The Effect of Imatinib Mesylate for Newly Diagnosed Philadelphia Chromosome-Positive, Chronic-Phase Myeloid Leukemia in Sub-Saharan African Patients: The Experience of Côte d'Ivoire

Imatinib mesylate, showed encouraging activity in chronic myelogenous leukemia. However, there are few data regarding his efficacy and response monitoring in Sub-Saharan African patients. Our objective was to assess response to imatinib mesylate (Glivec) in Côte d'Ivoire patients with newly diagnosed Chronic Myeloid Leukemia (CML). From May 2005 to September 2009, we treated 42 patients (40 years; range 16–69) with Philadelphia chromosome (Ph+) positive in chronic phase CML with oral imatinib mesylate at daily doses of 400 mg. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated. At a median follow up of 32 (range 7.6–113) months, the CHR rate in our study group was 76%. A major CR was found in 19 patients (45%) with 17% and 29% complete and partial CR respectively. There were no significant differences in the incidence of major cytogenetic response by known prognostics factors. Median time to CHR was 8 months (range 0.4–25), and 16 months (range: 0.1–36) for CR. Projected 5-year OS rate was 72% (95%CI 42–88). We conclude that imatinib therapy sub-Saharan African CML patients is very promising and has favorably changed the prognosis for black African patients with CML

Electron-phonon interaction in C70

The matrix elements of the deformation potential of C$_{70}$ are calculated by means of a simple, yet accurate solution of the electron-phonon coupling problem in fullerenes, based on a parametrization of the ground state electronic density of the system in terms of $sp^{2+x}$ hybridized orbitals. The value of the calculated dimensionless total electron-phonon coupling constant is $\lambda\approx0.1$, an order of magnitude smaller than in C$_{60}$, consistent with the lack of a superconducting phase transition in C$_{70}$A$_3$ fullerite, and in overall agreement with measurements of the broadening of Raman peaks in C$_{70}$K$_4$. We also calculate the photoemission cross section of C$_{70}^-$, which is found to display less structure than that associated with C$_{60}^-$, in overall agreement with the experimental findings.Comment: To be published in Phys. Rev.

Optimised use of Oxford Nanopore Flowcells for Hybrid Assemblies

Hybrid assemblies are highly valuable for studies of Enterobacteriaceae due to their ability to fully resolve the structure of mobile genetic elements, such as plasmids, which are involved in the carriage of clinically important genes (e.g. those involved in antimicrobial resistance/virulence). The widespread application of this technique is currently primarily limited by cost. Recent data have suggested that non-inferior, and even superior, hybrid assemblies can be produced using a fraction of the total output from a multiplexed nanopore [Oxford Nanopore Technologies (ONT)] flowcell run. In this study we sought to determine the optimal minimal running time for flowcells when acquiring reads for hybrid assembly. We then evaluated whether the ONT wash kit might allow users to exploit shorter running times by sequencing multiple libraries per flowcell. After 24 h of sequencing, most chromosomes and plasmids had circularized and there was no benefit associated with longer running times. Quality was similar at 12 h, suggesting that shorter running times are likely to be acceptable for certain applications (e.g. plasmid genomics). The ONT wash kit was highly effective in removing DNA between libraries. Contamination between libraries did not appear to affect subsequent hybrid assemblies, even when the same barcodes were used successively on a single flowcell. Utilizing shorter run times in combination with between-library nuclease washes allows at least 36 Enterobacteriaceae isolates to be sequenced per flowcell, significantly reducing the per-isolate sequencing cost. Ultimately this will facilitate large-scale studies utilizing hybrid assembly, advancing our understanding of the genomics of key human pathogens

Antimicrobial resistance in commensal opportunistic pathogens isolated from non-sterile sites can be an effective proxy for surveillance in bloodstream infections

Antimicrobial resistance (AMR) surveillance in bloodstream infections (BSIs) is challenging in low/middle-income countries (LMICs) given limited laboratory capacity. Other specimens are easier to collect and process and are more likely to be culture-positive. In 8102 E. coli BSIs, 322,087 E. coli urinary tract infections, 6952 S. aureus BSIs and 112,074 S. aureus non-sterile site cultures from Oxfordshire (1998–2018), and other (55,296 isolates) rarer commensal opportunistic pathogens, antibiotic resistance trends over time in blood were strongly associated with those in other specimens (maximum cross-correlation per drug 0.51–0.99). Resistance prevalence was congruent across drug-years for each species (276/312 (88%) species-drug-years with prevalence within ± 10% between blood/other isolates). Results were similar across multiple countries in high/middle/low income-settings in the independent ATLAS dataset (103,559 isolates, 2004–2017) and three further LMIC hospitals/programmes (6154 isolates, 2008–2019). AMR in commensal opportunistic pathogens cultured from BSIs is strongly associated with AMR in commensal opportunistic pathogens cultured from non-sterile sites over calendar time, suggesting the latter could be used as an effective proxy for AMR surveillance in BSIs

Antibiotic Review Kit for Hospitals (ARK-Hospital): study protocol for a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more diagnostic information becomes available. UK Department of Health guidance promotes an initiative called 'Start Smart then Focus': early effective antibiotics followed by active 'review and revision' 24-72 h later. However in 2017, < 10% of antibiotic prescriptions were discontinued at review, despite studies suggesting that 20-30% of prescriptions could be stopped safely. METHODS/DESIGN: Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex 'review and revise' behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients. DISCUSSION: ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at 'review and revise'. TRIAL REGISTRATION: ISRCTN Current Controlled Trials, ISRCTN12674243 . Registered on 10 April 2017

Aligning molecular studies of mycorrhizal fungal diversity with ecologically important levels of diversity in ecosystems.

Arbuscular mycorrhizal fungi (AMF) occur in the roots of most plants and are an ecologically important component of the soil microbiome. Richness of AMF taxa is a strong driver of plant diversity and productivity, thus providing a rationale for characterizing AMF diversity in natural ecosystems. Consequently, a large number of molecular studies on AMF community composition are currently underway. Most published studies, at best, only address species or genera-level resolution. However, several experimental studies indicate that variation in plant performance is large among plants colonised by different individuals of one AMF species. Thus, there is a potential disparity between how molecular community ecologists are currently describing AMF diversity and the level of AMF diversity that may actually be ecologically relevant. We propose a strategy to find many polymorphic loci that can define within-species genetic variability within AMF, or at any level of resolution desired within the Glomermycota. We propose that allele diversity at the intraspecific level could then be measured for target AMF groups, or at other levels of resolution, in environmental DNA samples. Combining the use of such markers with experimental studies on AMF diversity would help to elucidate the most important level(s) of AMF diversity in plant communities. Our goal is to encourage ecologists who are trying to explain how mycorrhizal fungal communities are structured to take an approach that could also yield meaningful information that is relevant to the diversity, functioning and productivity of ecosystems

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder : A systematic review

Magnesium supplementation is often suggested for restless legs syndrome (RLS) or period limb movement disorder (PLMD) based on anecdotal evidence that it relieves symptoms and because it is also commonly recommended for leg cramps. We aimed to review all articles reporting the effects of magnesium supplementation on changes in RLS and/or PLMD. We conducted a systematic search looking for all relevant articles and then two reviewers read all article titles and abstracts to identify relevant studies. Eligible studies were scored for their quality as interventional trials. We found 855 abstracts and 16 of these could not be definitively excluded for not addressing all aspects of our research question. Seven full-text articles were unlocatable and one was ineligible which left eight studies with relevant data. One was a randomised placebo-controlled trial, three were case series and four were case studies. The RCT did not find a significant treatment effect of magnesium but may have been underpowered. After quality appraisal and synthesis of the evidence we were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD. It is not clear whether magnesium helps relieve RLS or PLMD or in which patient groups any benefit might be seen. (c) 2019 Elsevier Ltd. All rights reserved.Peer reviewe

Antimicrobial resistance determinants are associated with Staphylococcus aureus bacteraemia and adaptation to the healthcare environment: a bacterial genome-wide association study

Staphylococcus aureus is a major bacterial pathogen in humans, and a dominant cause of severe bloodstream infections. Globally, antimicrobial resistance (AMR) in S. aureus remains challenging. While human risk factors for infection have been defined, contradictory evidence exists for the role of bacterial genomic variation in S. aureus disease. To investigate the contribution of bacterial lineage and genomic variation to the development of bloodstream infection, we undertook a genome-wide association study comparing bacteria from 1017 individuals with bacteraemia to 984 adults with asymptomatic S. aureus nasal carriage. Within 984 carriage isolates, we also compared healthcare-associated (HA) carriage with community-associated (CA) carriage. All major global lineages were represented in both bacteraemia and carriage, with no evidence for different infection rates. However, kmers tagging trimethoprim resistance-conferring mutation F99Y in dfrB were significantly associated with bacteraemia-vs-carriage (P=10-8.9-10-9.3). Pooling variation within genes, bacteraemia-vs-carriage was associated with the presence of mecA (HMP=10-5.3) as well as the presence of SCCmec (HMP=10-4.4). Among S. aureus carriers, no lineages were associated with HA-vs-CA carriage. However, we found a novel signal of HA-vs-CA carriage in the foldase protein prsA, where kmers representing conserved sequence allele were associated with CA carriage (P=10-7.1-10-19.4), while in gyrA, a ciprofloxacin resistance-conferring mutation, L84S, was associated with HA carriage (P=10-7.2). In an extensive study of S. aureus bacteraemia and nasal carriage in the UK, we found strong evidence that all S. aureus lineages are equally capable of causing bloodstream infection, and of being carried in the healthcare environment. Genomic variation in the foldase protein prsA is a novel genomic marker of healthcare origin in S. aureus but was not associated with bacteraemia. AMR determinants were associated with both bacteraemia and healthcare-associated carriage, suggesting that AMR increases the propensity not only to survive in healthcare environments, but also to cause invasive disease