. , Hill Colin , Ross R. Paul 
Published: April 2014

ABSTRACT

Bacteriocins are ribosomally synthesized peptides that can have a narrow or broad spectrum of antimicrobial activity. Bacteriocin producers typically possess dedicated immunity systems that often consist of an ATP-binding cassette (ABC) transporter system and/or a dedicated immunity protein. Here we investigated the genes responsible for immunity to thuricin CD, a narrow-spectrum two-peptide sactibiotic produced by
Bacillus thuringiensis
DPC6431. Heterologous expression of putative thuricin CD immunity determinants allowed us to identify and investigate the relative importance of the individual genes and gene products that contribute to thuricin CD immunity. We established that TrnF and TrnG are the individual components of an ABC transporter system that provides immunity to thuricin CD. We also identified a hitherto overlooked open reading frame located upstream of
trnF
predicted to encode a 79-amino-acid transmembrane protein. We designated this newly discovered gene
trnI
and established that TrnI alone can provide protection against thuricin CD.
Bactericidal Activity of the Human Skin Fatty Acid
cis
-6-Hexadecanoic Acid on Staphylococcus aureus
Authors: Cartron Michaël L. , England Simon R. , Chiriac Alina Iulia , Josten Michaele , Turner Robert , Rauter Yvonne , Hurd Alexander , Sahl Hans-Georg , Jones Simon , Foster Simon J. 
Published: April 2014

ABSTRACT

Human skin fatty acids are a potent aspect of our innate defenses, giving surface protection against potentially invasive organisms. They provide an important parameter in determining the ecology of the skin microflora, and alterations can lead to increased colonization by pathogens such as
Staphylococcus aureus
. Harnessing skin fatty acids may also give a new avenue of exploration in the generation of control measures against drug-resistant organisms. Despite their importance, the mechanism(s) whereby skin fatty acids kill bacteria has remained largely elusive. Here, we describe an analysis of the bactericidal effects of the major human skin fatty acid
cis
-6-hexadecenoic acid (C6H) on the human commensal and pathogen
S. aureus
. Several C6H concentration-dependent mechanisms were found. At high concentrations, C6H swiftly kills cells associated with a general loss of membrane integrity. However, C6H still kills at lower concentrations, acting through disruption of the proton motive force, an increase in membrane fluidity, and its effects on electron transfer. The design of analogues with altered bactericidal effects has begun to determine the structural constraints on activity and paves the way for the rational design of new antistaphylococcal agents.
SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients
Authors: Dieterich Douglas , Asselah Tarik , Guyader Dominique , Berg Thomas , Schuchmann Marcus , Mauss Stefan , Ratziu Vlad , Ferenci Peter , Larrey Dominique , Maieron Andreas , Stern Jerry O. , Ozan Melek , Datsenko Yakov , Böcher Wulf Otto , Steinmann Gerhard 
Published: April 2014

ABSTRACT

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to
IL28B
genotype imbalances;
IL28B
genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).
Safety and Efficacy of Long-Term Outpatient Ertapenem Therapy
Authors: Qureshi Zubair A. , Syed Alveena , Doi Yohei 
Published: April 2014

ABSTRACT
Ertapenem is increasingly utilized in outpatient parenteral antimicrobial therapy (OPAT), but data regarding the efficacy and safety of long-term ertapenem therapy have been limited. We conducted a retrospective cohort study of adult patients who received outpatient ertapenem therapy at our center between 2010 and 2013. Among 306 unique patients who were discharged on ertapenem therapy, the most common indications were intra-abdominal infections (38%), followed by pneumonia (12%), bone and joint infections (11%), bloodstream infections (10%), urinary tract infections (10%), surgical site infections (5%), and skin and soft-tissue infections (4%). Of these 306 patients, 68 received regular outpatient follow-up visits at our infectious disease clinic, where the majority of patients (91%) were successfully treated with ertapenem by the end of therapy. Of the 6 patients who experienced clinical failure, 2 had adverse events leading to discontinuation of therapy and 4 required additional source control for clinical success. In addition, 2 patients had recurrent infection at 6 months.
Two Novel Functions of Hyaluronidase from Streptococcus agalactiae Are Enhanced Intracellular Survival and Inhibition of Proinflammatory Cytokine Expression
Authors: Wang Zhaofei , Guo Changming , Xu Yannan , Liu Guangjin , Lu Chengping , Liu Yongjie 
Published: April 2014

ABSTRACT

Streptococcus agalactiae
is the causative agent of septicemia and meningitis in fish. Previous studies have shown that hyaluronidase (Hyl) is an important virulence factor in many Gram-positive bacteria. To investigate the role of
S. agalactiae
Hyl during interaction with macrophages, we inactivated the gene encoding extracellular hyaluronidase,
hylB
, in a clinical Hyl
+
isolate. The isogenic
hylb
mutant (Δ
hylb
) displayed reduced survival in macrophages compared to the wild type and stimulated a significantly higher release of proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α), than the wild type in macrophages as well as in mice. Furthermore, only Hyl
+
strains could grow utilizing hyaluronic acid (HA) as the sole carbon source, suggesting that Hyl permits the organism to utilize host HA as an energy source. Fifty percent lethal dose (LD
50
) determinations in zebrafish demonstrated that the
hylb
mutant was highly attenuated relative to the wild-type strain. Experimental infection of BALB/c mice revealed that bacterial loads in the blood, spleen, and brain at 16 h postinfection were significantly reduced in the Δ
hylB
mutant compared to those in wild-type-infected mice. In conclusion, hyaluronidase has a strong influence on the intracellular survival of
S. agalactiae
and proinflammatory cytokine expression, suggesting that it plays a key role in
S. agalactiae
pathogenicity.
Lack of Long-Lasting Hydrosalpinx in A/J Mice Correlates with Rapid but Transient Chlamydial Ascension and Neutrophil Recruitment in the Oviduct following Intravaginal Inoculation with Chlamydia muridarum
Authors: Zhang Hongbo , Zhou Zhou , Chen Jianlin , Wu Ganqiu , Yang Zhangsheng , Zhou Zhiguang , Baseman Joel , Zhang Jin , Reddick Robert Lee , Zhong Guangming 
Published: April 2014

ABSTRACT

Lower genital tract infection with
Chlamydia trachomatis
and
C. muridarum
can induce long-lasting hydrosalpinx in the upper genital tract of women and female mice, respectively. However, A/J mice were highly resistant to induction of long-lasting hydrosalpinx by
C. muridarum
. We further compared host inflammatory responses and chlamydial infection courses between the hydrosalpinx-resistant A/J mice and CBA/J mice known to be susceptible to hydrosalpinx induction. Both mouse strains developed robust pyosalpinx during the acute phase followed by hydrosalpinx during the chronic phase. However, the hydrosalpinges disappeared in A/J mice by day 60 after infection, suggesting that some early hydrosalpinges are reversible. Although the overall inflammatory responses were indistinguishable between CBA/J and A/J mice, we found significantly more neutrophils in oviduct lumen of A/J mice on days 7 and 10, which correlated with a rapid but transient oviduct invasion by
C. muridarum
with a peak infection on day 7. In contrast, CBA/J mice developed a delayed and extensive oviduct infection. These comparisons have revealed an important role of the interactions of oviduct infection with inflammatory responses in chlamydial induction of long-lasting hydrosalpinx, suggesting that a rapid but transient invasion of oviduct by chlamydial organisms can prevent the development of the long-lasting hydrosalpinges.
GRA25 Is a Novel Virulence Factor of Toxoplasma gondii and Influences the Host Immune Response
Authors: Shastri Anjali J. , Marino Nicole D. , Franco Magdalena , Lodoen Melissa B. , Boothroyd John C. 
Published: April 2014

ABSTRACTThe obligate intracellular parasiteToxoplasma gondiiis able to infect a broad range of hosts and cell types due, in part, to the diverse arsenal of effectors it secretes into the host cell. Here, using genetic crosses between type II and type IIIToxoplasmastrains and quantitative trait locus (QTL) mapping of the changes they induce in macrophage gene expression, we identify a novel dense granule protein, GRA25. Encoded on chromosome IX, GRA25 is a phosphoprotein that is secreted outside the parasites and is found within the parasitophorous vacuole.In vitroexperiments with a type II Δgra25strain showed that macrophages infected with this strain secrete lower levels of CCL2 and CXCL1 than those infected with the wild-type or complemented control parasites.In vivoexperiments showed that mice infected with a type II Δgra25strain are able to survive an otherwise lethal dose ofToxoplasmatachyzoites and that complementation of the mutant with an ectopic copy ofGRA25largely rescues this phenotype. Interestingly, the type II and type III versions of GRA25 differ in endogenous expression levels; however, both are able to promote parasite expansionin vivowhen expressed in a type II Δgra25strain. These data establish GRA25 as a novel virulence factor and immune modulator.
Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans
Authors: Kretschmer Matthias , Reiner Ethan , Hu Guanggan , Tam Nicola , Oliveira Debora L. , Caza Melissa , Yeon Ju Hun , Kim Jeongmi , Kastrup Christian J. , Jung Won Hee , Kronstad James W. 
Published: April 2014

ABSTRACT

Nutrient acquisition and sensing are critical aspects of microbial pathogenesis. Previous transcriptional profiling indicated that the fungal pathogen
Cryptococcus neoformans
, which causes meningoencephalitis in immunocompromised individuals, encounters phosphate limitation during proliferation in phagocytic cells. We therefore tested the hypothesis that phosphate acquisition and polyphosphate metabolism are important for cryptococcal virulence. Deletion of the high-affinity uptake system interfered with growth on low-phosphate medium, perturbed the formation of virulence factors (capsule and melanin), reduced survival in macrophages, and attenuated virulence in a mouse model of cryptococcosis. Additionally, analysis of nutrient sensing functions for
C. neoformans
revealed regulatory connections between phosphate acquisition and storage and the iron regulator Cir1, cyclic AMP (cAMP)-dependent protein kinase A (PKA), and the calcium-calmodulin-activated protein phosphatase calcineurin. Deletion of the
VTC4
gene encoding a polyphosphate polymerase blocked the ability of
C. neoformans
to produce polyphosphate. The
vtc4
mutant behaved like the wild-type strain in interactions with macrophages and in the mouse infection model. However, the fungal load in the lungs was significantly increased in mice infected with
vtc4
deletion mutants. In addition, the mutant was impaired in the ability to trigger blood coagulation
in vitro
, a trait associated with polyphosphate. Overall, this study reveals that phosphate uptake in
C. neoformans
is critical for virulence and that its regulation is integrated with key signaling pathways for nutrient sensing.
Immunosuppressive Compounds Exhibit Particular Effects on Functional Properties of Human Anti-Aspergillus T
H
1 Cells
Authors: Tramsen Lars , Schmidt Stanislaw , Roeger Frauke , Schubert Ralf , Salzmann-Manrique Emilia , Latgé Jean-Paul , Klingebiel Thomas , Lehrnbecher Thomas 
Published: April 2014

ABSTRACT

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-
Aspergillus
T
H
1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-
Aspergillus
T
H
1 cells. Anti-
Aspergillus
T
H
1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin. Immunosuppressants were tested in concentrations reflecting common target levels in serum and in significantly lower and higher concentrations. Apoptosis of anti-
Aspergillus
T
H
1 cells, as well as proliferation and production of gamma interferon (IFN-γ) and CD154 upon restimulation, was evaluated in the presence and absence of immunosuppressive compounds. All dosages of CsA, MPA, and methylprednisolone significantly decreased the number of viable anti-
Aspergillus
T
H
1 cells in the cell culture, which was due partly to an impaired proliferative capacity of the cells and partly to an increased rate of apoptosis. In addition, CsA significantly decreased the number of IFN-γ-producing cells and had the highest impact of all immunosuppressants on IFN-γ levels in the supernatant. CsA also significantly decreased the expression of CD154 by anti-
Aspergillus
T
H
1 cells. Variant dosages of immunosuppressants exhibit particular effects on essential functional properties of anti-
Aspergillus
T
H
1 cells. Our findings may have an important impact on the design of clinical trials evaluating the therapeutic benefit of anti-
Aspergillus
T
H
1 cells in allogeneic HSCT recipients suffering from invasive aspergillosis.
Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations
Authors: Ducharme F M , Zemek R , Gravel J , Chalut D , Poonai N , Laberge S , Quach C , Krajinovic M , Guimont C , Lemière C , Guertin M C 
Published: April 2014

IntroductionOral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids.Methods and analysisThe design is a prospective cohort study of 1008 children aged 1–17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05.Ethics and disseminationEthical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host–environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations.ResultsResults will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists.Trial registration numberThis study is registered at Clinicaltrials.gov (NCT02013076).
Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis
Authors: Rana Malay , Wong-See Denise , Katz Tamarah , Gaskin Kevin , Whitehead Bruce , Jaffe Adam , Coakley John , Lochhead Alistair 
Published: April 2014

AimsDetermine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010.MethodsA retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed.ResultsDeficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%–35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient.ConclusionsThis is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.
Self-sealing barriers of sand/clay mixtures – lessons learnt from
in situ
experiment and retrospective modelling
Authors: Czaikowski O. , Miehe R. , Rothfuchs T. 
Published: April 2014

Abstract

In the framework of the SB experiment (‘Self-sealing barriers of sand/clay mixtures’), a series of small
in situ
tests in several vertical boreholes were installed in October 2005 at the underground rock laboratory at Mont Terri. The boreholes were backfilled with sand/clay mixtures at different ratios as well as pure MX-80 bentonite. At the GRS laboratory the experimental setup was installed in advance and has run under nearly the same boundary conditions since March 2005. Sand/clay mixtures exhibit a high permeability to gas in the dry state and a low gas entry pressure and moderate permeability to gas in the saturated state, while the permeability to water is comparable to that of the undisturbed host rock. Therefore, gaseous corrosion products will be preferentially conducted through the seal, mitigating the risk of opening new pathways (fractures) in the host rock. The main objective of the SB experiment presented here is to test and demonstrate that the advantageous sealing properties of clay/sand mixtures determined in the laboratory can technically be achieved and maintained under repository-relevant
in situ
conditions.