bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized, Double-Blind, Phase II, Multicenter Study Evaluating the Safety/Tolerability and Efficacy of JNJ-Q2, a Novel Fluoroquinolone, Compared with Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infection
Authors: Covington Paul , Davenport J. Michael , Andrae David , O'Riordan William , Liverman Lisa , McIntyre Gail , Almenoff June 
Published: September 2011

ABSTRACT

JNJ-Q2 is a fluoroquinolone with broad coverage including methicillin-resistant
Staphylococcus aureus
(MRSA). A double-blind, multicenter, phase II noninferiority study treated 161 patients for 7 to 14 days, testing the efficacy of JNJ-Q2 (250 mg, twice a day [BID]) versus linezolid (600 mg, BID) in patients with acute bacterial skin and skin structure infections (ABSSSI). The prespecified criterion for noninferiority was 15%. Primary intent-to-treat analysis was unable to declare noninferiority, as the risk difference lower bound of the 95% confidence interval between treatments was 19% at 36 to 84 h postrandomization for the composite end point of lesion assessment and temperature. Prespecified clinical cure rates 2 to 14 days after completion of therapy were similar (83.1% for JNJ-Q2 versus 82.1% for linezolid).
Post hoc
analyses revealed that JNJ-Q2 was statistically noninferior to linezolid (61.4% versus 57.7%, respectively;
P
= 0.024) based on the 2010 FDA guidance, which defines treatment success as lack of lesion spread and afebrile status within 48 to 72 h postrandomization. Despite evidence of systemic disease, <5% of patients presented with fever, suggesting fever is not a compelling surrogate measure of systemic disease resolution for this indication. Nausea and vomiting were the most common adverse events. Of the patients, 86% (104/121) had
S. aureus
isolated from the infection site; 63% of these were MRSA. The results suggest JNJ-Q2 shows promise as an effective treatment for ABSSSI, demonstrating (i) efficacy for early clinical response (i.e., lack of spread of lesions and absence of fever at 48 to 72 h), and (ii) cure rates for ABSSSI pathogens (especially MRSA) consistent with the historical literature.
Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria
Authors: Rijken Marcus J. , McGready Rose , Phyo Aung Phae , Lindegardh Niklas , Tarning Joel , Laochan Natthapon , Than Hla Hla , Mu Oh , Win Aye Kyi , Singhasivanon Pratap , White Nicholas , Nosten François 
Published: September 2011

ABSTRACT

Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (
P
= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (
P
= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (
P
= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days;
P
= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml,
P
= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
Role of Aspergillus lentulus 14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility
Authors: Mellado Emilia , Alcazar-Fuoli Laura , Cuenca-Estrella Manuel , Rodriguez-Tudela Juan L. 
Published: September 2011

ABSTRACT

Recent studies have demonstrated that some morphologically atypical
Aspergillus fumigatus
strains are different species belonging to the section
Fumigati
.
Aspergillus lentulus
, one of these sibling species, is increasingly reported in patients under corticosteroid treatment. MICs of most antifungals in clinical use are elevated against
A. lentulus
, and it shows primary resistance to azole drugs. Two
A. lentulus
cytochrome P450 14-α sterol demethylases, encoded by
A. lentulus
c
yp51
A (Alc
yp51A
) and Al
cyp51B
genes, were identified. Targeted
cyp51A
gene knockout in
A. lentulus
showed that the intrinsic azole resistance of this species is
cyp51A
dependent. The Δ
cyp51A
strain was morphologically indistinguishable from the
A. lentulus
wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice. The heterologous expression of
A. lentulus
cyp51A
was performed in an
A. fumigatus
cyp51A
-deficient strain, confirming that Cyp51A is responsible for the differences in
A. lentulus
-azole drug interaction.
Production of Autoantibodies by Murine B-1a Cells Stimulated with Helicobacter pylori Urease through Toll-Like Receptor 2 Signaling
Authors: Kobayashi Fumiko , Watanabe Eri , Nakagawa Yohko , Yamanishi Shingo , Norose Yoshihiko , Fukunaga Yoshitaka , Takahashi Hidemi 
Published: September 2011

ABSTRACTHelicobacter pyloriinfection is associated with several autoimmune diseases, in which autoantibody-producing B cells must be activated. Among these B cells, CD5-positive B-1a cells from BALB/c mice were confirmed to secrete autoantibodies when cocultured with purifiedH. pyloriurease in the absence of T cells. To determine the mechanisms for autoantibody production, CD5-positive B-1a cells were sorted from murine spleen cells and stimulated with either purifiedH. pyloriurease orH. pyloricoated onto plates (referred to hereafter as plate-coatedH. pylori), and autoantibody production was measured by enzyme-linked immunosorbent assay (ELISA). Complete urease was not secreted fromH. pyloribut was visually expressed over the bacterium-like endotoxin. Urease-positive plated-coatedH. pyloristimulated B-1a cells to produce autoantibodies, although urease-deficient isotype-matchedH. pyloridid not. Autoantibody secretion by B-1a cells was inhibited when bacteria were pretreated with anti-H. pyloriurease-specific antibody having neutralizing ability against urease enzymatic activity but not with anti-H. pyloriurease-specific antibody without neutralizing capacity. The B-1a cells externally express various Toll-like receptors (TLRs): TLR1, TLR2, TLR4, and TLR6. Among the TLRs, blocking of TLR2 on B-1a cells with a specific monoclonal antibody (MAb), T2.5, inhibited autoantibody secretion when B-1a cells were stimulated with plate-coatedH. pyloriorH. pyloriurease. Moreover, B-1a cells from TLR2-knockout mice did not produce those autoantibodies. The present study provides evidence that functional urease expressed on the surface ofH. pyloriwill directly stimulate B-1a cells via innate TLR2 to produce various autoantibodies and may induce autoimmune disorders.
Infection with Conditionally Virulent Streptococcus pneumoniae Δ
pab
Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains
Authors: Chimalapati Suneeta , Cohen Jonathan , Camberlein Emilie , Durmort Claire , Baxendale Helen , de Vogel Corné , van Belkum Alex , Brown Jeremy S. 
Published: September 2011

ABSTRACT

Avirulent strains of a bacterial pathogen could be useful tools for investigating immunological responses to infection and potentially effective vaccines. We have therefore constructed an auxotrophic TIGR4 Δ
pab
strain of
Streptococcus pneumoniae
by deleting the
pabB
gene Sp_0665. The TIGR4 Δ
pab
strain grew well in complete medium but was unable to grow in serum unless it was supplemented with
para
-aminobenzoic acid (PABA). The TIGR4 Δ
pab
strain was markedly attenuated in virulence in mouse models of
S. pneumoniae
nasopharyngeal colonization, pneumonia, and sepsis. Supplementing mouse drinking water with PABA largely restored the virulence of TIGR4 Δ
pab
. An additional Δ
pab
strain constructed in the D39 capsular serotype 2 background was also avirulent in a sepsis model. Systemic inoculation of mice with TIGR4 Δ
pab
induced antibody responses to
S. pneumoniae
protein antigens, including PpmA, PsaA, pneumolysin, and CbpD, but not capsular polysaccharide. Flow cytometry demonstrated that IgG in sera from TIGR4 Δ
pab
-vaccinated mice bound to the surface of TIGR4 and D39 bacteria but not to a capsular serotype 3 strain, strain 0100993. Mice vaccinated with the TIGR4 Δ
pab
or D39 Δ
pab
strain by intraperitoneal inoculation were protected from developing septicemia when challenged with the homologous
S. pneumoniae
strain. Vaccination with the TIGR4 Δ
pab
strain provided only weak or no protection against heterologous challenge with the D39 or 0100993 strain but did strongly protect against a TIGR4 capsular-switch strain expressing a serotype 2 capsule. The failure of cross-protection after systemic vaccination with Δ
pab
bacteria suggests that parenteral administration of a live attenuated vaccine is not an attractive approach for preventing
S. pneumoniae
infection.
Implementing a systems-oriented morbidity and mortality conference in remote rural Nepal for quality improvement: Table 1
Authors: Schwarz Dan , Schwarz Ryan , Gauchan Bikash , Andrews Jason , Sharma Ranju , Karelas Gregory , Rajbhandari Ruma , Acharya Bibhav , Mate Kedar , Bista Amir , Bista Megha Giri , Sox Colin , Smith-Rohrberg Maru Duncan 
Published: September 2011

ProblemIn hospitals in rural, resource-limited settings, there is an acute need for simple, practical strategies to improve healthcare quality.SettingA district hospital in remote western Nepal.Key measures for improvementTo provide a mechanism for systems-level reflection so that staff can identify targets for quality improvement in healthcare delivery.Strategies for changeTo develop a morbidity and mortality conference (M&M) quality improvement initiative that aims to facilitate structured analysis of patient care and identify barriers to providing quality care, which can subsequently be improved.DesignThe authors designed an M&M involving clinical and non-clinical staff in conducting root-cause analyses of healthcare delivery at their hospital. Weekly conferences focus on seven domains of causal analysis: operations, supply chain, equipment, personnel, outreach, societal, and structural. Each conference focuses on assessing the care provided, and identifying ways in which services can be improved in the future.Effects of changeStaff reception of the M&Ms was positive. In these M&Ms, staff identified problem areas in healthcare delivery and steps for improvement. Subsequently, changes were made in hospital workflow, supply procurement, and on-site training.Lessons learntWhile widely practiced throughout the world, M&Ms typically do not involve both clinical and non-clinical staff members and do not take a systems-level approach. The authors' experience suggests that the adapted M&M conference is a simple, feasible tool for quality improvement in resource-limited settings. Senior managerial commitment is crucial to ensure successful implementation of M&Ms, given the challenging logistics of implementing these programmes in resource-limited health facilities.
Acupuncture: a treatment for breakthrough pain in cancer?
Authors: Paley Carole A , Johnson Mark I , Bennett Michael I 
Published: September 2011

ContextPatients with chronic cancer pain frequently suffer severe exacerbations of pain intensity which are difficult to control adequately via pharmaceutical management. Management of these episodes of breakthrough pain (BTP) presents a challenge both to the physician and the patient, and supplemental ‘rescue’ doses of opioids required to control BTP can produce intolerable side-effects and often do not act rapidly enough to provide adequate analgesia. There is very little evidence to support the use of acupuncture for BTP in cancer and few studies have considered the rapidity of the analgesic response to acupuncture for any type of pain. However, the available physiological evidence provides a convincing rationale and one which warrants research.ObjectiveThe objective of this paper is to debate the available physiological evidence for a rapid analgesic response to acupuncture in the context of the needs of the patient with cancer BTP, current interventions, acupuncture technique and the practical considerations involved in administering treatment rapidly and safely.ConclusionCurrent evidence suggests that acupuncture has the potential to produce rapid and effective analgesia when needles are inserted deeply enough and manipulated sufficiently. For cancer BTP this represents a possible adjunctive treatment, and consideration should be given to administering acupuncture alongside ‘rescue’ doses of medication to ‘kick-start’ the analgesic response before the medication takes effect. However, research is needed to provide evidence that acupuncture is effective for BTP in cancer, and the feasibility, practicality and safety of patients administering acupuncture themselves must also be taken into account.
Republished review: An update on contraindications for lung function testing
Authors: Cooper Brendan G 
Published: September 2011

ABSTRACT
Guidelines on contraindications for lung function tests have been based on expert opinion from &gt;30 years ago. High-risk contraindications to lung function testing are associated with cardiovascular complications such as myocardial infarct, pulmonary embolism or ascending aortic aneurysm. Slightly less risky but still serious contraindications are predominantly centred on recovery from major thoracic, abdominal or head surgery. Less serious surgical procedures will present a possible risk, but the RR depends upon whether the lung function is essential or can wait until the patient’s condition improves. In recent decades there have been moves towards less invasive surgical techniques, keyhole surgery and new technology such as laser surgery which minimise the amount of collateral damage to surrounding tissues. In thoracic surgery there is a shift in emphasis to quicker postsurgical mobility. Furthermore there has been little analysis of the scientific facts behind the current recommendations and contraindications. The principle absolute and relative contraindications are in need of revision, and recommended times of abstaining from lung function tests needs to be reviewed. This review aims to outline the key issues and suggests newer recommendations for contraindications for performing lung function using a risk matrix, as well as offering alternative approaches to testing patients who may be at risk of complication from testing. In general, the previous recommendation of waiting for 6 weeks after surgical procedures or medical complications before performing lung function can often now be reduced to &lt;3 weeks with modern less invasive surgical techniques.
Partial convex recolorings of trees and galled networks
Authors: Moran Shlomo , Snir Sagi , Sung Wing-Kin 
Published: September 2011

A coloring of a graph is convex if the vertices that pertain to any color induce a connected subgraph; a partial coloring (which assigns colors to a subset of the vertices) is convex if it can be completed to a convex (total) coloring. Convex coloring has applications in fields such as phylogenetics, communication or transportation networks, etc.When a coloring of a graph is not convex, a natural question is how far it is from a convex one. This problem is denoted asconvex recoloring(CR). While the initial works on CR defined and studied the problem on trees, recent efforts aim at either generalizing the underlying graphs or specializing the input colorings.In this work, we extend the underlying graph and the input coloring to partially colored galled networks. We show that although determining whether a coloring is convex on an arbitrary network is hard, it can be found efficiently on galled networks. We present a fixed parameter tractable algorithm that finds the recoloring distance of such a network whose running time is quadratic in the network size and exponential in that distance. This complexity is achieved by amortized analysis that uses a novel technique for contracting colored graphs that seems to be of independent interest.
ALK Mutations Conferring Differential Resistance to Structurally Diverse ALK Inhibitors
Authors: Heuckmann Johannes M. , Hölzel Michael , Sos Martin L. , Heynck Stefanie , Balke-Want Hyatt , Koker Mirjam , Peifer Martin , Weiss Jonathan , Lovly Christine M. , Grütter Christian , Rauh Daniel , Pao William , Thomas Roman K. 
Published: September 2011

Abstract
Purpose: EML4–ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4–ALK-positive tumors.
Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.
Results: Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4–ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.
Conclusions: Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4–ALK fusions and ALK mutations. Clin Cancer Res; 17(23); 7394–401. ©2011 AACR.
Catheter Ablation of Atrial Fibrillation in Patients With Chronic Lung Disease
Authors: Roh Seung-Young , Choi Jong-Il , Lee June Young , Kwak Jae-Jin , Park Jae-Seok , Kim Ji-Bak , Lim Hong-Euy , Kim Young-Hoon 
Published: September 2011

Background—
Chronic lung disease (CLD) is one of the important underlying diseases of atrial fibrillation (AF). The outcomes after radiofrequency catheter ablation of AF in patients with CLD have not yet been reported. We investigated the electroanatomic alterations in pulmonary veins (PVs) in CLD patients with AF and assessed their effect on the outcomes of radiofrequency catheter ablation of AF.

Method and Results—

We assessed 15 patients who had CLD and underwent radiofrequency catheter ablation of AF. CLD included chronic obstructive pulmonary disease, a tuberculosis-destroyed lung, and interstitial lung disease. For controls, we selected 60 sex-, age-, and procedure era–matched non-CLD patients who received radiofrequency catheter ablation for AF (4 controls for each CLD patient). Eight patients had chronic obstructive pulmonary disease, 6 had a tuberculosis-destroyed lung, and 1 had interstitial lung disease. PV morphology in the affected lung was altered significantly, ie, obliteration, pulling of the PVs toward the destroyed lung, or compensatory bulging of the PV antrum. These alterations were related to arrhythmogenicity in 6 (40%) of 15 patients with CLD. Non-PV foci were more common in the CLD group (4/15, 26.7%) than in the control group (3/60, 5.0%;
P
=0.025). All non-PV foci were located in the right atrium. The AF recurrence rate in the CLD group (26.7%, 4/15) was similar to that in the control group (18.3%, 11/60;
P
=0.45).

Conclusions—
Significant alteration of PV anatomy was related to arrhythmogenicity, and non-PV foci from the right atrium were commonly observed in the CLD group. Radiofrequency catheter ablation can be performed safely for AF in CLD patients with a comparable success rate to that in patients with normal lungs.
Impact of Exercise on Heart Rate Recovery
Authors: Jolly Michael A. , Brennan Danielle M. , Cho Leslie 
Published: September 2011

Background—
Abnormal heart rate recovery (HRR) has been shown to predict mortality. Although small studies have found that HRR can be improved with cardiac rehabilitation, it is unknown whether an improvement would affect mortality. The aim of this study was to determine whether HRR could be improved with cardiac rehabilitation and whether it would be predictive of mortality.

Methods and Results—

We evaluated 1070 consecutive patients who underwent exercise stress testing before and after completion of a phase 2 cardiac rehabilitation program. Heart rate recovery, defined as the difference between heart rate at peak exercise and exactly 1 minute into the recovery period, and mortality were followed up as the primary end points. Of 544 patients with abnormal baseline HRR, 225 (41%) had normal HRR after rehabilitation. Of the entire cohort, 197 patients (18%) died. Among patients with an abnormal HRR at baseline, failure to normalize after rehabilitation predicted a higher mortality (
P
<0.001). After multivariable adjustment, the presence of an abnormal HRR at exit was predictive of death in all patients (hazard ratio, 2.15; 95% confidence interval 1.43–3.25). Patients with abnormal HRR at baseline who normalized afterward had survival rates similar to those of the group with normal HRR at baseline and after cardiac rehabilitation (
P
=0.143).

Conclusions—
Heart rate recovery improved after phase 2 cardiac rehabilitation in the overall cohort. There was a strong association of abnormal HRR at exit with all-cause mortality. Patients with abnormal HRR at baseline who normalized HRR with exercise had a mortality similar to that of individuals with baseline normal HRR.