Optimising workplace interventions for health and wellbeing: a commentary on the limitations of the public health perspective within the workplace health arena [forthcoming]

Purpose: This paper discusses contemporary approaches to workplace health and well-being, articulating key differences in the intervention architecture between public and workplace health contexts and implications for intervention design. Approach: Contemporary practice is discussed in light of calls for a paradigm shift in occupational health from a treatment orientation to an holistic approach focused on mitigation of the causes of ill health and the promotion of well-being. In practice, relatively few organizations have or seem able to engage with a broader perspective that encompasses challenges to health and well-being associated with contextual organizational drivers, e.g. job design/role, workload, systems of reward, leadership style and the underpinning climate. Drawing upon insights from public health and the workplace safety tradition, the scope for broadening the perspective on intervention (in terms of vectors of harm addressed, theory of change and intervention logic) is discussed. Findings: There are important differences in scope and options for intervention between public health and workplace health contexts. While there is scope to emulate public health practice, this should not constrain thinking over intervention opinions. Increased awareness of these key differences within work organizations, and an evidence-based epidemiological approach to learning has the potential to strengthen and broaden the approach to workplace health and well-being management. Originality/Value: We argue that approaches to workplace well-being interventions that selectively cross-fertilise and adapt elements of public health interventions offer promise for realising a broader change agenda and for building inherently healthy workplaces

The Novel Coronavirus COVID-19 Outbreak: Global Implications for Antimicrobial Resistance

This is the final version. Available on open access from Frontiers Media via the DOI in this recordIntroduction: We are in the midst of the novel coronavirus (COVID-19) pandemic, the most significant global health event since Spanish influenza in the early 20th century. Increasingly draconian measures are being implemented worldwide to try to slow the spread of the virus. Antimicrobial resistance (AMR) has been cited as the most significant threat to the global health and global economy in recent years, but is now likely to be eclipsed by COVID-19 for some time. However, the emergence of COVID-19 also presents some important consequences for the development of AMR. This piece will highlight how managing the COVID-19 crisis could impact AMR in the clinic, beyond the clinic in the community, in the environment and in relation to public awareness. When civilization emerges from the other side of this global health emergency, efforts should be made to understand these potential effects on AMR, the other significant, and constant global health issue of our time.Natural Environment Research Council (NERC

Carbapenem resistance in bacteria isolated from soil and water environments in Algeria.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordOBJECTIVES: Recent research has demonstrated that natural populations of bacteria carry large numbers of mobile genetic elements which may harbour antibiotic resistance determinants. The aim of this study was to investigate carbapenem resistance in Gram negative bacteria isolated from natural environments in Bejaia (Algeria), and determine the horizontal gene transfer potential of a subset of these resistance genes. METHODS: Resistant bacteria were isolated and host identified with MALDI-TOF/16S rRNA sequencing. Resistance gene carriage was investigated using double disc synergy, metallo-β-lactamase (MBL) production tests and PCR screening for carbapenemase resistance genes. To determine potential mobility, conjugation experiments were performed. To identify resistance genes, genomic libraries were constructed, functionally screened; then inserts were sequenced. RESULTS: From soil and water samples, 62 resistant strains were classified as belonging to the Enterobacteriaceae, Pseudomonadaceae, Xanthomonadaceae and Aeromonadaceae families. Four highly imipenem and cefotaxime resistant (MICs >64μg/ml and >8μg/ml, respectively), clinically relevant strains were selected for further characterization. All four strains produced extended spectrum β-lactamases, but MBL production was not confirmed. Imipenem and cefotaxime resistance was transferable to E. coli strains but was not conferred by blaAMPc, blaIMP, blaNDM, blaKPC, blaOXA-48 or blaGES genes. Novel putative resistance mechanisms were identified, including a novel DHA β-lactamase which conferred clinical resistance to cefotaxime. CONCLUSIONS: The environment is a reservoir of carbapenem resistant bacteria. Further investigation of evolution and dissemination of antibiotic resistance in environmental bacteria is required, to understand and prevent the emergence of resistance in clinical environment

Comparing the selective and co-selective effects of different antimicrobials in bacterial communities

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordBacterial communities are exposed to a cocktail of antimicrobial agents, including antibiotics, heavy metals and biocidal antimicrobials such as quaternary ammonium compounds (QACs). The extent to which these compounds may select or co-select for antimicrobial resistance (AMR) is not fully understood. In this study, human associated, wastewater derived, bacterial communities were exposed to either benzalkonium chloride (BAC), ciprofloxacin or trimethoprim at sub-point of use concentrations for one week, in order to determine selective and co-selective potential. Metagenome analyses were performed to determine effects on bacterial community structure and prevalence of antibiotic resistance genes (ARGs) and metal or biocide resistance genes (MBRGS). Ciprofloxacin had the greatest co-selective potential, significantly enriching for resistance mechanisms to multiple antibiotic classes. Conversely, BAC exposure significantly reduced relative abundance of ARGs and MBRGS, including the well characterised qac efflux genes. However, BAC exposure significantly impacted bacterial community structure. This suggests BAC and potentially other QACs did not play as significant a role in co-selection for AMR relative to antibiotics such as ciprofloxacin at below point of use concentrations in this study. This approach can be used to identify priority compounds for further study, to better understand evolution of AMR in bacterial communities exposed to sub-point of use concentrations of antimicrobials.Natural Environment Research Council (NERC)Biotechnology and Biological Sciences Research Council (BBSRC

Evolution of antibiotic resistance at low antibiotic concentrations including selection below the minimal selective concentration

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The datasets associated with Figs. 1–6 are included in this published article as a Supplementary Data file. Metagenome sequence files have been deposited in the European Nucleotide Archive. Accession number: PRJEB38942.Code availability: Code used for metagenome analysis: FastQC; MultiQC; FLASH2; Metaphlan2; Hclust2 and ARGs-OAP v2.Determining the selective potential of antibiotics at environmental concentrations is critical for designing effective strategies to limit selection for antibiotic resistance. This study determined the minimal selective concentrations (MSCs) for macrolide and fluoroquinolone antibiotics included on the European Commission's Water Framework Directive's priority hazardous substances Watch List. The macrolides demonstrated positive selection for ermF at concentrations 1-2 orders of magnitude greater (>500 and 7.8 and <15.6 µg/L). This highlights the need for compound specific assessment of selective potential. In addition, a sub-MSC selective window defined by the minimal increased persistence concentration (MIPC) is described. Differential rates of negative selection (or persistence) were associated with elevated prevalence relative to the no antibiotic control below the MSC. This increased persistence leads to opportunities for further selection over time and risk of human exposure and environmental transmission.Biotechnology and Biological Sciences Research Council (BBSRC)Natural Environment Research Council (NERC

Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities

This is the final version of the article. Available from American Society for Microbiology via the DOI in this record.Recent research has demonstrated that selection for antibiotic resistance occurs at very low antibiotic concentrations in single-species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show that the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low subinhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a 2-order-magnitude concentration range. This is likely to be due to cross protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses of sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment for blaCTX-M genes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far-reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.Aimee K. Murray was supported by a BBSRC/AZ CASE Studentship, BB/L502509/1. Lihong Zhang was supported by Natural Environment Research Council grant NE/ M011259/1. Chemical quantification was performed at the University of Exeter Streatham Campus by Maciek Trnzadel and Malcolm Hetheridge, cofunded by Astra Zeneca Global SHE and the University of Exeter

Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase

The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat cap at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that counts TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this counting mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme

Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction

BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival. CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI

Dawning of a new ERA: Environmental Risk Assessment of antibiotics and their potential to select for antimicrobial resistance

This is the final version. Available on open access from Elsevier via the DOI in this recordAntibiotics and antimicrobials are used, misused and overused in human and veterinary medicine, animal husbandry and aquaculture. These compounds can persist in both human and animal waste and then enter the environment through a variety of mechanisms. Though generally measured environmental concentrations (MECs) of antibiotics in aquatic systems are significantly lower than point of therapeutic use concentrations, there is increasing evidence that suggests these concentrations may still enrich antimicrobial resistant bacteria. In light of this evidence, a rigorous and standardised novel methodology needs to be developed which can perform environmental risk assessment (ERA) of antimicrobials in terms of their selective potential as well as their environmental impact, to ensure that diffuse and point source discharges are safe. This review summarises and critically appraises the current methodological approaches that study selection at below point of therapeutic use, or sub-inhibitory, concentrations of antibiotics. We collate and compare selective concentration data generated to date. We recommend how these data can be interpreted in line with current ERA guidelines; outlining and describing novel concepts unique to risk assessment of AMR (such as direct selection of AMR or increased persistence of AMR). We consolidate terminology used thus far into a single framework that could be adopted moving forward, by proposing predicted no effect concentrations for resistance (PNECRs) and predicted no effect concentrations for persistence (PNECPs) be determined in AMR risk assessment. Such a framework will contribute to antibiotic stewardship and by extension, protection of human health, food security and the global economy

SPH Simulations of Negative (Nodal) Superhumps: A Parametric Study

Negative superhumps in cataclysmic variable systems result when the accretion disc is tilted with respect to the orbital plane. The line of nodes of the tilted disc precesses slowly in the retrograde direction, resulting in a photometric signal with a period slightly less than the orbital period. We use the method of smoothed particle hydrodynamics to simulate a series of models of differing mass ratio and effective viscosity to determine the retrograde precession period and superhump period deficit $\varepsilon_-$ as a function of system mass ratio $q$. We tabulate our results and present fits to both $\varepsilon_-$ and $\varepsilon_+$ versus $q$, as well as compare the numerical results with those compiled from the literature of negative superhump observations. One surprising is that while we find negative superhumps most clearly in simulations with an accretion stream present, we also find evidence for negative superhumps in simulations in which we shut off the mass transfer stream completely, indicating that the origin of the photometric signal is more complicated than previously believed.Comment: 14 pages, 15 figures. Accepted for publication in MNRA