bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comprehensive Approach to Benefit–Risk Assessment in Drug Development
Authors: Sarac Sinan B. , Rasmussen Christian H. , Rasmussen Morten A. , Hallgreen Christine E. , Søeborg Tue , Colding‐Jørgensen Morten , Christensen Per K. , Thirstrup Steffen , Mosekilde Erik 
Published: February 2012

AbstractMajor regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit–risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data‐driven benefit–risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase. The proposed benefit–risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit–risk evaluation approach offers comprehensive, data‐driven assessments that can facilitate decision processes. It employs descriptive statistical methods to highlight the clinically significant differences between drugs in clinical trials. The approach can be used in single as well as in multiple trials and provides clear diagrams as the basis for presentation and discussion of the results.
Experimental Infection of Horses with Bartonella henselae and Bartonella bovis
Authors: Palmero J. , Pusterla N. , Cherry N.A. , Kasten R.W. , Mapes S. , Boulouis H.J. , Breitschwerdt E.B. , Chomel B.B. 
Published: February 2012

BackgroundExperimental infection of horses with Bartonella species is not documented.ObjectivesDetermine clinical signs, hematologic changes, duration of bacteremia, and pattern of seroconversion in Bartonella henselae or Bartonella bovis‐inoculated horses.AnimalsTwelve (2 groups of 6) randomly selected healthy adult horses seronegative and culture negative for Bartonella spp.MethodsExperimental/observational study: Group I: B. henselae or saline control was inoculated intradermally into 4 naïve and 2 sentinel horses, respectively. Group II: same design was followed by means of B. bovis. Daily physical examinations, once weekly CBC, immunofluorescent antibody assay serology, real‐time polymerase chain reaction (PCR), and twice weekly blood cultures were performed for 6 weeks and at postinoculation day 80 and 139. Bartonella alpha‐Proteobacteria growth medium (BAPGM) enrichment blood culture was performed for horses that seroconverted to B. henselae antigens.ResultsTransient clinical signs consistent with bartonellosis occurred in some Bartonella‐inoculated horses, but hematological alterations did not occur. Three B. henselae‐inoculated horses seroconverted, whereas 1 B. bovis‐inoculated horse was weakly seropositive. In Group I, B. henselae was amplified and sequenced from BAPGM blood culture as well as a subculture isolate from 1 horse, blood from a 2nd horse, and BAPGM blood culture from a 3rd horse although a subculture isolate was not obtained. All sentinels remained PCR, culture, and serology negative.ConclusionsDetection of Bartonella sp. in blood after experimental inoculation supports bacteremia and seroconversion. Culture with BAPGM may be required to detect Bartonella sp. Although mild clinical signs followed acute infection, no long‐term effects were noted for 2 years postinoculation.
Differential
In Vivo
Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and without
FKS
Resistance Mutations
Authors: Arendrup Maiken Cavling , Perlin David S. , Jensen Rasmus Hare , Howard Susan Julie , Goodwin Joanne , Hope William 
Published: February 2012

ABSTRACT

We recently observed that the micafungin MICs for some
Candida glabrata fks
hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical
C. glabrata
isolates with or without (S3)
fks
hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the
in vivo
efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E
50
s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (
E
max
) for caspofungin was higher against S3 than R83, but the estimates for E
50
were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.
Microbiological Analysis of a Prospective, Randomized, Double-Blind Trial Comparing Moxifloxacin and Clindamycin in the Treatment of Odontogenic Infiltrates and Abscesses
Authors: Sobottka Ingo , Wegscheider Karl , Balzer Ludwig , Böger Rainer H. , Hallier Olaf , Giersdorf Ina , Streichert Thomas , Haddad Munif , Platzer Ursula , Cachovan Georg 
Published: February 2012

ABSTRACT

The objective of this study was to identify the oral pathogens found in odontogenic infections, to determine their susceptibilities to amoxicillin-clavulanic acid (AMC), clindamycin (CLI), doxycycline (DOX), levofloxacin (LVX), moxifloxacin (MXF), and penicillin (PEN), and to search for associations between specific pathogens and types of infection. Swabs from patients enrolled in a randomized, double-blind phase II trial comparing MXF with CLI for the treatment of odontogenic abscesses or inflammatory infiltrates were cultured on media for aerobes and anaerobes. All bacterial isolates were identified at the species level. Overall, 205 isolates were cultured from 71 patients: 77 viridans group streptococci, 56
Prevotella
spp., 19
Neisseria
spp., 17
Streptococcus anginosus
group isolates and hemolytic streptococci, 15 other anaerobes, and 21 other bacteria. Ninety-eight percent of pathogens were susceptible to MXF, 96% to AMC, 85% to LVX, 67% to PEN, 60% to CLI, and 50% to DOX.
S. anginosus
group and hemolytic streptococci were found significantly more frequently (
P
= 0.04) in patients with abscesses (12/95) than in patients with infiltrates (5/110). In four patients with infiltrates who failed to respond to CLI therapy, three isolates of the
Streptococcus mitis
group and four
Neisseria
spp. resistant to CLI were found. In this study,
S. anginosus
group and hemolytic streptococci were clearly associated with odontogenic abscesses. Our analysis suggests that viridans group streptococci and
Neisseria
spp. play a decisive role in the etiology of odontogenic infiltrates. The high
in vitro
activity of MXF against odontogenic bacteria corresponds well to its clinical results in the treatment of odontogenic abscesses and infiltrates.
Ceramide and Toll-Like Receptor 4 Are Mobilized into Membrane Rafts in Response to Helicobacter pylori Infection in Gastric Epithelial Cells
Authors: Lu Dah-Yuu , Chen Hui-Chen , Yang Mei-Shiang , Hsu Yuan-Man , Lin Hwai-Jeng , Tang Chih-Hsin , Lee Che-Hsin , Lai Cheng-Kuo , Lin Chun-Jung , Shyu Woei-Cherng , Lin Fong-Yan , Lai Chih-Ho 
Published: February 2012

ABSTRACT

Helicobacter pylori
infection is thought to be involved in the development of several gastric diseases. Two
H. pylori
virulence factors (vacuolating cytotoxin A and cytotoxin-associated gene A) reportedly interact with lipid rafts in gastric epithelial cells. The role of Toll-like receptor (TLR)-mediated signaling in response to
H. pylori
infection has been investigated extensively in host cells. However, the receptor molecules in lipid rafts that are involved in
H. pylori
-induced innate sensing have not been well characterized. This study investigated whether lipid rafts play a role in
H. pylori
-induced ceramide secretion and TLR4 expression and thereby contribute to inflammation in gastric epithelial cells. We observed that both TLR4 and MD-2 mRNA and protein levels were significantly higher in
H. pylori
-infected AGS cells than in mock-infected cells. Moreover, significantly more TLR4 protein was detected in detergent-resistant membranes extracted from
H. pylori
-infected AGS cells than in those extracted from mock-infected cells. However, this effect was attenuated by the treatment of cells with cholesterol-usurping agents, suggesting that
H. pylori
-induced TLR4 signaling is dependent on cholesterol-rich microdomains. Similarly, the level of cellular ceramide was elevated and ceramide was translocated into lipid rafts after
H. pylori
infection, leading to interleukin-8 (IL-8) production. Using the sphingomyelinase inhibitor imipramine, we observed that
H. pylori
-induced TLR4 expression was ceramide dependent. These results indicate the mobilization of ceramide and TLR4 into lipid rafts by
H. pylori
infection in response to inflammation in gastric epithelial cells.
The Vibrio cholerae Pst2 Phosphate Transport System Is Upregulated in Biofilms and Contributes to Biofilm-Induced Hyperinfectivity
Authors: Mudrak Benjamin , Tamayo Rita 
Published: February 2012

ABSTRACT

Vibrio cholerae
is the causative agent of the deadly diarrheal disease cholera. As part of its life cycle,
V. cholerae
persists in marine environments, where it forms surface-attached communities commonly described as biofilms. Evidence indicates that these biofilms constitute the infectious form of the pathogen during outbreaks. Previous work has shown that biofilm-derived
V. cholerae
cells, even when fully dispersed from the biofilm matrix, are vastly more infectious than planktonic (free-living) cells. Here, we sought to identify factors that contribute to biofilm-induced hyperinfectivity in
V. cholerae
, and we present evidence for one aspect of the molecular basis of this phenotype. We identified proteins upregulated during growth in biofilms and determined their contributions to the hyperinfectivity phenotype. We found that PstS2, the periplasmic component of the Pst2 phosphate uptake system, was enriched in biofilms. Another gene in the
pst2
locus was transcriptionally upregulated in biofilms. Using the infant mouse model, we found that mutation of two
pst2
components resulted in impaired colonization. Importantly, deletion of the Pst2 inner membrane complex caused a greater colonization defect after growth in a biofilm compared to shaking culture. Based on these data, we propose that
V. cholerae
cells in biofilms upregulate the Pst2 system and therefore gain an advantage upon entry into the host. Further characterization of factors contributing to biofilm-induced hyperinfectivity in
V. cholerae
will improve our understanding of the transmission of the bacteria from natural aquatic habitats to the human host.
Generic quality of life predicts all-cause mortality in the short term: evidence from British Household Panel Survey
Authors: Netuveli Gopalakrishnan , Pikhart Hynek , Bobak Martin , Blane David 
Published: February 2012

BackgroundWhether the quality of life (QOL) impacts longevity is an interesting research question that has been investigated only in the context of disease and health-related QOL. This paper aims to examine prospectively whether Control, Autonomy, Self-realisation, and Pleasure (CASP) scores, a measure of generic QOL, can predict mortality in the British Household Panel Survey sample during 2001–2006.MethodsThe authors used data from the British Household Panel Survey wave 11 (2001–2002) when CASP was first presented to the participants in the survey. The authors selected all those who were interviewed directly and face to face and who were 40 years or older (N=10 291). The authors followed them for the next five waves (waves 12–16) and in this study primary outcome was all-cause mortality. Other covariates used were age, sex, socioeconomic position, household income, self-rated health, limiting long-standing illness and medical conditions.ResultsCompared with a mortality of 12/1000 person-years in those having average QOL (CASP score 29.4–45.8), those with below-average QOL had more than twice (27/1000 person-years) and those above average had a third less (8/1000 person-years) mortality. This gradient was retained for the most part when age and sex strata were examined separately. Regression models adjusted for covariates confirmed the protective effect of QOL on mortality. Domain-specific analysis showed that only control and self-realisation had this effect.ConclusionCASP predicted 5-year all-cause mortality significantly. Improvement in the QOL reduced the probability of death.
Data base administration in accounting information systems
Authors: Rushinek Avi , Rushinek Sara F. 
Published: February 2012

This research will explain the innovations in gathering and communicating data, outside the traditional role of the accounting function, which are required to adequately fulfill the information needs of all levels of management. Data Base Management Systems (DBMS) and their respective administration offer a good basis for collecting and utilizing available data, to aid the decision-making process at all levels of management.
At the functional level, managers are concerned with the use of historic data. Using a DBMS, these managers will be able to obtain specific, updated summary information from the database as needed.
Data Base Management, as part of an overall management information system, offers vast opportunities for more effective decision-making, installing the system that's best for your type of information, means whether or not you'll he getting appropriate data.
Inactivation of Heat Shock Factor Hsf4 Induces Cellular Senescence and Suppresses Tumorigenesis In Vivo
Authors: Jin Xiongjie , Eroglu Binnur , Cho Wonkyoung , Yamaguchi Yukihiro , Moskophidis Demetrius , Mivechi Nahid F. 
Published: February 2012

Abstract
Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated β-galactosidase (SA-β-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4−/− mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-β-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy. Mol Cancer Res; 10(4); 523–34. ©2012 AACR.
Prognostic Significance of Elevated Baseline Troponin in Patients With Acute Coronary Syndromes and Chronic Kidney Disease Treated With Different Antithrombotic Regimens
Authors: Acharji Subasit , Baber Usman , Mehran Roxana , Fahy Martin , Kirtane Ajay J. , Lansky Alexandra J. , Stone Gregg W. 
Published: February 2012

Background—
Elevation of baseline cardiac troponin in patients presenting with acute coronary syndromes (ACS) confers an adverse prognosis. The prognostic value of troponin elevation in patients with chronic kidney disease (CKD) and ACS is less certain.

Methods and Results—

In the ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) trial, 13 819 patients with moderate and high-risk ACS were assigned randomly to receive heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin monotherapy. Among 2179 patients with CKD (creatinine clearance <60 mL/min), baseline troponin elevation was present in 1291 patients (59.2%). Major bleeding and major adverse cardiac events (MACE), including death, myocardial infarction (MI), or unplanned revascularization, were examined according to baseline troponin status and randomization arm. Patients with CKD in whom the baseline troponin level was elevated had significantly higher rates of death, MI, and MACE at 30 days and 1 year compared with CKD patients without elevated baseline troponin. By multivariable analysis, baseline troponin elevation in patients with CKD was an independent predictor of composite death or MI at 30 days (hazard ratio [95% CI]=2.05 [1.48, 2.83],
P
<0.0001) and 1 year (1.72 [1.36, 2.17],
P
<0.0001). In CKD patients with baseline troponin elevation, bivalirudin monotherapy compared with heparin plus a GPI significantly reduced the 30-day rates of major bleeding with nonsignificantly different rates of MACE at 30 days and 1 year.

Conclusions—
In patients with ACS and CKD, baseline troponin elevation is associated with significantly worse short- and long-term clinical outcomes. Bivalirudin monotherapy safely reduces major bleeding in ACS patients with CKD and baseline troponin elevation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00093158.
Association of IREB2 and CHRNA3polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency
Authors: Kim Woo Jin , Wood Alice M , Barker Alan F , Brantly Mark L , Campbell Edward J , Eden Edward , McElvaney Gerard , Rennard Stephen I , Sandhaus Robert A , Stocks James M , Stoller James K , Strange Charlie , Turino Gerard , Silverman Edwin K , Stockley Robert A , DeMeo Dawn L 
Published: February 2012

Abstract

Background
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.

Methods
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.

Results
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.

Conclusions

IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
Correlation between magnifying narrow band imaging and histopathology in gastric protruding/or polypoid lesions: a pilot feasibility trial
Authors: Omori Takafumi , Kamiya Yoshio , Tahara Tomomitsu , Shibata Tomoyuki , Nakamura Masakatsu , Yonemura Joh , Okubo Masaaki , Yoshioka Daisuke , Ishizuka Takamitsu , Maruyama Naoko , Kamano Toshiaki , Fujita Hiroshi , Nakagawa Yoshihito , Nagasaka Mitsuo , Iwata Masami , Arisawa Tomiyasu , Hirata Ichiro 
Published: February 2012

Abstract

Background
Several study showed usefulness of microscopic capillaries, seen by magnifying narrow band imaging (NBI) endoscopy for predicting histopathology among superficial depressed or flat elevated gastric neoplasia (GN). Here we assessed the diagnostic efficacy of magnifying NBI for predicting histopathology among gastric protruding/or polypoid lesions.

Methods
Using endoscopic pictures of magnifying NBI from 95 protruding/or polypoid lesions (19 fundic gland polyps: FGP, 47 hyperplastic polyps: HP, and 29 GN), fine mucosal patterns were classified into four categories: small round, prolonged, villous or ridge, and unclear patterns, and micro vascular patterns were classified into five categories: honey comb, dense vascular, fine net work, core vascular, and unclear patterns.

Results
Most suggestive micro vascular patterns for predicting FGP, and HP were honeycomb (sensitivity 94.7%, specificity 97.4%), and dense vascular patterns (sensitivity 93.6%, specificity 91.6%), respectively. Fine net work, core vascular, and unclear patterns presented higher specificity (97%, 100%, and 100%) for predicting GN, and diagnostic efficacy of combined of those patterns was favorable (sensitivity 86.2%, specificity 97.0%).

Conclusion
Micro vascular patterns by using magnifying NBI provides meaningful information for predicting the histopathology of gastric protruding/or polypoid lesions.