bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and Evaluation of Improved 4′-
O
-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics
Authors: Duscha Stefan , Boukari Heithem , Shcherbakov Dimitri , Salian Sumantha , Silva Sandrina , Kendall Ann , Kato Takayuki , Akbergenov Rashid , Perez-Fernandez Deborah , Bernet Bruno , Vaddi Swapna , Thommes Pia , Schacht Jochen , Crich David , Vasella Andrea , Böttger Erik C. 
Published: October 2014

ABSTRACT

The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in
in vitro
ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and
in vivo
ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity.

IMPORTANCE
The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.
Clinical Characteristics and Outcomes of Prosthetic Joint Infection Caused by Small Colony Variant Staphylococci
Authors: Tande Aaron J. , Osmon Douglas R. , Greenwood-Quaintance Kerryl E. , Mabry Tad M. , Hanssen Arlen D. , Patel Robin 
Published: October 2014

ABSTRACT

Small colony variants (SCVs) are naturally occurring subpopulations of bacteria. The clinical characteristics and treatment outcomes of patients with prosthetic joint infection (PJI) caused by staphylococcal SCVs are unknown. This study was a retrospective series of 113 patients with staphylococcal PJI, with prospective testing of archived sonicate fluid samples. SCVs were defined using two-investigator review. Treatment failure was defined as (i) subsequent revision surgery for any reason, (ii) PJI after the index surgery, (iii) prosthesis nonreimplantation due to ongoing infection, or (iv) amputation of the affected limb. There were 38 subjects (34%) with SCVs and 75 (66%) with only normal-phenotype (NP) bacteria. Subjects with SCVs were more likely to have been on chronic antimicrobials prior to surgery (
P
= 0.048), have had prior surgery for PJI (
P
= 0.03), have had a longer duration of symptoms (
P
= 0.0003), and have had a longer time since joint implantation (
P
= 0.007), compared to those with only NP bacteria. Over a median follow-up of 30.6 months, 9 subjects (24%) with SCVs and 23 (32%) with only NP bacteria experienced treatment failure (
P
= 0.51). Subjects infected with
Staphylococcus aureus
were more likely to fail than were those infected with
Staphylococcus epidermidis
(hazard ratio [HR], 4.03; 95% confidence interval [CI], 1.80 to 9.04). While frequently identified in subjects with PJI and associated with several potential predisposing factors, SCVs were not associated with excess treatment failure compared to NP infections in this study, where they were primarily managed with two-stage arthroplasty exchange.

IMPORTANCE
Bacteria with the small colony variant (SCV) phenotype are described in small case series as causing persistent or relapsing infection, but there are insufficient data to suggest that they should be managed differently than infection with normal-phenotype bacteria. In an effort to investigate the clinical importance of this phenotype, we determined whether SCVs were present in biofilms dislodged from the surfaces of arthroplasties of patients with staphylococcal prosthetic joint infection and assessed the clinical outcomes associated with detection of SCVs. We found that prosthetic joint infection caused by SCV staphylococci was associated with a longer duration of symptoms and more prior treatment for infection but not with an increased rate of treatment failure, compared to infection caused by normal-phenotype staphylococci.
Risk Factors Associated with Adverse Events of Acupuncture: A Prospective Study
Authors: Chung Ka-Fai , Yeung Wing-Fai , Kwok Chi-Wa , Yu Yee-Man 
Published: October 2014

Objective Mild adverse events (AEs) are common with acupuncture, but the risk factors remain unclear. A prospective study using a standardised AE assessment and acupuncture protocol was undertaken to address the question. Methods A 20-item AE report form investigated local and systemic AEs in 150 adults with insomnia randomised to receive traditional, minimal and non-invasive sham acupuncture. Sociodemographic, clinical and psychological variables at baseline and past history and perceived credibility of acupuncture were assessed. Results The incidence of any AEs per patient was 42.4% with traditional acupuncture, 40.7% with minimal acupuncture and 16.7% with non-invasive sham acupuncture. Traditional and minimal acupuncture were associated with a greater number of local AEs, while the presence of a chronic medical condition was predictive of fewer local and systemic AEs. Greater severity of insomnia, anxiety, depression, somatic symptoms and pain catastrophising thoughts were associated with lower risk, but most of the significant correlations disappeared after logistic regression. Divorce and widowhood were the only significant sociodemographic variables, while previous acupuncture treatment and perceived credibility of acupuncture were found to be unrelated. The risk of any AEs was higher in participants receiving traditional acupuncture (OR 4.26) and minimal acupuncture (OR 4.27) and in those without medical comorbidity (OR 3.39). Conclusions The prevalence of AEs was higher than usual, probably due to the low threshold in our definition of AEs and the systematic collection from the patients’ perspective. Baseline variables were largely unable to predict AEs associated with acupuncture. Further studies should explore the roles of practitioners, patients’ anxiety during treatment and patient–practitioner interactions. Trial Registration Number NCT01707706.
Risk of bias in industry-funded oseltamivir trials: comparison of core reports versus full clinical study reports
Authors: Jefferson Tom , Jones Mark A , Doshi Peter , Del Mar Chris B , Hama Rokuro , Thompson Matthew J , Onakpoya Igho , Heneghan Carl J 
Published: October 2014

BackgroundThe Cochrane risk of bias tool is a prominent instrument used to evaluate potential biases in clinical trials. In three updates of our Cochrane review on neuraminidase inhibitors, we assessed risk of bias on the same trials using different levels of detail: the trials in journal publications, in core reports, and in full clinical study reports. Here we analyse whether progressively greater amounts of information and detail in full clinical study reports (including trial protocols, statistical analysis plans, certificates of analyses, individual participant data listings and randomisation lists) affected our risk of bias assessments.Methods and findingsWe used the Cochrane risk of bias tool to assess and compare risk of bias in 14 oseltamivir trials (reported in 10 clinical study reports) obtained from the European Medicines Agency (EMA) and the manufacturer, Roche. With more detailed information, reported in clinical study reports, no previous assessment of ‘high’ risk of bias was reclassified as ‘low’ or ‘unclear’ in the main analysis, and over half (55%, 34/62) of the previous assessments of ‘low’ risk of bias were reclassified as ‘high’. Most assessments of ‘unclear’ risk of bias (67%, or 28/42) were reclassified as ‘high’ risk of bias when our judgements were based on full clinical study reports. The limits of our study were our relative inexperience in dealing with large information sets, sometimes subjective bias judgements and focus on industry trials. Comparison with journal publications was not possible because of the low number of trials published.ConclusionsWe found that as information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.
Does a ‘direct’ transfer protocol reduce time to coronary angiography for patients with non-ST-elevation acute coronary syndromes? A prospective observational study
Authors: Gallagher S M , Lovell M J , Jones D A , Ferguson E , Ahktar A , Buckhoree Z , Wragg A , Knight C J , Mathur A , Smith E J , Cliffe S , Archbold R A , Rothman M T , Jain A K 
Published: October 2014

ObjectiveNational guidelines recommend ‘early’ coronary angiography within 96 h of presentation for patients with non-ST elevation acute coronary syndromes (NSTE-ACS). Most patients with NSTE-ACS present to their district general hospital (DGH), and await transfer to the regional cardiac centre for angiography. This care model has inherent time delays, and delivery of timely angiography is problematic. The objective of this study was to assess a novel clinical care pathway for the management of NSTE-ACS, known locally as the Heart Attack Centre-Extension or HAC-X, designed to rapidly identify patients with NSTE-ACS while in DGH emergency departments (ED) and facilitate transfer to the regional interventional centre for ‘early’ coronary angiography.MethodsThis was an observational study of 702 patients divided into two groups; 391 patients treated before the instigation of the HAC-X pathway (Pre-HAC-X), and 311 patients treated via the novel pathway (Post-HAC-X). Our primary study end point was time from ED admission to coronary angiography. We also assessed the length of hospital stay.ResultsMedian time from ED admission to coronary angiography was 7.2 (IQR 5.1–10.2) days pre-HAC-X compared to 1.0 (IQR 0.7–2.0) day post-HAC-X (p<0.001). Median length of hospital stay was 3.0 (IQR 2.0–6.0) days post-HAC-X v 9.0 (IQR 6.0–14.0) days pre-HAC-X (p<0.0005). This equates to a reduction of six hospital bed days per NSTE-ACS admission.ConclusionsThe introduction of this novel care pathway was associated with significant reductions in time to angiography and in total hospital bed occupancy for patients with NSTE-ACS.
Beyond the ‘dyad’: a qualitative re-evaluation of the changing clinical consultation
Authors: Swinglehurst Deborah , Roberts Celia , Li Shuangyu , Weber Orest , Singy Pascal 
Published: October 2014

ObjectiveTo identify characteristics of consultations that do not conform to the traditionally understood communication ‘dyad’, in order to highlight implications for medical education and develop a reflective ‘toolkit’ for use by medical practitioners and educators in the analysis of consultations.DesignA series of interdisciplinary research workshops spanning 12 months explored the social impact of globalisation and computerisation on the clinical consultation, focusing specifically on contemporary challenges to the clinician–patient dyad. Researchers presented detailed case studies of consultations, taken from their recent research projects. Drawing on concepts from applied sociolinguistics, further analysis of selected case studies prompted the identification of key emergent themes.SettingUniversity departments in the UK and Switzerland.ParticipantsSix researchers with backgrounds in medicine, applied linguistics, sociolinguistics and medical education. One workshop was also attended by PhD students conducting research on healthcare interactions.ResultsThe contemporary consultation is characterised by a multiplicity of voices. Incorporation of additional voices in the consultation creates new forms of order (anddisorder) in the interaction. The roles ‘clinician’ and ‘patient’ are blurred as they become increasingly distributed between different participants. These new consultation arrangements make new demands on clinicians, which lie beyond the scope of most educational programmes for clinical communication.ConclusionsThe consultation is changing. Traditional consultation models that assume a ‘dyadic’ consultation do not adequately incorporate the realities of many contemporary consultations. A paradox emerges between the need to manage consultations in a ‘super-diverse’ multilingual society, while also attending to increasing requirements for standardised protocol-driven approaches to care prompted by computer use. The tension between standardisation and flexibility requires addressing in educational contexts. Drawing on concepts from applied sociolinguistics and the findings of these research observations, the authors offer a reflective ‘toolkit’ of questions to ask of the consultation in the context of enquiry-based learning.
The role and significance of nurses in managing transitions to palliative care: a qualitative study
Authors: Kirby Emma , Broom Alex , Good Phillip 
Published: October 2014

ObjectivesNurses are generally present, and often influential, in supporting patient and family acceptance of medical futility and in assisting doctors in negotiating referral to palliative care. Yet the specificities of the nursing role and how nurses may contribute to timely and effective referrals is not well understood. This study aimed to systematically explore hospital-based nurses’ accounts of the transition to palliative care, and the potential role of nurses in facilitating more effective palliative care transitions.DesignQualitative study using semistructured interviews.SettingTwo health services with public as well as private clinical environments in a major metropolitan area of Australia.ParticipantsHospital-based nurses (n=20) who regularly work with patients at the point of referral and in managing transitions to palliative care.ResultsFour significant themes emerged from thematic analysis. These include: (1) professional dynamics and the roles played by nurses in initiating the transition to palliative care; (2) the value of nurses’ informal interactions in timely and effective transitions; (3) the emerging challenge of managing task-oriented nursing versus intense emotional nursing work at the point of medical futility and (4) the emotional burden experienced by nurses within this clinical context. Nurses self-reported occupying critical albeit complex roles in the management of medical futility and the transition to palliative care. They reported experiencing significant emotional burden in balancing interpersonal and interprofessional relationships during this time.ConclusionsThe results suggest that nurses may be utilised in a more formalised and systematic fashion in the context of managing medical futility and the need to topicalise the transition, with the focus shifted away from medical referrals towards more team-based and patient-centred timely transitions. Further research focused on the experiences of doctors, allied health professionals, patients and families is required to provide a broader interdisciplinary understanding of futility and contributions to the negotiation of palliative care.
Changes in left ventricular relaxation after azelnidipine treatment in hypertensive patients with diabetes: subanalysis of a prospective single-arm multicentre study
Authors: Iwakura Katsuomi , Ito Hiroshi , Ishii Katsuhisa , Date Motoo , Nakamura Fumiaki , Nagano Toshihiko , Takiuchi Shin 
Published: October 2014

ObjectivesWe previously demonstrated that a calcium channel blocker, azelnidipine, improves left ventricular relaxation in patients with hypertension and diastolic dysfunction in a multicentre, Clinical impact of Azelnidipine on Left VentricuLar diastolic function and OutComes in patients with hypertension (CALVLOC) trial. The objectives of the present subanalysis were to investigate the differences in diastolic function in hypertensive patients with and without diabetes, and the efficacy of azelnidipine on diastolic function among them.DesignSubanalysis of a prospective single-arm multicentre study.Participants228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e′velocity <8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes.InterventionsAdministration of 16 mg of azelnidipine for 8 months (range 6–10 months).Main outcome measuresSeptal e′velocity before and at the end of the study.ResultsWhereas patients with diabetes (n=53, 23.2%) had lower systolic blood pressure (BP) than patients without diabetes (155±17 vs 161±16 mm Hg, p=0.03), they had lower e′velocity (5.7±1.5 vs 6.1±1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e′velocity similarly in patients with diabetes (5.7±1.5 to 6.3±1.5 cm/s, p=0.0003) and without diabetes (6.1±1.4 to 6.9±1.4 cm/s, p<0.0001). Increase in e′velocity was not influenced by presence of diabetes, and patients with diabetes still had lower e′velocity after treatment (p=0.006). There was a significant correlation between increase in e′velocity and decrease in systolic BP (R=0.25, p=0.0001), which was not influenced by diabetes.ConclusionsComorbid diabetes could impair left ventricular relaxation independently in patients with hypertension, which might not be improved solely by BP lowering.
Associations of chronic individual-level and neighbourhood-level stressors with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis
Authors: Kershaw Kiarri N , Diez Roux Ana V , Bertoni Alain , Carnethon Mercedes R , Everson-Rose Susan A , Liu Kiang 
Published: October 2014

BackgroundSeveral individual-level stressors have been linked to incident coronary heart disease (CHD), but less attention has focused on the influence of neighbourhood-level sources of stress. In this study we examined prospective associations of individual-level and neighbourhood-level stressors with incident CHD.MethodsMulti-Ethnic Study of Atherosclerosis participants aged 45–84 years at baseline (2000–2002) with complete data were included in the analyses (n=6678 for individual-level and n=6105 for neighbourhood-level stressors). CHD was defined as non-fatal myocardial infarction, resuscitated cardiac arrest or CHD death. Median follow-up was 10.2 years. Multivariable Cox proportional hazards models were fitted to estimate associations of individual-level and neighbourhood-level stressors (categorised into approximate tertiles) with incident CHD.ResultsHigher reported individual-level stressors were associated with higher incident CHD. Participants in the high individual-level stressor category had 65% higher risk of incident CHD (95% CI 1.23 to 2.22) than those in the low category after adjusting for sociodemographics (P for trend=0.002). This association weakened but remained significant with further adjustment for behavioural and biological risk factors. There was a non-linear relationship between neighbourhood-level stressors and incident CHD (P for quadratic term=0.01). Participants in the medium category had 49% higher CHD risk (95% CI 1.06 to 2.10) compared with those in the low category; those in the high category had only 27% higher CHD risk (95% CI 0.83 to 1.95). These associations persisted with adjustment for risk factors and individual-level stressors.ConclusionsIndividual-level and neighbourhood-level stressors were independently associated with incident CHD, though the nature of the relationships differed.
CMD
Authors: Chen Licheng , Wei Zhipeng , Cui Zehan , Chen Mingyu , Pan Haiyang , Bao Yungang 
Published: October 2014

Limited main memory size is considered as one of the major bottlenecks in virtualization environments. Content-Based Page Sharing (CBPS) is an efficient memory deduplication technique to reduce server memory requirements, in which pages with same content are detected and shared into a single copy. As the widely used implementation of CBPS, Kernel Samepage Merging (KSM) maintains the whole memory pages into two global comparison trees (a stable tree and an unstable tree). To detect page sharing opportunities, each tracked page needs to be compared with pages already in these two large global trees. However since the vast majority of compared pages have different content with it, that will induce massive futility comparisons and thus heavy overhead.
In this paper, we propose a lightweight page Classification-based Memory Deduplication approach named CMD to reduce futile page comparison overhead meanwhile to detect page sharing opportunities efficiently. The main innovation of CMD is that pages are grouped into different classifications based on page access characteristics. Pages with similar access characteristics are suggested to have higher possibility with same content, thus they are grouped into the same classification. In CMD, the large global comparison trees are divided into multiple small trees with dedicated local ones in each page classification. Page comparisons are performed just in the same classification, and pages from different classifications are never compared (since they probably result in futile comparisons). The experimental results show that CMD can efficiently reduce page comparisons (by about 68.5%) meanwhile detect nearly the same (by more than 98%) or even more page sharing opportunities.
Friendly barriers
Authors: Kumar Vivek , Blackburn Stephen M. , Grove David 
Published: October 2014

This paper addresses the problem of efficiently supporting parallelism within a managed runtime. A popular approach for exploiting software parallelism on parallel hardware is task parallelism, where the programmer explicitly identifies potential parallelism and the runtime then schedules the work. Work-stealing is a promising scheduling strategy that a runtime may use to keep otherwise idle hardware busy while relieving overloaded hardware of its burden. However, work-stealing comes with substantial overheads. Recent work identified sequential overheads of work-stealing, those that occur even when no stealing takes place, as a significant source of overhead. That work was able to reduce sequential overheads to just 15%.
In this work, we turn to dynamic overheads, those that occur each time a steal takes place. We show that the dynamic overhead is dominated by introspection of the victim's stack when a steal takes place. We exploit the idea of a low overhead return barrier to reduce the dynamic overhead by approximately half, resulting in total performance improvements of as much as 20%. Because, unlike prior work, we attack the overheads directly due to stealing and therefore attack the overheads that grow as parallelism grows, we improve the scalability of work-stealing applications. This result is complementary to recent work addressing the sequential overheads of work-stealing. This work therefore substantially relieves work-stealing of the increasing pressure due to increasing intra-node hardware parallelism.