bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Activity of Delafloxacin against Contemporary Bacterial Pathogens from the United States and Europe, 2014
Authors: Pfaller M. A. , Sader H. S. , Rhomberg P. R. , Flamm R. K. 
Published: February 2017

ABSTRACT

The
in vitro
activities of delafloxacin and comparator antimicrobial agents against 6,485 bacterial isolates collected from medical centers in Europe and the United States in 2014 were tested. Delafloxacin was the most potent agent tested against methicillin-susceptible
Staphylococcus aureus
(MSSA), methicillin-resistant
S. aureus
,
Streptococcus pneumoniae
, viridans group streptococci, and beta-hemolytic streptococci and had activity similar to that of ciprofloxacin and levofloxacin against certain members of the
Enterobacteriaceae
. Overall, the broadest coverage of the tested pathogens (Gram-positive cocci and Gram-negative bacilli) was observed with meropenem and tigecycline in both Europe and the United States. Delafloxacin was shown to be active against organisms that may be encountered in acute bacterial skin and skin structure infections, respiratory infections, and urinary tract infections.
Decreased Expression of Stable RNA Can Alleviate the Lethality Associated with RNase E Deficiency in Escherichia coli
Authors: Himabindu P. , Anupama K. 
Published: February 2017

ABSTRACT

The endoribonuclease RNase E participates in mRNA degradation, rRNA processing, and tRNA maturation in
Escherichia coli
, but the precise reasons for its essentiality are unclear and much debated. The enzyme is most active on RNA substrates with a 5′-terminal monophosphate, which is sensed by a domain in the enzyme that includes residue R169;
E. coli
also possesses a 5′-pyrophosphohydrolase, RppH, that catalyzes conversion of 5′-terminal triphosphate to 5′-terminal monophosphate on RNAs. Although the C-terminal half (CTH), beyond residue approximately 500, of RNase E is dispensable for viability, deletion of the CTH is lethal when combined with an R169Q mutation or with deletion of
rppH
. In this work, we show that both these lethalities can be rescued in derivatives in which four or five of the seven
rrn
operons in the genome have been deleted. We hypothesize that the reduced stable RNA levels under these conditions minimize the need of RNase E to process them, thereby allowing for its diversion for mRNA degradation. In support of this hypothesis, we have found that other conditions that are known to reduce stable RNA levels also suppress one or both lethalities: (i) alterations in
relA
and
spoT
, which are expected to lead to increased basal ppGpp levels; (ii) stringent
rpoB
mutations, which mimic high intracellular ppGpp levels; and (iii) overexpression of DksA. Lethality suppression by these perturbations was RNase R dependent. Our work therefore suggests that its actions on the various substrates (mRNA, rRNA, and tRNA) jointly contribute to the essentiality of RNase E in
E. coli
.

IMPORTANCE
The endoribonuclease RNase E is essential for viability in many Gram-negative bacteria, including
Escherichia coli
. Different explanations have been offered for its essentiality, including its roles in global mRNA degradation or in the processing of several tRNA and rRNA species. Our work suggests that, rather than its role in the processing of any one particular substrate, its distributed functions on all the different substrates (mRNA, rRNA, and tRNA) are responsible for the essentiality of RNase E in
E. coli
.
The History of Bordetella pertussis Genome Evolution Includes Structural Rearrangement
Authors: Weigand Michael R. , Peng Yanhui , Loparev Vladimir , Batra Dhwani , Bowden Katherine E. , Burroughs Mark , Cassiday Pamela K. , Davis Jamie K. , Johnson Taccara , Juieng Phalasy , Knipe Kristen , Mathis Marsenia H. , Pruitt Andrea M. , Rowe Lori , Sheth Mili , Tondella M. Lucia , Williams Margaret M. 
Published: February 2017

ABSTRACT

Despite high pertussis vaccine coverage, reported cases of whooping cough (pertussis) have increased over the last decade in the United States and other developed countries. Although
Bordetella pertussis
is well known for its limited gene sequence variation, recent advances in long-read sequencing technology have begun to reveal genomic structural heterogeneity among otherwise indistinguishable isolates, even within geographically or temporally defined epidemics. We have compared rearrangements among complete genome assemblies from 257
B. pertussis
isolates to examine the potential evolution of the chromosomal structure in a pathogen with minimal gene nucleotide sequence diversity. Discrete changes in gene order were identified that differentiated genomes from vaccine reference strains and clinical isolates of various genotypes, frequently along phylogenetic boundaries defined by single nucleotide polymorphisms. The observed rearrangements were primarily large inversions centered on the replication origin or terminus and flanked by IS
481
, a mobile genetic element with >240 copies per genome and previously suspected to mediate rearrangements and deletions by homologous recombination. These data illustrate that structural genome evolution in
B. pertussis
is not limited to reduction but also includes rearrangement. Therefore, although genomes of clinical isolates are structurally diverse, specific changes in gene order are conserved, perhaps due to positive selection, providing novel information for investigating disease resurgence and molecular epidemiology.

IMPORTANCE
Whooping cough, primarily caused by
Bordetella pertussis
, has resurged in the United States even though the coverage with pertussis-containing vaccines remains high. The rise in reported cases has included increased disease rates among all vaccinated age groups, provoking questions about the pathogen's evolution. The chromosome of
B. pertussis
includes a large number of repetitive mobile genetic elements that obstruct genome analysis. However, these mobile elements facilitate large rearrangements that alter the order and orientation of essential protein-encoding genes, which otherwise exhibit little nucleotide sequence diversity. By comparing the complete genome assemblies from 257 isolates, we show that specific rearrangements have been conserved throughout recent evolutionary history, perhaps by eliciting changes in gene expression, which may also provide useful information for molecular epidemiology.
Adopting and sustaining a Virtual Fracture Clinic model in the District Hospital setting – a quality improvement approach
Authors: Logishetty Kartik , Subramanyam Soosainathan 
Published: February 2017

Virtual Fracture Clinics (VFCs) are an alternative to the conventional fracture clinics, to manage certain musculoskeletal injuries. This has recently been reported as a safe, cost-effective and efficient care model. As demonstrated at vanguard sites in the United Kingdom, VFCs can enhance patient care by standardising treatment and reducing outpatient appointments.This project demonstrates how a Quality Improvement approach was applied to introduce VFCs in the District General Hospital setting. We demonstrate how undertaking Process Mapping, Driver Diagrams, and Stakeholder Analysis can assist implementation. We discuss Whole Systems Measures applicable to VFCs, to consider how robust and specific data collection can progress this care model.Three Plan-Do-Study-Act cycles led to a change in practice over a 21-month period. Our target for uptake of new patients seen in VFCs within 6 months of starting was set at 50%. It increased from 0% to 56.1% soon after introduction, and plateaued at an average of 56.4% in the six-months before the end of the study period.Careful planning, frequent monitoring, and gathering feedback from a multidisciplinary team of varying seniority, were the important factors in transitioning to, and sustaining, a successful VFC model.
Improving community access to terminal phase medicines through the implementation of a ‘Core Medicines List’ in South Australian community pharmacies
Authors: Tait Paul , Horwood Chris , Hakendorf Paul , To Timothy 
Published: February 2017

ObjectivesDifficulties accessing medicines in the terminal phase hamper the ability of patients to die at home. The aim of this study was to identify changes in community access to medicines for managing symptoms in the terminal phase throughout South Australia (SA), following the development of a ‘Core Medicines List’ (the List) while exploring factors predictive of pharmacies carrying a broad range of useful medicines.MethodsIn 2015, SA community pharmacies were invited to participate in a repeat survey exploring the availability of specific medicines. Comparisons were made between 2012 and 2015. A ‘preparedness score’ was calculated for each pharmacy, scoring 1 point for each medicine held from the following 5 classes: opioid, benzodiazepine, antiemetic, anticholinergic and antipsychotic.ResultsThe proportion of pharmacies carrying all items from the List rose from 7% in 2012 to 18% in 2015 (p=0.01). Multiple linear regression demonstrated that a monthly online newsletter subscription (p=0.04) and provision of a clinical service to aged care facilities (p=0.02) were predictors of pharmacies carrying all items on the List. Furthermore, multiple linear regression demonstrated that the provision of an afterhours service (p=0.02) and clinical services to aged care facilities (p=0.04) were predictors of pharmacies with a high ‘preparedness score’. In responding to issues with supply of medicines at end of life, respondents were more likely to contact the prescriber if aware of palliative patients (p=0.03).ConclusionsThese results suggest that there is value in developing and promoting a standardised list of medicines, ensuring that community palliative patients have timely access to medicines in the terminal phase.
From concept to practice, is multidimensional care the leading principle in hospice care? An exploratory mixed method study
Authors: de Graaf Everlien , van Klinken Merel , Zweers Danielle , Teunissen Saskia 
Published: February 2017

BackgroundHospice care (HC) aims to optimise the quality of life of patients and their families by relief and prevention of multidimensional suffering. The aim of this study is to gain insight into multidimensional care (MC) provided to hospice inpatients by a multiprofessional team (MT) and identify facilitators, to ameliorate multidimensional HC.MethodsThis exploratory mixed-method study with a sequential quantitative–qualitative design was conducted from January to December 2015. First a quantitative study of 36 patient records (12 hospices, 3 patient records/hospice) was performed. The outcomes were MC, clinical reasoning and assessment tools. Second, MC was qualitatively explored using semistructured focus group interviews with multiprofessional hospice teams. Both methods had equal priority and were integrated during analysis.ResultsThe physical dimension was most prevalent in daily care, reflecting the patients' primary expressed priority at admission and the nurses' and physicians' primary focus. The psychological, social and spiritual dimensions were less frequently described. Assessment tools were used systematically by 4/12 hospices. Facilitators identified were interdisciplinary collaboration, implemented methods of clinical reasoning and structures.ConclusionsMC is not always verifiable in patient records; however, it is experienced by hospice professionals. The level of MC varied between hospices. The use of assessment tools and a stepped skills approach for spiritual care are recommended and multidimensional assessment tools should be developed. Leadership and commitment of all members of the MT is needed to establish the integration of multidimensional symptom management and interdisciplinary collaboration as preconditions for integrated multidimensional HC.
Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer
Authors: Manu Kanjoormana Aryan , Chai Tin Fan , Teh Jing Tsong , Zhu Wan Long , Casey Patrick J. , Wang Mei 
Published: February 2017

Abstract
Pancreatic cancer remains one of the most difficult to treat human cancers despite recent advances in targeted therapy. Inhibition of isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that posttranslationally modifies a group of proteins including several small GTPases, suppresses proliferation of some human cancer cells. However, the efficacy of ICMT inhibition on human pancreatic cancer has not been evaluated. In this study, we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition. In these cells, ICMT suppression inhibited proliferation and induced apoptosis. This responsiveness to ICMT inhibition was confirmed in in vivo xenograft tumor mouse models using both a small-molecule inhibitor and shRNA-targeting ICMT. Mechanistically, we found that, in sensitive pancreatic cancer cells, ICMT inhibition induced mitochondrial respiratory deficiency and cellular energy depletion, leading to significant upregulation of p21. Furthermore, we characterized the role of p21 as a regulator and coordinator of cell signaling that responds to cell energy depletion. Apoptosis, but not autophagy, that is induced via p21-activated BNIP3 expression accounts for the efficacy of ICMT inhibition in sensitive pancreatic cancer cells in both in vitro and in vivo models. In contrast, cells resistant to ICMT inhibition demonstrated no mitochondria dysfunction or p21 signaling changes under ICMT suppression. These findings not only identify pancreatic cancers as potential therapeutic targets for ICMT suppression but also provide an avenue for identifying those subtypes that would be most responsive to agents targeting this critical enzyme. Mol Cancer Ther; 16(5); 914–23. ©2017 AACR.
Tuber and root resistance of potato genotypes against Meloidogyne chitwoodi in the presence of Avena strigosa, related to tuber quality
Authors: Teklu Misghina G. , Schomaker Corrie H. , Been Thomas H. , Molendijk Leendert P.G. 
Published: February 2017

Relative tuber infestation and quality of two Meloidogyne chitwoodi resistant potato genotypes, AR04-4096 and 2011M1, were compared in glasshouse experiments at initial population density () = 16 second-stage juveniles (g dry soil)−1 in the presence and absence of the bristle oat, Avena strigosa. When A. strigosa was added, ( final population) on both AR04-4096 and 2011M1 increased 130×, increased 1.9 and 3.7×, respectively, while × fresh root weight (FRW)−1 was the same. Nematode hatch from peel of AR04-4096, without A. strigosa, was delayed by 3 weeks but relative hatching rate was increased. Although the RStuber (RS = Relative Susceptibility) of both AR04-4096 and 2011M1 were lower than 1%, in the presence of A. strigosa tuber quality of 2011M1 dropped below the marketable level, while that of AR04-4096 was hardly affected. We conclude that: i) is influenced by root mass; ii) root quality influences nematode hatch; iii) tuber quality is not an estimator for tuber resistance, and the reverse; iv) root resistance is equal to tuber resistance.
How do hospital doctors manage patients with medically unexplained symptoms: a qualitative study of physicians
Authors: Warner Alex , Walters Kate , Lamahewa Kethakie , Buszewicz Marta 
Published: February 2017

Objective Medically unexplained symptoms are a common presentation in medical practice and are associated with significant morbidity and high levels of service use. Most research exploring the attitudes and training of doctors in treating patients with unexplained symptoms has been conducted in primary care. This study aims to explore the ways in which doctors working in secondary care approach and manage patients with medically unexplained symptoms. Design A qualitative study using in-depth interviews and thematic analysis. Setting Three hospitals in the North Thames area. Participants Twenty consultant and training-grade physicians working in cardiology, gastroenterology, rheumatology and neurology. Main outcome measure Physicians' approach to patients with medically unexplained symptoms and their views on managing these patients. Results There was considerable variation in how the physicians approached patients who presented with medically unexplained symptoms. Investigations were often ordered without a clear rationale and the explanations given to patients when results of investigations were normal were highly variable, both within and across specialties. The doctor’s level of experience appeared to be a more important factor in their investigation and management strategies than their medical specialty. Physicians reported little or no formal training in how to manage such presentations, with no apparent consistency in how they had developed their approach. Doctors described learning from their own experience and from senior role models. Organisational barriers were identified to the effective management of these patients, particularly in terms of continuity of care. Conclusions Given the importance of this topic, there is a need for serious consideration as to how the management of patients with medically unexplained symptoms is included in medical training and in the planning and delivery of services.
Analysis of Audiometric Outcomes following Combined Middle Cranial Fossa/Transmastoid Approaches for Spontaneous Cerebrospinal Fluid Otorrhea
Authors: Stevens Shawn M. , Crane Ryan , Pensak Myles L. , Samy Ravi N. 
Published: February 2017

Outcome ObjectivesTo (1) explore audiometric outcomes following use of a combined transmastoid/middle cranial fossa (TM‐MCF) approach in the treatment of spontaneous cerebrospinal fluid (CSF) otorrhea and (2) determine the influence of dehiscence location and reconstructive methodology on audiometric outcomes.Study DesignCase series with chart review.SettingTertiary care center.Subjects and MethodsAdults with spontaneous CSF otorrhea were reviewed from 2007 to 2016 if they underwent combined TM‐MCF. Definitive audiometric evaluations were performed at least 3 months postoperatively. The primary outcomes measures were pre‐ to postoperative changes in pure‐tone average (PTA) and air‐bone gap (ABG). Two subset analyses were performed for audiometric outcomes comparisons: first, patients with skull base dehiscences anterior to the ossicular chain were compared with those with posterior dehiscences. Second, patients undergoing skull base resurfacing plus abdominal fat graft mastoid obliteration (AFGMO) were compared with those undergoing resurfacing alone.ResultsA total of 28 patients and 31 ears were reviewed. There was 1 recurrent leak (3.5%). The cohort demonstrated significant improvement in mean postoperative ABG (P =. 008) but not PTA. On subset analysis, ears with posterior dehiscences demonstrated significant improvements in PTA (P =. 03) and ABG (P =. 05), while ears with anterior dehiscences did not. In addition, ears undergoing resurfacing plus AFGMO achieved significant improvements on all parameters (P =. 01). Only 3 of 15 ears undergoing resurfacing plus AFGMO experienced worsened postoperative hearing.ConclusionUse of the combined TM‐MCF approach for treating spontaneous CSF otorrhea achieved good audiometric outcomes. Patients with skull base dehiscences posterior to the ossicles and those undergoing skull base resurfacing plus AFGMO achieved the most favorable results.
Direct cannulation of arch vessels for total arch replacement
Authors: Matsuzaki Yuichi , Hirayama Touitsu , Uesugi Hideyuki , Ideta Ichiro , Oshitomi Takashi 
Published: February 2017

Objectives: To observe the efficiency and safety of direct and indirect three arch vessels’ cannulation for bilateral antegrade cerebral perfusion during total arch replacement. Methods: Between 2002 and 2014, 130 patients underwent total arch replacement with direct and 66 patients with indirect cannulation for antegrade cerebral perfusion under moderate hypothermia. Patients were assigned to the direct cannulation group based on the condition of the aortic arch vessels. Demographics and concomitant surgeries were similar in the two groups. Patient characteristics, surgical and haemodynamic measurements, and postoperative neurologic findings were observed. Results: Aortic cross-clamping (120 ± 42 vs 139 ± 65 min; p = 0.032) and cardiopulmonary bypass (178 ± 57 vs 206 ± 71 min; p = 0.025) times were lower in the direct cannulation group. There were no differences in overall hospital mortality (4% vs 6%; p = 0.87), selective antegrade cerebral perfusion time (91 ± 52 vs 100 ± 65 min; p = 0.185), and incidence of neurologic deficit (3% vs 9%; p = 0.07). Indirect cannulation led to more frequent re-exploration for bleeding (5% vs 13%; p = 0.0356). There was no difference in midterm survival (log-rank p = 0.103; mean follow-up times: 4.74 years (direct cannulation), 5.50 years (indirect cannulation)). Conclusion: Direct cannulation during mild systemic hypothermia yields excellent outcomes while reducing time and rate of reoperation for bleeding and can be used in total arch replacement without increasing morbidity and mortality.
Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth
Authors: Bujisic Bojan , De Gassart Aude , Tallant Rémy , Demaria Olivier , Zaffalon Léa , Chelbi Sonia , Gilliet Michel , Bertoni Francesco , Martinon Fabio 
Published: February 2017

Key PointsGCB DLBCLs are characterized by a defective IRE1-XBP1 pathway. XBP1 expression reduces GCB DLBCL tumor growth in a mouse xenograft model.
Asymptotic Optimality of Tailored Base-Surge Policies in Dual-Sourcing Inventory Systems
Authors: Xin Linwei , Goldberg David A. 
Published: February 2017

Dual-sourcing inventory systems, in which one supplier is faster (i.e., express) and more costly, while the other is slower (i.e., regular) and cheaper, arise naturally in many real-world supply chains. These systems are notoriously difficult to optimize because of the complex structure of the optimal solution and the curse of dimensionality, having resisted solution for over 40 years. Recently, so-called tailored base-surge (TBS) policies have been proposed as a heuristic for the dual-sourcing problem. Under such a policy, a constant order is placed at the regular source in each period, while the order placed at the express source follows a simple order-up-to rule. Numerical experiments by several authors have suggested that such policies perform well as the lead time difference between the two sources grows large, which is exactly the setting in which the curse of dimensionality leads to the problem becoming intractable. However, providing a theoretical foundation for this phenomenon has remained a major open problem. In this paper, we provide such a theoretical foundation by proving that a simple TBS policy is indeed asymptotically optimal as the lead time of the regular source grows large, with the lead time of the express source held fixed. Our main proof technique combines novel convexity and lower-bounding arguments, an explicit implementation of the vanishing discount factor approach to analyzing infinite-horizon Markov decision processes, and ideas from the theory of random walks and queues, significantly extending the methodology and applicability of a novel framework for analyzing inventory models with large lead times recently introduced by Goldberg and coauthors in the context of lost-sales models with positive lead times. This paper was accepted by Gad Allon, operations management.