Discovering antiviral restriction factors and pathways using genetic screens

Research in the Hughes lab is supported by a grant from the Academy of Medical Sciences (SFB003/1028), a grant from Tenovus Scotland (T20/63), and The Wellcome Trust Institutional Strategic Support Fund (ISSF). Research in the Gray lab is supported Medical Research Council (MR/N001796/1) and the Biotechnology and Biological Sciences Research Council (BBS/E/D/20002172). C. E. J. is supported by a University of St Andrews Ph.D. scholarship.Viral infections activate the powerful interferon (IFN) response that induces the expression of several hundred IFN stimulated genes (ISGs). The principal role of this extensive response is to create an unfavourable environment for virus replication and to limit spread; however, untangling the biological consequences of this large response is complicated. In addition to a seemingly high degree of redundancy, several ISGs are usually required in combination to limit infection as individual ISGs often have low to moderate antiviral activity. Furthermore, what ISG or combination of ISGs are antiviral for a given virus is usually not known. For these reasons, and that the function(s) of many ISGs remains unexplored, genome-wide approaches are well placed to investigate what aspects of this response results in an appropriate, virus-specific phenotype. This review discusses the advances screening approaches have provided for the study of host defence mechanisms, including CRISPR/Cas9, ISG expression libraries and RNAi technologies.Publisher PDFPeer reviewe

Borders and Catastrophe: lessons from COVID-19 for the European Green Deal

This article considers how the European Union and Member States’ responses to the COVID-19 crisis in the first half of 2020 could inform climate action in Europe, and particularly the resumption of actions on the EGD. It first outlines the EU’s public health and economic responses to COVID-19 and Europe’s role in the global response to the pandemic. We find that, based on the challenges and successes of all these responses, a strong argument can be made for ‘more Europe’ – greater integration, and stronger EU-level institutions – to lead and govern the COVID-19 response. This has direct lessons for the governance and scope of future climate action

The effects of diet on anatomy, physiology and health in the guinea pig

Given the increasing popularity of the guinea pig as a pet, it is perhaps surprising that relatively little is published as to their husbandry and dietary requirements. Indeed, a review of the literature currently available to owners, scientists and clinicians alike has found it to be scarce, highly variable, and at times overtly contradictory. This review and data collection collates the husbandry and dietary information available and discusses the variable information available and the differing practices published in the literature in relation to the guinea pig. A questionnaire was also used to gather owner-reported data on feeding regimens from both the UK and Poland in order to better understand the range of feeding habits that owners employ. Despite the lack of information available in comparison with that available for other companion and livestock animals, advances in knowledge are being made. With guinea pig numbers increasing in many countries and owners seeking husbandry and veterinary advice and interventions, it is imperative that we understand guinea pig health and welfare issues. The data and review gives novel insights into how guinea pig husbandry affects health and welfare

Does 3D-speckle tracking echocardiography improve prediction of major cardiovascular events in a multi-ethnic general population? A Southall and Brent Revisited (SABRE) cohort study

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small

Relationship Between Image Quality and Bias in 3D Echocardiographic Measures: Data From the SABRE (Southall and Brent Revisited) Study

Background: Image‐quality (IQ) compromises left ventricle assessment by 3‐dimensional echocardiography (3DE). Sicker/frailer patients often have suboptimal IQ, and therefore observed associations may be biased by IQ. We investigated its effect in an observational study of older people and when IQ was modified experimentally in healthy volunteers. / Methods and Results: 3DE feasibility by IQ was assessed in 1294 individuals who attended the second wave of the Southall and Brent Revisited study and was compared with 2‐dimensional (2D)‐echocardiography feasibility in 147 individuals. Upon successful analysis, means of ejection fraction (3D‐EF) and global longitudinal strain (3D‐GLS) (plus 2D‐EF) were compared in individuals with poor versus good IQ. In 2 studies of healthy participants, 3DE‐IQ was impaired by (1) intentionally poor echocardiographic technique, and (2) use of a sheet of ultrasound‐attenuating material (neoprene rubber; 2–4 mm). The feasibility was 41% (529/1294) for 3DE versus 61% (89/147) for 2D‐EF, P<0.0001. Among acceptable images (n=529), good IQ by the 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging criteria was 33.6% (178/529) and 71.3% (377/529) for 3D‐EF and 3D‐GLS, respectively. Individuals with poor IQ had lower 3D‐EF and 3D‐GLS (absolute) than those with good IQ (3D‐EF: 52.8±6.0% versus 55.7±5.7%, Mean‐Δ −2.9 [−3.9, 1.8]; 3D‐GLS: 18.6±3.2% versus 19.2±2.9%, Mean‐Δ −0.6 [−1.1, 0.0]). In 2 experimental models of poor IQ (n=36 for both), mean differences were (−2.6 to −3.2) for 3D‐EF and (−1.2 to −2.0) for 3D‐GLS. Similar findings were found for other 3DE left ventricle volumes and strain parameters. / Conclusions: 3DE parameters have low feasibility and values are systematically lower in individuals with poor IQ. Although 3D‐EF and 3D‐GLS have potential advantages over conventional echocardiography, further technical improvements are required to improve the utility of 3DE in clinical practice

Using the theoretical domains framework to inform strategies to support dietitians undertaking body composition assessments in routine clinical care

BACKGROUND: Malnutrition, sarcopenia and cachexia are clinical wasting syndromes characterised by muscle loss. Systematic monitoring by body composition assessment (BCA) is recommended for the diagnosis, treatment and monitoring of the syndrome(s). This study investigated practices, competency, and attitudes of Australian dietitians regarding BCA, to inform a local implementation process. METHODS: Applying the Action cycle in the Knowledge to Action framework, surveys were distributed to the 26 dietitians of an 800-bed tertiary hospital. The survey assessed barriers and enablers to performing routine BCA in clinical care. Results were categorised using the Theoretical Domains Framework (TDF) and suitable interventions mapped using the Behaviour Change Wheel. RESULTS: Twenty-two dietitians (84.6%) completed the survey. Barriers to BCA were identified in all TDF domains, particularly in Knowledge, Skills, Social/professional role and identity, Beliefs about capabilities, and Environmental context and resources. Enablers existed in domains of: Skills; Beliefs about consequences; Goals; Environmental context and resources; Social influences; Intentions; Optimism; Reinforcement. CONCLUSIONS: This study showed that hospital dietitians experience individual, team, and organisational barriers to adopt BCAs in clinical practice. We were able to formulate targeted implementation strategies to overcome these barriers to assist BCA adoption into routine practice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-021-06375-7

The prevalence of mental health problems among users of NHS stop smoking services: effects of implementing a routine screening procedure

<p>Abstract</p> <p>Background</p> <p>Tobacco dependence among people with mental health problems is an issue that deserves attention both from a clinical and from a public health perspective. Research suggests that Stop Smoking Services often fail to ask clients about underlying mental health problems and thus fail to put in place the treatment adaptations and liaison procedures often required to meet the needs of clients with a mental health condition who want to stop smoking. This study assesses the recording of mental health problems in a large NHS stop smoking service in England and examines the effect of implementing a short screening procedure on recording mental health conditions.</p> <p>Methods</p> <p>Treatment records from the Stop Smoking Service covering a period of 13 months were audited. The prevalence of reported mental health problems in the six month period before the implementation of the mental health screening procedure was compared with that of the six month period following implementation. The screening procedure was only implemented in the support services directly provided by the Stop Smoking Service. Comparisons were also made with third-party sections of the service where no such screening procedure was introduced.</p> <p>Results</p> <p>The prevalence of reported mental health problems among a total of n = 4999 clients rose from less than 1% before implementation of the screening procedure to nearly 12% in the period following implementation, with the change being statistically significant. No significant rise was observed over the same period in the sections of the service where no screening procedure was implemented.</p> <p>Conclusions</p> <p>The absence of standard procedures to record mental health problems among service users in many stop smoking services is currently likely to prevent the detection of co morbidity. Implementing a simple screening procedure appears suitable to increase the routine recording of mental health problems in a stop smoking service, which is an essential step to ensure services can be tailored and delivered appropriately to the client group.</p

A lifecourse mendelian randomization study highlights the long-term influence of childhood body size on later life heart structure

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10-10). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10-4), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.</p

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity

BACKGROUND: Three-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences. METHODS: 922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint). RESULTS: There were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. CONCLUSIONS: 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population

Single-photon stored-light Ramsey interferometry using Rydberg polaritons

We demonstrate a single-photon stored-light interferometer, where a photon is stored in a laser-cooled atomic ensemble in the form of a Rydberg polariton with a spatial extent of 10×1×1µm3. The photon is subject to a Ramsey sequence, i.e., “split” into a superposition of two paths. After a delay of up to 450 ns, the two paths are recombined to give an output dependent on their relative phase. The superposition time of 450 ns is equivalent to a free-space propagation distance of 135 m. We show that the interferometer fringes are sensitive to external fields and suggest that stored-light interferometry could be useful for localized sensing applications