bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations
Authors: Joice April C. , Yang Sihyung , Farahat Abdelbasset A. , Meeds Heidi , Feng Mei , Li Junan , Boykin David W. , Wang Michael Zhuo , Werbovetz Karl A. 
Published: October 2017

ABSTRACTGiven the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority.In vitrocombination studies with DB766 and antifungal azoles against intracellularLeishmania donovanishowed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. InL. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinationsin vivois influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.
Assessing the Combined Antibacterial Effect of Isoniazid and Rifampin on Four Mycobacterium tuberculosis Strains Using
In Vitro
Experiments and Response-Surface Modeling
Authors: Genestet Charlotte , Ader Florence , Pichat Catherine , Lina Gérard , Dumitrescu Oana , Goutelle Sylvain 
Published: October 2017

ABSTRACT

While isoniazid and rifampin have been the cornerstone of tuberculosis therapy caused by drug-susceptible
Mycobacterium tuberculosis
for more than 40 years, their combined action has never been thoroughly assessed by modern quantitative pharmacology approaches. The aims of this work were to perform
in vitro
experiments and mathematical modeling of the antibacterial effect of isoniazid and rifampin alone and in combination against various strains of
Mycobacterium tuberculosis
. After MIC determination of H37Rv and three strains belonging to the Beijing, Euro-American, and Indo-Oceanic lineages, the antibacterial effects of isoniazid and rifampin alone and in combination were studied in static time-kill experiments. A sigmoidal maximum effect model (Hill equation) and a response-surface model were used to describe the effect of the drugs alone and in combination, respectively. The killing effect of isoniazid and rifampin alone were well described by the Hill equation. Rifampin displayed a more concentration-dependent effect than isoniazid around the MIC. The pharmacodynamics parameters of each drug (maximal effect, median effect concentration, and coefficient of sigmoidicity) were quite similar between the four strains. The response-surface model from Minto et al. fit data of combined effect very well with low bias and imprecision (C. F. Minto, T. W. Schnider, T. G. Short, K. M. Gregg, A. Gentilini, Anesthesiology
92:
1603–1616, 2000,
https://doi.org/10.1097/00000542-200006000-00017
). Response-surface modeling showed that the combined action of isoniazid and rifampin was synergistic for the H37Rv, Beijing, and Euro-American strains but only additive for the Indo-Oceanic strain. This study can serve as a motivating example for preclinical evaluation of combined action of antituberculous drugs.
Effect of Incubation Temperature on Antibiotic Resistance and Virulence Factors of Acinetobacter baumannii ATCC 17978
Authors: De Silva P. Malaka , Chong Patrick , Fernando Dinesh M. , Westmacott Garrett , Kumar Ayush 
Published: October 2017

ABSTRACT

Acinetobacter baumannii
is a notorious opportunistic pathogen that is prevalent mainly in hospital settings. The ability of
A. baumannii
to adapt and to survive in a range of environments has been a key factor for its persistence and success as an opportunistic pathogen. In this study, we investigated the effect of temperature on the clinically relevant phenotypes displayed by
A. baumannii
at 37°C and 28°C. Surface-associated motility was significantly reduced at 28°C, while biofilm formation on plastic surfaces was increased at 28°C. Decreased susceptibility to aztreonam and increased susceptibility to trimethoprim-sulfamethoxazole were observed at 28°C. No differences in virulence, as assayed in a
Galleria mellonella
model, were observed. Proteomic analysis showed differential expression of 629 proteins, of which 366 were upregulated and 263 were downregulated at 28°C. Upregulation of the Csu and iron uptake proteins at 28°C was a key finding for understanding some of the phenotypes displayed by
A. baumannii
at 28°C.
Exploring the theory, barriers and enablers for patient and public involvement across health, social care and patient safety: a protocol for a systematic review of reviews
Authors: Ocloo Josephine , Garfield Sarah , Dawson Shoba , Dean Franklin Bryony 
Published: October 2017

IntroductionThe emergence of patient and public involvement (PPI) in healthcare in the UK can be traced as far back as the 1970s. More recently, campaigns by harmed patients and their relatives have emerged as a result of clinical failings in the NHS, challenging paternalistic healthcare, which have led to a new focus on PPI in quality and safety, nationally and internationally. Evidence suggests that PPI within patient safety is often atheoretical and located within a biomedical discourse. This review will explore the literature on PPI across patient safety, healthcare and social care to identify theory, barriers and enablers that can be used to develop PPI in patient safety.Methods and analysisSystematic searches of three electronic bibliographic databases will be conducted, using both MeSH and free-text terms to identify empirical literature published from database inception to May 2017. The screening process will involve input from at least two researchers and any disagreement will be resolved through discussion with a third reviewer. Initial inclusion and exclusion criteria have been developed and will be refined iteratively throughout the process. Data extraction from included articles will be conducted by at least two researchers using a data extraction form. Extracted information will be analysed using a narrative review approach, which synthesises data using a descriptive method.Ethics and DisseminationNo ethical approval is required for this review as no empirical data were collected. We believe that the findings and recommendations from this review will be particularly relevant for an audience of academics and policymakers. The findings will, therefore, be written up and disseminated in international peer-reviewed journals and academic conferences with a health focus. They will also be disseminated to leading health policy organisations in the NHS, such as NHS England and NHS Improvement and national policy bodies such as the Health Foundation.
Cast versus functional brace in the rehabilitation of patients treated non-operatively for a rupture of the Achilles tendon: protocol for the UK study of tendo achilles rehabilitation (UK STAR) multi-centre randomised trial
Authors: Achten Juul , Parsons Nick R , Kearney Rebecca L , Maia Schlüssel Michael , Liew Anna S , Dutton Susan , Petrou Stavros , Ollivere Benjamin , Lamb Sarah E , Costa Matthew L 
Published: October 2017

IntroductionAchilles tendon rupture affects over 11 000 people yearly in the UK, and the incidence is increasing. Controversy remains with regard to the best rehabilitation strategy for these patients. In operatively treated patients, functional bracing provides better outcomes compared with plaster casts. However, the role of functional bracing in non-operatively managed patients is unclear. This is the protocol for a multicentre randomised trial of plaster cast immobilisation versus functional bracing for patients with a non-operatively managed Achilles tendon rupture.Methods and analysisAll adults presenting with a primary rupture of the Achilles tendon will be screened. Non-operatively treated patients will be eligible to take part in the trial. Broad eligibility criteria will ensure that the results of the study can be generalised to the wider patient population. Randomisation will be on a 1:1 basis. Both rehabilitation strategies are widely used within the National Health Service. Standardised protocols will be followed, and details of plaster material and brace will be as per the site’s usual practice.A minimum of 330 patients will be randomised to obtain 90% power to detect a difference of 8 points in Achilles Tendon Total Rupture Score at 9 months. Quality of life and resource use will be collected at 3, 6 and 9 months. The differences between treatment groups will be assessed on an intention-to-treat basis. The results of the trial-based economic evaluation will be expressed in terms of incremental cost per quality-adjusted life-year gained.Ethics and disseminationThe National Research Ethic Committee approved this study on 18 March 2016 (16/SC/0109).The National Institute for Health Research Health Technology Assessment monograph and a manuscript to a peer-reviewed journal will be submitted on completion of the trial (summer 2019). The results of this trial will substantially inform clinical practice on the clinical and cost-effectiveness of the treatment of this injury. This study has been registered on the International Standard Randomised Controlled Trial Number registry with reference noISRCTN62639639.
Multilayered Omics-Based Analysis of a Head and Neck Cancer Model of Cisplatin Resistance Reveals Intratumoral Heterogeneity and Treatment-Induced Clonal Selection
Authors: Niehr Franziska , Eder Theresa , Pilz Tanja , Konschak Robert , Treue Denise , Klauschen Frederick , Bockmayr Michael , Türkmen Seval , Jöhrens Korinna , Budach Volker , Tinhofer Ingeborg 
Published: October 2017

Abstract
Purpose: Platinum-based drugs, in particular cisplatin (cis-diamminedichloridoplatinum(II), CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown.
Experimental Design: By applying targeted next-generation sequencing, fluorescence in situ hybridization, microarray-based transcriptome, and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline, and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in patients with SCCHN with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset.
Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy-numbers and overexpression of the gain-of-function (GOF) mutant variant p53R248L. siRNA-mediated knockdown established a causal relationship between mutant p53R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K–AKT–mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort.
Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization. Clin Cancer Res; 24(1); 158–68. ©2017 AACR.
A Comparative Analysis of Chinese Historical Sources and y-dna Studies with Regard to the Early and Medieval Turkic Peoples
Authors: Lee Joo-Yup , Kuang Shuntu 
Published: October 2017

AbstractIn the past 10 years, geneticists have investigated the genetic variation of modern Turkic populations as well as ancientdnaof the Xiongnu and others. The accumulated findings of these surveys, however, have not been adequately noted by specialists in Inner Asian history. In order to fill this gap, we conducted a comparative analysis of textual information and genetic survey data on the early and medieval Turkic peoples. First, we examined the information on the origins, identity, and physiognomy of the early and medieval Turkic peoples contained in the Chinese Standard Histories (zhengshi正史). We then discussed how the findings of genetic surveys complement the textual information. Both Chinese histories and moderndnastudies indicate that the early and medieval Turkic peoples were made up of heterogeneous populations. The Turkicisation of central and western Eurasia was not the product of migrations involving a homogeneous entity, but that of language diffusion.
Milk, Game or Grain for a Manchurian Outpost
Authors: Bello David 
Published: October 2017

Abstract
The long record of imperial China’s Inner Asian borderland relations is not simply multi-ethnic, but ‘multi-environmental’. Human dependencies on livestock, wild animals and cereal cultivars were the prerequisite environmental relations for borderland incorporation. This paper examines such dependencies during the Qing Dynasty’s (1644–1912) establishment of the Manchurian garrison of Hulun Buir near the Qing border with Russia. Garrison logistics proved challenging because provisioning involved several indigenous groups—Solon-Ewenki, Bargut and Dagur (Daur)—who did not uniformly subsist on livestock, game or grain, but instead exhibited several, sometimes overlapping, practices not always confined within a single ethnicity. Ensuing deliberations reveal official convictions, some of which can be traced back to the preceding Ming Dynasty (1368–1644), regarding the variable effects of these practices on the formation of Inner Asian military identities. Such issues were distinctive of Qing borderland dynamics that constructed ‘Chinese’ empire not only in more diverse human society, but also in more diverse ecological spheres.
Local Representations of Evenkiness and Managing Identities among Evenki Adolescents in Buryatia
Authors: Huusko Svetlana 
Published: October 2017

Abstract
This article explores Evenki adolescents’ response to Russian representations of indigeneity in Buryatia (Russia) to gain an understanding of how Indigenous adolescents negotiate their space and identity in the context of local representations of Evenkiness. I position indigenous identity within social interactions. In Russia, these relations are not only political in nature, but also are located within a set of institutionally sanctioned dominant discourses and stereotypes based on them. The results show that Evenki adolescents in Nizhneangarsk often employ a strategy of managing ethnic identities, which could be viewed as a product of cultural-political context, formed during the Soviet Union and reinforced by modern Russian politics. It is a product of marginalisation and manifestation of assimilation of the Evenkis.
Buddhism and Kalmyk Secular Law in the Seventeenth to Nineteenth Centuries
Authors: Ulanov Mergen S. , Badmaev Valeriy N. , Holland Edward C. 
Published: October 2017

AbstractBuddhism endorses a set of rules and standards of conduct set out in the religion’s canonical texts. The text of the 1640 Steppe Code, both a peace treaty among the Mongols and an attempt at alliance buildingvis-à-visthe Manchus, also reflects the adaptation of the ethical norms of Buddhism to secular law and political relations. Secular law among the Kalmyks further evolved in the eighteenth and nineteenth centuries. The Toktols issued by Khan Donduk-Dashi in the eighteenth century addressed a wide range of religious and secular elements in Kalmyk life, while also serving to strengthen the moral authority of the Buddhist clergy. Further revisions to Kalmyk law and the position of Buddhism within the secular system were promulgated at the Jinjil assembly in 1822. The Kalmyks’ inclusion of religious provisions in secular law helped to strengthen the connection between Buddhism and Kalmyk society, consolidating the normative role of religion as the basis for secular conduct and action.
Treating anxiety and depression in young adults: A randomised controlled trial comparing clinician-guided versus self-guided Internet-delivered cognitive behavioural therapy
Authors: Dear Blake F , Fogliati Vincent J , Fogliati Rhiannon , Johnson Bareena , Boyle Olivia , Karin Eyal , Gandy Milena , Kayrouz Rony , Staples Lauren G , Titov Nickolai 
Published: October 2017

Background: Internet-delivered cognitive behaviour therapy may increase access by young adults to evidence-based treatments for anxiety and depression. Objective: The aim of this study was to compare the efficacy of an Internet-delivered cognitive behaviour therapy intervention designed for adults aged 18–24 years, when delivered in clinician-guided versus self-guided formats. Design: The intervention, the Mood Mechanic Course, is a transdiagnostic treatment that simultaneously targets symptoms of anxiety and depression using cognitive and behavioural skills. The brief intervention comprised four lessons, delivered over 5 weeks. Following a brief telephone interview, young adults ( n = 191) with symptoms of anxiety and depression were randomly allocated to either (1) clinician-guided treatment ( n = 96) or (2) self-guided treatment ( n = 95). Results: At post treatment, large reductions (average improvement; clinician guided vs self-guided) were observed in symptoms of anxiety (44% vs 35%) and depression (40% vs 31%) in both groups. Significant improvements were also observed in general psychological distress (33% vs 29%), satisfaction with life (18% vs 15%) and disability (36% vs 29%). No marked or consistent differences in clinical outcomes emerged between conditions at post-treatment, at 3-month or 12-month follow-up. Satisfaction was high with both treatment formats, but slightly higher for clinician-guided treatment. Conclusion: These results indicate the potential of carefully developed Internet-delivered cognitive behaviour therapy interventions for young adults with anxiety and depression provided in either self or therapist-guided format. Further large-scale research is required to determine the short- and long-term advantages and disadvantages of different models of support.
Australian elapid snake envenomation in cats: Clinical priorities and approach
Authors: Mcalees Trudi J , Abraham Linda A 
Published: October 2017

Practical relevance: No fewer than 140 species of terrestrial snakes reside in Australia, 92 of which possess venom glands. With the exception of the brown tree snake, the venom-producing snakes belong to the family Elapidae. The venom of a number of elapid species is more toxic than that of the Indian cobra and eastern diamondback rattle snake, which has earned Australia its reputation for being home to the world’s most venomous snakes. Clinical challenges: The diagnosis of elapid snake envenomation is not always easy. Identification of Australian snakes is not straightforward and there are no pathognomonic clinical signs. In cats, diagnosis of envenomation is confounded by the fact that, in most cases, there is a delay in seeking veterinary attention, probably because snake encounters are not usually witnessed by owners, and also because of the tendency of cats to hide and seek seclusion when unwell. Although the administration of antivenom is associated with improved outcomes, the snake venom detection kit and antivenom are expensive and so their use may be precluded if there are financial constraints. Evidence base: In providing comprehensive guidance on the diagnosis and treatment of Australian elapid snake envenomation in cats, the authors of this review draw on the published veterinary, medical and toxicology literature, as well as their professional experience as specialists in medicine, and emergency medicine and critical care.
Percutaneous pinning versus volar locking plate internal fixation for unstable distal radius fractures: a meta-analysis
Authors: Peng Fei , Liu Yuan-xiang , Wan Zhen-yu 
Published: October 2017

This meta-analysis compared outcomes between percutaneous pinning/wiring and open reduction internal fixation (ORIF) with locking plates for treatment of unstable distal radius fractures. Medline, Cochrane, EMBASE, and Google Scholar were searched through December 30, 2015. Twenty randomised controlled trials (RCTs) and non-randomised two-arm studies were included. Outcomes included scores of Disabilities of the Arms, Shoulders and Hands (DASH), visual analogue scale (VAS) pain, and patient rated wrist evaluation (PRWE) score, as well as range of motion (ROM) and complication incidence. ORIF/plating was associated with lower DASH scores but longer procedure time, while there was no difference between the two methods with respect to VAS pain score and PRWE score. The overall incidence of complications, including complex regional pain syndrome, was higher with pinning/wiring, though the incidence of carpal tunnel syndrome and nerve defects was not different. Supination and grip strength were better with ORIF. Radiographically, ulnar variation was greater with pinning/wiring. These results suggest that ORIF/plating is the preferred method of managing unstable distal radius fractures. Level of evidence: II
Perinatal management of hepatitis B virus: Clinical implementation of updated Australasian management guidelines
Authors: Bergin Hannah , Wood Gillian , Walker Susan P , Hui Lisa 
Published: October 2017

Objective To evaluate the implementation of the 2013 Royal Australian and New Zealand College of Obstetricians and Gynaecologists ‘Management of Hepatitis B in Pregnancy’ guideline. Methods Retrospective cohort study of the clinical management and obstetric outcomes among hepatitis B virus-positive women in a single tertiary maternity hospital. Women with viral load >200,000 IU/ml were referred to a specialised clinic for consideration of tenofovir disoproxil fumarate therapy to reduce mother to child transmission. Results A total of 11,496 women gave birth during the study period, of which 101 (0.9%) women were hepatitis B virus positive. Viral load was measured in 99 (98%) of 101 hepatitis B virus-positive women; 30 (30%) had a viral load >200,000 IU/ml. Twenty-six women accepted tenofovir disoproxil fumarate; of these, 23 had a successful virological response (viral load <200,000 IU/ml before delivery). Conclusions Adherence to updated management guidelines and patient acceptance of tenofovir disoproxil fumarate in our Australian population were high when provided in the context of a dedicated perinatal service.