In Silico Assigned Resistance Genes Confer Bifidobacterium with Partial Resistance to Aminoglycosides but Not to Β-Lactams

peer-reviewedBifidobacteria have received significant attention due to their contribution to human gut health and the use of specific strains as probiotics. It is thus not surprising that there has also been significant interest with respect to their antibiotic resistance profile. Numerous culture-based studies have demonstrated that bifidobacteria are resistant to the majority of aminoglycosides, but are sensitive to β-lactams. However, limited research exists with respect to the genetic basis for the resistance of bifidobacteria to aminoglycosides. Here we performed an in-depth in silico analysis of putative Bifidobacterium-encoded aminoglycoside resistance proteins and β-lactamases and assess the contribution of these proteins to antibiotic resistance. The in silico-based screen detected putative aminoglycoside and β-lactam resistance proteins across the Bifidobacterium genus. Laboratory-based investigations of a number of representative bifidobacteria strains confirmed that despite containing putative β-lactamases, these strains were sensitive to β-lactams. In contrast, all strains were resistant to the aminoglycosides tested. To assess the contribution of genes encoding putative aminoglycoside resistance proteins in Bifidobacterium sp. two genes, namely Bbr_0651 and Bbr_1586, were targeted for insertional inactivation in B. breve UCC2003. As compared to the wild-type, the UCC2003 insertion mutant strains exhibited decreased resistance to gentamycin, kanamycin and streptomycin. This study highlights the associated risks of relying on the in silico assignment of gene function. Although several putative β-lactam resistance proteins are located in bifidobacteria, their presence does not coincide with resistance to these antibiotics. In contrast however, this approach has resulted in the identification of two loci that contribute to the aminoglycoside resistance of B. breve UCC2003 and, potentially, many other bifidobacteria.Fiona Fouhy is in receipt of an Irish Research Council for Science, Engineering and Technology EMBARK scholarship and is a Teagasc Walsh fellow. Research in the PDC laboratory is supported by the Irish Government under the National Development Plan through the Science Foundation Ireland Investigator award 11/PI/1137. Research in the RPR, CS, PDC and DvS laboratories is also supported by the Science Foundation of Ireland-funded Centre for Science, Engineering and Technology, the Alimentary Pharmabiotic Centre (grant no.s 02/CE/B124 and 07/CE/B1368) and a HRB postdoctoral fellowship (Grant no. PDTM/20011/9) awarded to MOCM

Low Temperature Plasma : A Novel Focal Therapy for Localized Prostate Cancer?

Despite considerable advances in recent years for the focal treatment of localized prostate cancer, high recurrence rates and detrimental side effects are still a cause for concern. In this review, we compare current focal therapies to a potentially novel approach for the treatment of early onset prostate cancer: low temperature plasma. The rapidly evolving plasma technology has the potential to deliver a wide range of promising medical applications via the delivery of plasma-induced reactive oxygen and nitrogen species. Studies assessing the effect of low temperature plasma on cell lines and xenografts have demonstrated DNA damage leading to apoptosis and reduction in cell viability. However, there have been no studies on prostate cancer, which is an obvious candidate for this novel therapy. We present here the potential of low temperature plasma as a focal therapy for prostate cancer

Estimating influenza incidence using search query deceptiveness and generalized ridge regression

Seasonal influenza is a sometimes surprisingly impactful disease, causing thousands of deaths per year along with much additional morbidity. Timely knowledge of the outbreak state is valuable for managing an effective response. The current state of the art is to gather this knowledge using in-person patient contact. While accurate, this is time-consuming and expensive. This has motivated inquiry into new approaches using internet activity traces, based on the theory that lay observations of health status lead to informative features in internet data. These approaches risk being deceived by activity traces having a coincidental, rather than informative, relationship to disease incidence; to our knowledge, this risk has not yet been quantitatively explored. We evaluated both simulated and real activity traces of varying deceptiveness for influenza incidence estimation using linear regression. We found that deceptiveness knowledge does reduce error in such estimates, that it may help automatically-selected features perform as well or better than features that require human curation, and that a semantic distance measure derived from the Wikipedia article category tree serves as a useful proxy for deceptiveness. This suggests that disease incidence estimation models should incorporate not only data about how internet features map to incidence but also additional data to estimate feature deceptiveness. By doing so, we may gain one more step along the path to accurate, reliable disease incidence estimation using internet data. This capability would improve public health by decreasing the cost and increasing the timeliness of such estimates.Comment: 27 pages, 8 figure

Feasibility, effectiveness and costs of a decision support intervention for consultees and legal representatives of adults lacking capacity to consent (CONSULT) : protocol for a randomised Study Within a Trial

Acknowledgements We would like to thank the lay advisory group who provide invaluable insight and support for this research programme. Funding This research was funded by Health and Care Research Wales as part of an NIHR Advanced Fellowship (NIHR-FS(A)-2021). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Primary and Emergency Care (PRIME) Research Centre Wales) is funded by the Welsh Government through Health and Care Research Wales and the Centre for Trials Research is funded by Health and Care Research Wales and Cancer Research UK. © 2022. The Author(s).Peer reviewedPublisher PD

Recruitment interventions for trials involving adults lacking capacity to consent: methodological and ethical considerations for designing Studies Within a Trial (SWATs)

Background: The number of interventions to improve recruitment and retention of participants in trials is rising, with a corresponding growth in randomised Studies Within Trials (SWATs) to evaluate their (cost-)efectiveness. Despite recognised challenges in conducting trials involving adults who lack capacity to consent, until now, no individual-level recruitment interventions have focused on this population. Following the development of a decision aid for family members making non-emergency trial participation decisions on behalf of people with impaired capacity, we have designed a SWAT to evaluate the decision aid in a number of host trials (CONSULT). Unlike in recruitment SWATs to date, the CONSULT intervention is aimed at a ‘proxy’ decision-maker (a family member) who is not a participant in the host trial and does not receive the trial intervention. This commentary explores the methodological and ethical considerations encountered when designing such SWATs, using the CONSULT SWAT as a case example. Potential solutions to address these issues are also presented. Discussion: We encountered practical issues around informed consent, data collection, and follow-up which involves linking the intervention receiver (the proxy) with recruitment and retention data from the host trial, as well as issues around randomisation level, resource use, and maintaining the integrity of the host trial. Unless addressed, methodological uncertainty about diferential recruitment and heterogeneity between trial populations could potentially limit the scope for drawing robust inferences and harmonising data from diferent SWAT host trials. Proxy consent is itself ethically complex, and so when conducting a SWAT which aims to disrupt and enhance proxy consent decisions, there are additional ethical issues to be considered. Conclusions: Designing a SWAT to evaluate a recruitment intervention for non-emergency trials with adults lacking capacity to consent has raised a number of methodological and ethical considerations. Explicating these challenges, and some potential ways to address them, creates a starting point for discussions about conducting these potentially more challenging SWATs. Increasing the evidence base for the conduct of trials involving adults lacking capacity to consent is intended to improve both the ability to conduct these trials and their quality, and so help build research capacity for this under-served populatio

Incidence of falls among adults with cerebral palsy: a cohort study using primary care data

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/1/dmcn14444_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/2/dmcn14444-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/3/dmcn14444.pd

Low temperature plasmas as emerging cancer therapeutics : the state of play and thoughts for the future

The field of plasma medicine has seen substantial advances over the last decade, with applications developed for bacterial sterilisation, wound healing and cancer treatment. Low temperature plasmas (LTPs) are particularly suited for medical purposes since they are operated in the laboratory at atmospheric pressure and room temperature, providing a rich source of reactive oxygen and nitrogen species (RONS). A great deal of research has been conducted into the role of reactive species in both the growth and treatment of cancer, where long-established radio- and chemo-therapies exploit their ability to induce potent cytopathic effects. In addition to producing a plethora of RONS, LTPs can also create strong electroporative fields. From an application perspective, it has been shown that LTPs can be applied precisely to a small target area. On this basis, LTPs have been proposed as a promising future strategy to accurately and effectively control and eradicate tumours. This review aims to evaluate the current state of the literature in the field of plasma oncology and highlight the potential for the use of LTPs in combination therapy. We also present novel data on the effect of LTPs on cancer stem cells, and speculatively outline how LTPs could circumvent treatment resistance encountered with existing therapeutics

The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Aims - Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods - Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings - At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance - SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease

Smoking cessation programmes for women living in disadvantaged communities, “We Can Quit 2”: A systematic review protocol [version 3]

Tobacco use is the leading cause of preventable death in Ireland with almost 6,000 smokers dying each year from smoking-related diseases. Amongst younger Irish women, smoking rates are considerably higher in those from socially disadvantaged areas compared to women from affluent areas. Women from poorer areas also experience higher rates of lung cancer. To our knowledge, there are no peer reviewed published systematic reviews on the effectiveness of interventions tailored to reduce smoking rates in women from disadvantaged areas. This systematic review protocol will aim to examine the effectiveness of such interventions and to describe trial processes such as recruitment, follow-up and dropout prevention strategies, as well as barriers and enablers of successful implementation. A systematic review will be conducted of peer-reviewed randomised controlled trials and associated process evaluations of smoking cessation interventions designed for women living in socially disadvantaged areas. If the search returns, less than five studies are review criteria will expand to include quasi-experimental studies. A number of databases of scholarly literature will be searched from inception using a detailed search strategy. Two independent reviewers will screen titles, abstracts and full-text articles to identify relevant studies using a pre-defined checklist based on PICOS. In the case of disagreement, a third reviewer will be consulted. The quality of included studies will be assessed using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) criteria. Quantitative data will be extracted and, if comparable, will be assessed using meta-analysis. A narrative meta-synthesis of qualitative data will be conducted. This review aims to synthesise information from relevant studies on smoking cessation interventions tailored for women from socially disadvantaged areas. The evidence obtained from studies and presented in this review will help guide future research in this area

The effectiveness of smoking cessation interventions for socio-economically disadvantaged women: A systematic review and meta-analysis

IntroductionThis systematic review and meta-analysis assessed the effectiveness of smoking cessation interventions among women smokers in low socio-economic status (SES) groups or women living in disadvantaged areas who are historically underserved by smoking cessation services.MethodsA systematic literature search was conducted using MEDLINE (OVID), EMBASE, Cochrane, CINAHL, PsychINFO and Web of Science databases. Eligibility criteria included randomised controlled trials of any smoking cessation intervention among women in low SES groups or living in socio-economically disadvantaged areas. A random effects meta-analysis assessed effectiveness of interventions on smoking cessation. Risk of bias was assessed with the Cochrane Risk of Bias tool. The GRADE approach established certainty of evidence.ResultsA total of 396 studies were screened for eligibility and 11 (6153 female participants) were included. Seven studies targeted women-only. 5/11 tested a form of face-to-face support. A pooled effect size was estimated in 10/11 studies. At end of treatment, two-thirds more low SES women who received a smoking cessation intervention were more likely to stop smoking than women in control groups (risk ratio (RR) 1.68, 95% CI 1.36–2.08, I2= 34%). The effect was reduced but remained significant when longest available follow-up periods were pooled (RR 1.23, 95% CI 1.04–1.48, I2 = 0%). There was moderate-to-high risk of bias in most studies. Certainty of evidence was low.ConclusionsBehavioural and behavioural + pharmacotherapy interventions for smoking cessation targeting women in low SES groups or women living in areas of disadvantage were effective in the short term. However, longer follow-up periods indicated reduced effectiveness. Future studies to explore ways to prevent smoking relapse in this population are needed.Systematic review registrationPROSPERO: CRD4201913016