Age at quitting smoking as a predictor of risk of cardiovascular disease incidence independent of smoking status, time since quitting and pack-years

BACKGROUND Risk prediction for CVD events has been shown to vary according to current smoking status, pack-years smoked over a lifetime, time since quitting and age at quitting. The latter two are closely and inversely related. It is not known whether the age at which one quits smoking is an additional important predictor of CVD events. The aim of this study was to determine whether the risk of CVD events varied according to age at quitting after taking into account current smoking status, lifetime pack-years smoked and time since quitting. FINDINGS We used the Cox proportional hazards model to evaluate the risk of developing a first CVD event for a cohort of participants in the Framingham Offspring Heart Study who attended the fourth examination between ages 30 and 74 years and were free of CVD. Those who quit before the median age of 37 years had a risk of CVD incidence similar to those who were never smokers. The incorporation of age at quitting in the smoking variable resulted in better prediction than the model which had a simple current smoker/non-smoker measure and the one that incorporated both time since quitting and pack-years. These models demonstrated good discrimination, calibration and global fit. The risk among those quitting more than 5 years prior to the baseline exam and those whose age at quitting was prior to 44 years was similar to the risk among never smokers. However, the risk among those quitting less than 5 years prior to the baseline exam and those who continued to smoke until 44 years of age (or beyond) was two and a half times higher than that of never smokers. CONCLUSIONS Age at quitting improves the prediction of risk of CVD incidence even after other smoking measures are taken into account. The clinical benefit of adding age at quitting to the model with other smoking measures may be greater than the associated costs. Thus, age at quitting should be considered in addition to smoking status, time since quitting and pack-years when counselling individuals about their cardiovascular risk.This research was supported by an NHMRC health services research grant (no. 465130), an NHMRC/NHF PhD scholarship and a Vichealth Fellowship

Self-Harm in Eating Disorders (SHINE):a mixed-methods exploratory study

Introduction Self-harm is highly prevalent among young people with eating disorders. However, why a young person may develop and continue to experience both an eating disorder and self-harm is unclear. This study will investigate the frequency, intensity, duration, function, context and processes of self-harm among people aged 16–25 diagnosed with an eating disorder. It will explore participants’ perspectives on the genesis and functions of both their self-harm and eating disorder, as well as their support needs. The study was designed with the input of members of a Young Persons’ Advisory Group, who will be key to study delivery and dissemination.Methods and analysis This exploratory study has a sequential mixed-methods explanatory design. Between 70 and 100 young people aged 16–25 with both an eating disorder diagnosis and self-harm thoughts and/or behaviours will be recruited from three NHS Eating Disorder outpatient services in England. Phase 1: a 14-day (six prompts per day) ecological momentary assessment (EMA) of participants’ feelings, thoughts, motivations, behaviours and experiences of self-harm. Phase 2: 20–30 participants from phase 1 will be reapproached to take part in an in-depth qualitative interview on the psychological, emotional and social factors that underlie their self-harm and eating disorder as well as their support needs. EMA data from phase 1 will be analysed using descriptive and multilevel statistics. Qualitative interview data from phase 2 will be analysed using inductive and deductive thematic analysis. Results from both phases will be integrated using a mixed-methods matrix, with each participant’s data from both phases compared alongside comparative analysis of the datasets as a whole.Ethics and dissemination The study gained ethical approval from the NHS HRA West Midlands–Black Country Research Ethics Committee (number: 296032). We anticipate disseminating findings to clinical, academic and lived experience audiences, at academic conferences, through peer-reviewed articles, and through various public engagement activities (eg, infographics, podcasts)

Identification of binding residues between periplasmic adapter protein (PAP) and RND efflux pumps explains PAP-pump promiscuity and roles in antimicrobial resistance

Active efflux due to tripartite RND efflux pumps is an important mechanism of clinically relevant antibiotic resistance in Gram-negative bacteria. These pumps are also essential for Gram-negative pathogens to cause infection and form biofilms. They consist of an inner membrane RND transporter; a periplasmic adaptor protein (PAP), and an outer membrane channel. The role of PAPs in assembly, and the identities of specific residues involved in PAP-RND binding, remain poorly understood. Using recent high-resolution structures, four 3D sites involved in PAP-RND binding within each PAP protomer were defined that correspond to nine discrete linear binding sequences or "binding boxes" within the PAP sequence. In the important human pathogen Salmonella enterica, these binding boxes are conserved within phylogenetically-related PAPs, such as AcrA and AcrE, while differing considerably between divergent PAPs such as MdsA and MdtA, despite overall conservation of the PAP structure. By analysing these binding sequences we created a predictive model of PAP-RND interaction, which suggested the determinants that may allow promiscuity between certain PAPs, but discrimination of others. We corroborated these predictions using direct phenotypic data, confirming that only AcrA and AcrE, but not MdtA or MsdA, can function with the major RND pump AcrB. Furthermore, we provide functional validation of the involvement of the binding boxes by disruptive site-directed mutagenesis. These results directly link sequence conservation within identified PAP binding sites with functional data providing mechanistic explanation for assembly of clinically relevant RND-pumps and explain how Salmonella and other pathogens maintain a degree of redundancy in efflux mediated resistance. Overall, our study provides a novel understanding of the molecular determinants driving the RND-PAP recognition by bridging the available structural information with experimental functional validation thus providing the scientific community with a predictive model of pump-contacts that could be exploited in the future for the development of targeted therapeutics and efflux pump inhibitors

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.British Society for Antimicrobial Chemotherapy BSAC-2018-0095NC3Rs NC/V001582/1Biological Sciences Research Council BB/V007823/1Academy of Medical Sciences SBF006\104

Antiviral, antimicrobial and antibiofilm activity of selenoesters and selenoanhydrides

Selenoesters and the selenium isostere of phthalic anhydride are bioactive selenium compounds with a reported promising activity in cancer, both due to their cytotoxicity and capacity to reverse multidrug resistance. Herein we evaluate the antiviral, the biofilm inhibitory, the antibacterial and the antifungal activities of these compounds. The selenoanhydride and 7 out of the 10 selenoesters were especially potent antiviral agents in Vero cells infected with herpes simplex virus-2 (HSV-2). In addition, the tested selenium derivatives showed interesting antibiofilm activity against Staphylococcus aureus and Salmonella enterica serovar Typhimurium, as well as a moderate antifungal activity in resistant strains of Candida spp. They were inactive against anaerobes, which may indicate that the mechanism of action of these derivatives depends on the presence of oxygen. The capacity to inhibit the bacterial biofilm can be of particular interest in the treatment of nosocomial infections and in the coating of surfaces of prostheses. Finally, the potent antiviral activity observed converts these selenium derivatives into promising antiviral agents with potential medical applications.

The effect of modifiable risk factors on geographic mortality differentials: a modelling study

Background Australian mortality rates are higher in regional and remote areas than in major cities. The degree to which this is driven by variation in modifiable risk factors is unknown. Methods We applied a risk prediction equation incorporating smoking, cholesterol and blood pressure to a national, population based survey to project all-causes mortality risk by geographic region. We then modelled life expectancies at different levels of mortality risk by geographic region using a risk percentiles model. Finally we set high values of each risk factor to a target level and modelled the subsequent shift in the population to lower levels of mortality risk and longer life expectancy. Results Survival is poorer in both Inner Regional and Outer Regional/Remote areas compared to Major Cities for men and women at both high and low levels of predicted mortality risk. For men smoking, high cholesterol and high systolic blood pressure were each associated with the mortality difference between Major Cities and Outer Regional/Remote areas--accounting for 21.4%, 20.3% and 7.7% of the difference respectively. For women smoking and high cholesterol accounted for 29.4% and 24.0% of the difference respectively but high blood pressure did not contribute to the observed mortality differences. The three risk factors taken together accounted for 45.4% (men) and 35.6% (women) of the mortality difference. The contribution of risk factors to the corresponding differences for inner regional areas was smaller, with only high cholesterol and smoking contributing to the difference in men-- accounting for 8.8% and 6.3% respectively-- and only smoking contributing to the difference in women--accounting for 12.3%. Conclusions These results suggest that health intervention programs aimed at smoking, blood pressure and total cholesterol could have a substantial impact on mortality inequities for Outer Regional/Remote areas. Background: Australian mortality rates are higher in regional and remote areas than in major cities. The degree to which this is driven by variation in modifiable risk factors is unknown. Methods. We applied a risk prediction equation incorporating smoking, cholesterol and blood pressure to a national, population based survey to project all-causes mortality risk by geographic region. We then modelled life expectancies at different levels of mortality risk by geographic region using a risk percentiles model. Finally we set high values of each risk factor to a target level and modelled the subsequent shift in the population to lower levels of mortality risk and longer life expectancy. Results: Survival is poorer in both Inner Regional and Outer Regional/Remote areas compared to Major Cities for men and women at both high and low levels of predicted mortality risk. For men smoking, high cholesterol and high systolic blood pressure were each associated with the mortality difference between Major Cities and Outer Regional/Remote areas - accounting for 21.4%, 20.3% and 7.7% of the difference respectively. For women smoking and high cholesterol accounted for 29.4% and 24.0% of the difference respectively but high blood pressure did not contribute to the observed mortality differences. The three risk factors taken together accounted for 45.4% (men) and 35.6% (women) of the mortality difference. The contribution of risk factors to the corresponding differences for inner regional areas was smaller, with only high cholesterol and smoking contributing to the difference in men - accounting for 8.8% and 6.3% respectively - and only smoking contributing to the difference in women - accounting for 12.3%. Conclusions: These results suggest that health intervention programs aimed at smoking, blood pressure and total cholesterol could have a substantial impact on mortality inequities for Outer Regional/Remote areas

Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak?

The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines

Age at quitting smoking as a predictor of risk of cardiovascular disease incidence independent of smoking status, time since quitting and pack-years

Background: Risk prediction for CVD events has been shown to vary according to current smoking status, pack-years smoked over a lifetime, time since quitting and age at quitting. The latter two are closely and inversely related. It is not known whether the age at which one quits smoking is an additional important predictor of CVD events. The aim of this study was to determine whether the risk of CVD events varied according to age at quitting after taking into account current smoking status, lifetime pack-years smoked and time since quitting. Findings. We used the Cox proportional hazards model to evaluate the risk of developing a first CVD event for a cohort of participants in the Framingham Offspring Heart Study who attended the fourth examination between ages 30 and 74 years and were free of CVD. Those who quit before the median age of 37 years had a risk of CVD incidence similar to those who were never smokers. The incorporation of age at quitting in the smoking variable resulted in better prediction than the model which had a simple current smoker/non-smoker measure and the one that incorporated both time since quitting and pack-years. These models demonstrated good discrimination, calibration and global fit. The risk among those quitting more than 5 years prior to the baseline exam and those whose age at quitting was prior to 44 years was similar to the risk among never smokers. However, the risk among those quitting less than 5 years prior to the baseline exam and those who continued to smoke until 44 years of age (or beyond) was two and a half times higher than that of never smokers. Conclusions: Age at quitting improves the prediction of risk of CVD incidence even after other smoking measures are taken into account. The clinical benefit of adding age at quitting to the model with other smoking measures may be greater than the associated costs. Thus, age at quitting should be considered in addition to smoking status, time since quitting and pack-years when counselling individuals about their cardiovascular risk

The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

Biochemical, structural and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) to be a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 to be more closely related to the JmjC hydroxylases than to the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the translation factor (TRAFAC) family of GTPases, developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(ii)- and 2OG-dependent hydroxylation of a highly conserved lysine residue in DRG1/2; amino-acid analyses reveal that JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.Fil: Markolovic, Suzana. University of Oxford; Reino UnidoFil: Zhuang, Qinqin. University Of Birmingham; Reino UnidoFil: Wilkins, Sarah E.. University of Oxford; Reino UnidoFil: Eaton, Charlotte D.. University Of Birmingham; Reino UnidoFil: Abboud, Martine I.. University of Oxford; Reino UnidoFil: Katz, Maximiliano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: McNeil, Helen E.. University Of Birmingham; Reino UnidoFil: Leśniak, Robert K.. University of Oxford; Reino UnidoFil: Hall, Charlotte. University Of Birmingham; Reino UnidoFil: Struwe, Weston B.. University of Oxford; Reino UnidoFil: Konietzny, Rebecca. University of Oxford; Reino UnidoFil: Davis, Simon. University of Oxford; Reino UnidoFil: Yang, Ming. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Ge, Wei. University of Oxford; Reino UnidoFil: Benesch, Justin L. P.. University of Oxford; Reino UnidoFil: Kessler, Benedikt M.. University of Oxford; Reino UnidoFil: Ratcliffe, Peter J.. University of Oxford; Reino Unido. The Francis Crick Institute; Reino UnidoFil: Cockman, Matthew E.. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Fischer, Roman. University of Oxford; Reino UnidoFil: Wappner, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Chowdhury, Rasheduzzaman. University of Stanford; Estados Unidos. University of Oxford; Reino UnidoFil: Coleman, Mathew L.. University Of Birmingham; Reino UnidoFil: Schofield, Christopher J.. University of Oxford; Reino Unid