bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three Phase III Randomized Controlled Trials of Topical Resiquimod 0.01-Percent Gel To Reduce Anogenital Herpes Recurrences
Authors: Mark Karen E. , Spruance Spotswood , Kinghorn George R. , Sacks Stephen L. , Slade Herbert B. , Meng Tze-Chiang , Selke Stacy , Magaret Amalia , Wald Anna 
Published: April 2014

ABSTRACT

Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days,
P
= 0.7; trial 2, 54 and 48 days,
P
= 0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days,
P
= not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days,
P
< 0.001; trial 2, 19 compared to 13 days,
P
= 0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days,
P
< 0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.
Identification of AP80978, a Novel Small-Molecule Inhibitor of Hepatitis C Virus Replication That Targets NS4B
Authors: Dufner-Beattie Jodi , O'Guin Andrew , O'Guin Stephanie , Briley Aaron , Wang Bin , Balsarotti Jennifer , Roth Robert , Starkey Gale , Slomczynska Urszula , Noueiry Amine , Olivo Paul D. , Rice Charles M. 
Published: April 2014

ABSTRACT

A small-molecule inhibitor of hepatitis C virus (HCV) designated AP89652 was identified by screening a compound library with an HCV genotype 1b subgenomic replicon assay. AP89652 contains two chiral centers, and testing of two
syn
enantiomers revealed that activity in the replicon assay resided with only one, AP80978, whose 50% effective concentration (EC
50
) (the concentration at which a 50% reduction in
Renilla
luciferase levels was observed relative to an untreated control) was 630 nM. AP80978 was inhibitory against HCV genotypes 1a and 1b but not genotype 2a. In a replicon clearance assay, the potency and clearance rate of AP80978 were similar to those of telaprevir (VX950) and cyclosporine (CsA). AP80978 was nontoxic when tested against a panel of human cell lines, and inhibitory activity was HCV specific in that there was limited activity against negative-strand viruses, an alphavirus, and flaviviruses. By selection of resistant replicons and assessment of activity in genotype 1b/2a intergenotypic replicons, the viral protein target of this compound was identified as NS4B. NS4B F98V/L substitutions were confirmed by site-directed mutagenesis as AP80978 resistance-associated mutations. When tested against HCV produced in cell culture, the compound was significantly more potent than other HCV inhibitors, including VX950, CsA, and 2′-C-methyladenosine (2′C-meA). In addition, AP80977, the enantiomer that was inactive in the replicon assay, had activity against the virus, although it was lower than the activity of AP80978. These results suggest that AP80978 has the potential to be optimized into an effective antiviral drug and is a useful tool to further study the role of NS4B in HCV replication.
Selective Inhibition of Hepatitis C Virus Infection by Hydroxyzine and Benztropine
Authors: Mingorance Lidia , Friesland Martina , Coto-Llerena Mairene , Pérez-del-Pulgar Sofía , Boix Loreto , López-Oliva Juan Manuel , Bruix Jordi , Forns Xavier , Gastaminza Pablo 
Published: April 2014

ABSTRACT
Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chemical library of compounds approved for clinical use in humans. This system enables identifying nontoxic antiviral compounds targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this analysis, we identified 12 compounds with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by determining their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compounds. We found that both compounds effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.
Molecular and Epidemiological Characterization of IMP-Type Metallo-β-Lactamase-Producing Enterobacter cloacae in a Large Tertiary Care Hospital in Japan
Authors: Hayakawa Kayoko , Miyoshi-Akiyama Tohru , Kirikae Teruo , Nagamatsu Maki , Shimada Kayo , Mezaki Kazuhisa , Sugiki Yuko , Kuroda Emi , Kubota Shiho , Takeshita Nozomi , Kutsuna Satoshi , Tojo Masayoshi , Ohmagari Norio 
Published: April 2014

ABSTRACT

IMP-type metallo-β-lactamase enzymes have been reported in different geographical areas and in various Gram-negative bacteria. However, the risk factors and epidemiology pertaining to IMP-type metallo-β-lactamase-producing
Enterobacter cloacae
(IMP-producing
E. cloacae
) have not been systematically evaluated. We conducted a retrospective, matched case-control study of patients from whom IMP-producing
E. cloacae
isolates were obtained, in addition to performing thorough molecular analyses of the clinically obtained IMP-producing
E. cloacae
isolates. Unique cases with IMP-producing
E. cloacae
isolation were included. Patients with IMP-producing
E. cloacae
were matched to uninfected controls at a ratio of 1 to 3. Fifteen IMP-producing
E. cloacae
cases were identified, with five of the isolates being obtained from blood, and they were matched to 45 uninfected controls. All (100%) patients from whom IMP-producing
E. cloacae
isolates were obtained had indwelling devices at the time of isolation, compared with one (2.2%) uninfected control. Independent predictors for isolation of IMP-producing
E. cloacae
were identified as cephalosporin exposure and invasive procedures within 3 months. Although in-hospital mortality rates were similar between cases and controls (14.3% versus 13.3%), the in-hospital mortality of patients with IMP-producing
E. cloacae
-caused bacteremia was significantly higher (40%) than the rate in controls. IMP-producing
E. cloacae
isolates were frequently positive for other resistance determinants. The MICs of meropenem and imipenem were not elevated; 10 (67%) and 12 (80%) of the 15 IMP-producing
E. cloacae
isolates had a MIC of ≤1 μg/ml. A phylogenetic tree showed a close relationship among the IMP-producing
E. cloacae
samples. Indwelling devices, exposure to cephalosporin, and a history of invasive procedures were associated with isolation of IMP-producing
E. cloacae
. Screening for carbapenemase production is important in order to apply appropriate clinical management and infection control measures.
Luliconazole Demonstrates Potent
In Vitro
Activity against Dermatophytes Recovered from Patients with Onychomycosis
Authors: Wiederhold Nathan P. , Fothergill Annette W. , McCarthy Dora I. , Tavakkol Amir 
Published: April 2014

ABSTRACT

The
in vitro
activities of luliconazole, amorolfine, ciclopirox, and terbinafine were determined against 320 dermatophyte isolates from large toenails of onychomycosis patients enrolled into an ongoing phase 2b/3 clinical study. The geometric mean MIC for luliconazole was 0.00022 μg/ml against all isolates, compared to 0.0194 to 0.3107 μg/ml for the three other agents. The
in vitro
potency of luliconazole was maintained regardless of the dermatophyte species.
Salmonella enterica Invasion of Polarized Epithelial Cells Is a Highly Cooperative Effort
Authors: Lorkowski Martin , Felipe-López Alfonso , Danzer Claudia A. , Hansmeier Nicole , Hensel Michael 
Published: April 2014

ABSTRACT

The invasion of polarized epithelial cells by
Salmonella enterica
requires the cooperative activity of the
Salmonella
pathogenicity island 1 (SPI1)-encoded type III secretion system (T3SS) and the SPI4-encoded adhesin SiiE. The invasion of polarized cells is more efficient than that of nonpolarized cells, and we observed the formation of clusters of bacteria on infected cells. Here we demonstrate that the invasion of polarized cells is a highly cooperative activity. Using a novel live-cell imaging approach, we visualized the cooperative entry of multiple bacteria into ruffles induced on the apical surfaces of polarized cells. The induction of membrane ruffles by activity of
Salmonella
enables otherwise noninvasive mutant strains to enter polarized host cells. Bacterial motility and chemotaxis were of lower importance for cooperativity in polarized-cell invasion. We propose that cooperative invasion is a key factor for the very efficient entry into polarized cells and a factor contributing to epithelial damage and intestinal inflammation.
Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial
Authors: Ajeganova Sofia , Svensson Björn , Hafström Ingiäld ,   on behalf of the BARFOT Study Group
Published: April 2014

ObjectiveTo examine the long-term effects of early low-dose prednisolone use in patients with rheumatoid arthritis (RA) on cardiovascular (CV) morbidity and mortality.DesignRetrieval of data from a 2-year open randomised trial comparing prednisolone 7.5 mg/day in addition to disease-modifying antirheumatic drugs (DMARDs) with DMARD therapy alone. Participants were followed for 10 years since inclusion into the original prednisolone trial or until occurrence of the studied outcomes.SettingSecondary level of care; six participating centres from southern Sweden; both urban and rural populations.ParticipantsOverall, 223 patients with early RA were included. The participants had no history of CV events at baseline and incident cases were identified via the Swedish Hospital Discharge and Cause of Death Registries.OutcomesComposite CV events, that is, ischaemic coronary and cerebrovascular events, components of the composite CV outcome, and death. Relative HRs from Cox proportional-hazards regression models were calculated.ResultsWithin 2041 person-years, 17 incident composite CV events occurred in 112 patients (15%) randomised to prednisolone, and 15 events of 111 patients (14%) who were assigned not to receive prednisolone. There were nine deaths (8%) in each group. The age-adjusted relative hazards (HRs; 95% CI) for the first composite CV event, first coronary event and death in the prednisolone group versus the group not treated with prednisolone were 1.8 (0.9 to 3.6), 0.98 (0.4 to 2.6) and 1.6 (0.6 to 4.1), respectively. The risk for the first cerebrovascular event showed a 3.7-fold increased relative hazard (95% CI 1.2 to 11.4) among prednisolone treated patients.ConclusionsIn this inception cohort study of low-dose prednisolone use during the first 2 years of RA disease, the incidence of ischaemic coronary artery events was similar in the two treatment groups, whereas the long-term risk of ischaemic cerebrovascular events was higher in the prednisolone group. There was a trend towards reduced survival in the prednisolone group.Trial registration numberISRCTN20612367.
The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus: meta-analysis of randomised controlled trials
Authors: Sun Yu-nan , Zhou Yi , Chen Xi , Che Weng-si , Leung Siu-wai 
Published: April 2014

ObjectivesThis meta-analysis aimed to evaluate whether dapagliflozin is synergistic with other antidiabetic drugs without body weight gain.SettingRandomised controlled trial (RCT) reports were retrieved from PubMed, Cochrane Library, EMBASE, ClinicalTrials.gov, Google Scholar and Google. Eligible RCTs were selected according to the criteria (including types of participants, intervention, outcomes) and assessed by the Cochrane risk of bias tool and GRADEpro software for evidential quality. Meta-analysis on the eligible RCTs was performed with the random effects model. The RCTs of low-quality and interim stages were excluded for further sensitivity analysis. Meta-regression was conducted on the follow-up durations. Publication bias was evaluated with funnel plots and the Egger's regression test and adjusted using the trim-and-fill procedure. Heterogeneity was assessed with the I2statistics.ParticipantsAdult patients with type 2 diabetes mellitus (T2DM).InterventionsDapagliflozin combined with conventional antidiabetic drugs.Primary and secondary outcome measuresGlycaemic level (measured by glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG)) and body weight.Results12 RCTs were eligible for quantitative synthesis and meta-analysis. The overall effect size of HbA1c calculated from mean difference was −0.52% (Z=−13.56, p<0.001) with 95% CI (−0.60 to −0.45). The effect size of FPG was −1.13 mmol/L (Z=−11.12, p<0.001) with 95% CI (−1.33 to −0.93). The effect size of body weight was −2.10 kg (Z=−18.77, p<0.001) with 95% CI (−2.32 to −1.88). Exclusions of low quality and interim RCTs changed the overall mean differences respectively to −0.56%, −1.11 mmol/L, 2.23 kg and −0.50%, −1.08 mmol/L, −2.08 kg. The sensitivity analysis indicated good robustness of the meta-analysis on HbA1c, FPG and body weight.ConclusionsThe meta-analysis showed that dapagliflozin as an add-on drug to conventional antidiabetic drugs improved the glycaemic control in T2DM participants without significant body weight gain.Trial registration numberCRD42013005034.
Long-term exposure to traffic-related air pollution and progression of carotid artery atherosclerosis: a prospective cohort study
Authors: Gan Wen Qi , Allen Ryan W , Brauer Michael , Davies Hugh W , Mancini G B John , Lear Scott A 
Published: April 2014

ObjectivesEpidemiological studies have demonstrated associations between long-term exposure to traffic-related air pollution and coronary heart disease (CHD). Atherosclerosis is the principal pathological process responsible for CHD events, but effects of traffic-related air pollution on progression of atherosclerosis are not clear. This study aimed to investigate associations between long-term exposure to traffic-related air pollution and progression of carotid artery atherosclerosis.SettingHealthy volunteers in metropolitan Vancouver, Canada.Participants and outcome measures509 participants aged 30–65 years were recruited and followed for approximately 5 years. At baseline and end of follow-up, participants underwent carotid artery ultrasound examinations to assess atherosclerosis severity, including carotid intima-media thickness, plaque area, plaque number and total area. Annual change of each atherosclerosis marker during the follow-up period was calculated as the difference between these two measurements divided by years of follow-up. Living close to major roads was defined as ≤150 m from a highway or ≤50 m from a major road. Residential exposures to traffic-related air pollutants including black carbon, fine particles, nitrogen dioxide and nitric oxide were estimated using high-resolution land-use regression models. The data were analysed using general linear models adjusting for various covariates.ResultsAt baseline, there were no significant differences in any atherosclerosis markers between participants living close to and those living away from major roads. After follow-up, the differences in annual changes of these markers between these two groups were small and not statistically significant. Also, no significant associations were observed with concentrations of traffic-related air pollutants including black carbon, fine particles, nitrogen dioxide and nitric oxide.ConclusionsThis study did not find significant associations between traffic-related air pollution and progression of carotid artery atherosclerosis in a region with lower levels and smaller contrasts of ambient air pollution.
The impact of different point-of-care testing lipid analysers on cardiovascular disease risk assessment
Authors: Whitehead Simon John , Ford Clare , Gama Rousseau 
Published: April 2014

AimsLipid point-of-care testing (POCT) analysers are being used to screen target populations to identify individuals at high risk of developing cardiovascular disease (CVD) as part of the National Health Service (NHS) Health Checks programme. We evaluated the performance of the Cholestech LDX and CardioChek PA POCT analysers against laboratory methods in CVD risk assessment.MethodsTen-year QRISK2, Joint British Societies' II (JBSII), and Framingham CVD risk scores were calculated for subjects recruited from Wolverhampton City PCT community NHS Health Check clinics. CVD risk scores derived using POCT capillary whole blood total cholesterol and HDL-cholesterol measurements were compared with those derived from the laboratory analysis of paired venous serum samples. Data from subjects with diabetes, overt CVD, and those who did not meet the risk algorithm age criteria were excluded.ResultsAll subjects classified as high risk (risk score >20%) by the three risk algorithms on the basis of the laboratory results were correctly identified by the LDX. One (2.2%) and four (7.0%) moderate-risk subjects were misclassified by the LDX as high risk, using the JBSII and Framingham risk algorithms, respectively. The CardioChek identified all subjects classed as high risk by QRISK2, but failed to identify 6/31 (19.4%) and 3/19 (15.8%) of subjects classed as high risk by the Framingham and JBSII algorithms, respectively. The CardioChek, however, did not misclassify any moderate-risk subjects as high risk.ConclusionsIdentification of subjects at risk of CVD depends on the cardiovascular risk algorithm and also on the performance of the POCT device.
Associations between obesogenic risk and depressive symptomatology in Australian adolescents: a cross-sectional study
Authors: Hoare E , Millar L , Fuller-Tyszkiewicz M , Skouteris H , Nichols M , Jacka F , Swinburn B , Chikwendu C , Allender S 
Published: April 2014

BackgroundDepression and obesity are significant health concerns currently facing adolescents worldwide. This paper investigates the associations between obesity and related risk behaviours and depressive symptomatology in an Australian adolescent population.MethodsData from the Australian Capital TerritoryIt's Your Moveproject, an Australian community-based intervention project were used. In 2012, 800 students (440 females, 360 males) aged 11–14 years (M=13.11 years, SD=0.62 years), from 6 secondary schools were weighed and measured and completed a questionnaire which included physical activity, sedentary behaviour and dietary intake. Weight status was defined by WHO criteria. A cut-off score ≥10 on the Short Mood and Feelings Questionnaire indicated symptomatic depression. Logistic regression was used to test associations.ResultsAfter controlling for potential confounders, results showed significantly higher odds of depressive symptomatology in males (OR=1.22, p<0.05) and females (OR=1.12, p<0.05) who exceeded guidelines for daily screen-time leisure sedentary activities. Higher odds of depressive symptoms were seen in females who consumed greater amounts of sweet drink (OR=1.18, p<0.05), compared to lower female consumers of sweet drinks, and males who were overweight/obese also had greater odds of depressive symptoms (OR=1.83, p<0.05) compared to male normal weight adolescents.ConclusionsThis study demonstrates the associations between obesogenic risks and depression in adolescents. Further research should explore the direction of these associations and identify common determinants of obesity and depression. Mental health outcomes need to be included in the rationale and evaluation for diet and activity interventions.
Disposition to home or acute rehabilitation is associated with a favorable clinical outcome in the SENTIS trial
Authors: Belagaje Samir R , Zander Kay , Thackeray Lisa , Gupta Rishi 
Published: April 2014

ObjectiveTo explore the impact of stroke severity and discharge disposition on 90-day outcomes in US patients enrolled in the SENTIS trial.MethodsSENTIS is a previously published prospective randomized controlled trial. We analyzed the demographic information, National Institutes of Health Stroke Scores (NIHSS) on day 4, discharge disposition and 90-day modified Rankin Score (mRS). Univariate models were constructed to determine the impact of discharge disposition on 90-day outcomes as well as the association of the day 4 NIHSS with outcomes.ResultsA total of 292 patients with a mean age of 65±14 years were analyzed. Discharge disposition was distributed as follows: 153 (52.1%) to an inpatient rehabilitation facility (IRF), 111 (38.0%) to home and 28 (9.6%) to a skilled nursing facility (SNF). Only 2 out of 28 patients (7.1%) discharged to a SNF achieved a 90-day mRS ≤2 compared with 60/153 (39.2%) in the IRF group (OR 8.39 (95% CI 1.92 to 36.64), p=0.0047). This association persisted after adjusting for age and admission NIHSS. Only 3 of 50 patients (6%) with a NIHSS of ≥14 at day 4 achieved a mRS 0–2 at day 90.ConclusionsThis analysis shows that discharge to an IRF is associated with better neurological outcomes than discharge to a SNF. Additionally, patients with a NIHSS of ≥14 at day 4 are unlikely to achieve independent function.