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Ingram J.R.,Institute of Infection and Immunity | Abbott R.,University of Wales | Ghazavi M.,Nottingham Treatment Center | Alexandroff A.B.,University of Leicester | And 3 more authors.
British Journal of Dermatology | Year: 2014

Background Hidradenitis suppurativa (HS) has been neglected by medical researchers and society in general, despite being a relatively common, painful, chronic skin disease. Objectives To generate a top 10 list of HS research priorities, from the perspectives of patients with HS, carers and clinicians, to take to funding bodies. Methods A priority setting partnership was established between patients with HS, carers and clinicians, following the James Lind Alliance process. Survey 1 requested submission of HS uncertainties, which were grouped into 'indicative uncertainties' for prioritization in survey 2. The 30 highest-ranked indicative uncertainties were reduced to a 'top 10' list using nominal group technique at a prioritization workshop attended by all relevant HS stakeholders. Results In total 1495 potential uncertainties were submitted in survey 1, including 57% from patients with HS and carers, and grouped into 55 indicative uncertainties. Ranking in survey 2 was completed by 371 participants, 50% of whom were patients and carers. The final workshop was attended by 22 HS stakeholders and four facilitators and produced a top 10 list, the three highest priorities in descending order being (i) What is the most effective and safe group of oral treatments in treating HS? (ii) What is the best management of an acute flare? (iii)What is the impact of HS and its treatment on people with HS? Conclusions The top 10 HS research priorities have been directly disseminated to funders to raise awareness of HS. The next step is to generate research questions that will provide the evidence needed to improve care for patients with HS. What's already known about this topic? Hidradenitis suppurativa (HS) has been relatively neglected by society and medical research funding bodies, resulting in a lack of evidence to guide HS care. Obtaining research funding for HS is challenging. Priority setting partnerships can be used to raise awareness of a condition and demonstrate to funders and researchers the priorities of both patients and clinicians. What does this study add? Using transparent and inclusive James Lind Alliance methodology, a top 10 list of HS research priorities was identified, from the perspective of people with HS, their carers and the clinicians involved in their care. This process is important because of the large number of HS uncertainties that exist, and it will help researchers and medical funding bodies to decide which HS projects should be prioritized. © 2014 British Association of Dermatologists.


Wailan A.M.,University of Queensland | Sidjabat H.E.,University of Queensland | Yam W.K.,University of Queensland | Yam W.K.,Agency for Science, Technology and Research Singapore | And 21 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2016

blaNDM genes confer carbapenem resistance and have been identified on transferable plasmids belonging to different incompatibility (Inc) groups. Here we present the complete sequences of four plasmids carrying a blaNDM gene, pKP1-NDM-1, pEC2-NDM-3, pECL3-NDM-1, and pEC4-NDM-6, from four clinical samples originating from four different patients. Different plasmids carry segments that align to different parts of the blaNDM region found on Acinetobacter plasmids. pKP1-NDM-1 and pEC2-NDM-3, from Klebsiella pneumoniae and Escherichia coli, respectively, were identified as type 1 IncA/C2 plasmids with almost identical backbones. Different regions carrying blaNDM are inserted in different locations in the antibiotic resistance island known as ARI-A, and ISCR1 may have been involved in the acquisition of blaNDM-3 by pEC2-NDM-3. pECL3-NDM-1 and pEC4-NDM-6, from Enterobacter cloacae and E. coli, respectively, have similar IncFIIY backbones, but different regions carrying blaNDM are found in different locations. Tn3-derived inverted-repeat transposable elements (TIME) appear to have been involved in the acquisition of blaNDM-6 by pEC4-NDM-6 and the rmtC 16S rRNA methylase gene by IncFIIY plasmids. Characterization of these plasmids further demonstrates that even very closely related plasmids may have acquired blaNDM genes by different mechanisms. These findings also illustrate the complex relationships between antimicrobial resistance genes, transposable elements, and plasmids and provide insights into the possible routes for transmission of blaNDM genes among species of the Enterobacteriaceae family. Copyright © 2016, American Society for Microbiology. All Rights Reserved.


Liu Y.-Y.,South China Agricultural University | Wang Y.,China Agricultural University | Walsh T.R.,Institute of Infection and Immunity | Yi L.-X.,South China Agricultural University | And 16 more authors.
The Lancet Infectious Diseases | Year: 2016

Background: Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. Methods: The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. Findings: Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10-1 to 10-3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011-14, and 16 (1%) of 1322 samples from inpatients with infection. Interpretation: The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Funding: Ministry of Science and Technology of China, National Natural Science Foundation of China. © 2016 Elsevier Ltd.


Krishna S.,Institute of Infection and Immunity | Ganapathi S.,St Georges, University of London | Ster I.C.,Institute of Infection and Immunity | Saeed M.E.M.,Johannes Gutenberg University Mainz | And 7 more authors.
EBioMedicine | Year: 2015

Background: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. Aim: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). Methods: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n. =. 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200. mg; n. =. 12) or placebo (n. =. 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if >. 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. Findings: 20 patients (artesunate. =. 9, placebo. =. 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in >. 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42. months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. Interpretation: Artesunate has anti-proliferative properties in CRC and is generally well tolerated. © 2014.


Edelstein M.V.,Smolensk State Medical Academy | Skleenova E.N.,Smolensk State Medical Academy | Shevchenko O.V.,Smolensk State Medical Academy | D'souza J.W.,Smolensk State Medical Academy | And 7 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: Multidrug-resistant and extensively-drug-resistant Pseudomonas aeruginosa are increasing therapeutic challenges worldwide. We did a longitudinal epidemiological and clinical study of extensively-drug-resistant P aeruginosa in Belarus, Kazakhstan, and Russia. Methods: The study was done in three prospectively defined phases: Jan 1, 2002-Dec 31, 2004; Jan 1, 2006-Dec 31, 2007; and Jan 1, 2008-Dec 31, 2010. The first two phases were in Russia only. All consecutive, non-duplicate, nosocomial isolates and case report forms were sent to the coordinating centre (Institute of Antimicrobial Chemotherapy, Smolensk, Russia), where species reidentification, susceptibility testing, and molecular typing of isolates were done. We did susceptibility testing by agar dilution. The presence of metallo-β-lactamase (MBL) genes was established by PCR and sequencing, and class 1 integrons containing MBL gene cassettes were analysed by the PCR restriction fragment length polymorphism approach. Strain relatedness was analysed by multiple loci variable-number tandem-repeat (VNTR) analysis (at six VNTR loci) and multilocus sequence typing. Results: In 2002-04, 628 of 1053 P aeruginosa isolates were insusceptible to carbapenems and 47 (4·5%) possessed MBLs. In 2006-07, 584 of 787 isolates were insusceptible to carbapenems and 160 (20·3%) possessed MBLs. In 2008-10, 1238 of 1643 Russian P aeruginosa isolates were insusceptible to carbapenems and 471 (28·7%) possessed MBLs. Additionally, the 32 P aeruginosa isolates from Belarus and Kazakhstan were all carbapenem insusceptible and all possessed MBLs. More than 96% of MBL-positive P aeruginosa isolates were resistant to all antibiotics except colistin (ie, extensively drug resistant), and, in 2010, 5·9% were resistant to colistin. 685 (96·5%) of 710 MBL-positive P aeruginosa belonged to ST235. blaVIM-2 genes were detected in 707 (99·6%) of 710 MBL-positive isolates. Interpretation: Extensively-drug-resistant ST235 P aeruginosa has rapidly spread throughout Russia and into Belarus and Kazakhstan via clonal dissemination. Increases in the use of colistin will probably result in further spread of ST235 P aeruginosa resistant to all drugs. Funding: HEFC, Ministry of Health of the Russian Federation, Government of the Republic of Belarus, Government of the Republic of Kazakhstan, European Union, Medical Research Council UK-Canada partnership. © 2013 Elsevier Ltd.

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