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Pulmonary talaromycosis: a window into the immunopathogenesis of an endemic mycosis
No full textTalaromycosis is an invasive mycosis caused by the thermally dimorphic saprophytic fungus Talaromyces marneffei (Tm) endemic in Asia. Like other endemic mycoses, talaromycosis occurs predominantly in immunocompromised and, to a lesser extent, immunocompetent hosts. The lungs are the primary portal of entry, and pulmonary manifestations provide a window into the immunopathogenesis of talaromycosis. Failure of alveolar macrophages to destroy Tm results in reticuloendothelial system dissemination and multi-organ disease. Primary or secondary immune defects that reduce CD4+ T cells, INF-γ, IL-12, and IL-17 functions, such as HIV infection, anti-interferon-γ autoantibodies, STAT-1 and STAT-3 mutations, and CD40 ligand deficiency, highlight the central roles of Th1 and Th17 effector cells in the control of Tm infection. Both upper and lower respiratory infections can manifest as localised or disseminated disease. Upper respiratory disease appears unique to talaromycosis, presenting with oropharyngeal lesions and obstructive tracheobronchial masses. Lower respiratory disease is protean, including alveolar consolidation, solitary or multiple nodules, mediastinal lymphadenopathy, cavitary disease, and pleural effusion. Structural lung disease such as chronic obstructive pulmonary disease is an emerging risk factor in immunocompetent hosts. Mortality, up to 55%, is driven by delayed or missed diagnosis. Rapid, non-culture-based diagnostics including antigen and PCR assays are shown to be superior to blood culture for diagnosis, but still require rigorous clinical validation and commercialisation. Our current understanding of acute pulmonary infections is limited by the lack of an antibody test. Such a tool is expected to unveil a larger disease burden and wider clinical spectrum of talaromycosis
Comparing the responses of the UK, Sweden and Denmark to COVID-19 using counterfactual modelling
No full textThe UK and Sweden have among the worst per-capita COVID-19 mortality in Europe. Sweden stands out for its greater reliance on voluntary, rather than mandatory, control measures. We explore how the timing and effectiveness of control measures in the UK, Sweden and Denmark shaped COVID-19 mortality in each country, using a counterfactual assessment: what would the impact have been, had each country adopted the others’ policies? Using a Bayesian semi-mechanistic model without prior assumptions on the mechanism or effectiveness of interventions, we estimate the time-varying reproduction number for the UK, Sweden and Denmark from daily mortality data. We use two approaches to evaluate counterfactuals which transpose the transmission profile from one country onto another, in each country’s first wave from 13th March (when stringent interventions began) until 1st July 2020. UK mortality would have approximately doubled had Swedish policy been adopted, while Swedish mortality would have more than halved had Sweden adopted UK or Danish strategies. Danish policies were most effective, although differences between the UK and Denmark were significant for one counterfactual approach only. Our analysis shows that small changes in the timing or effectiveness of interventions have disproportionately large effects on total mortality within a rapidly growing epidemic
Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses
No full textBackground
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.
Methods
Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.
Findings
Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0·69 [95% CI 0·59–0·80]; p<0·0001) and non-significant inverse associations for stroke (0·85 [0·70–1·02], p=0·09) and coronary heart disease (0·89 [0·76–1·04]; p=0·14). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L.
Interpretation
Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies.
Funding
British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer
Ένας Αρχαίος Ναός - Προβολή παρουσίασης
No full textΣυνοδευτικό εποπτικό υλικό της Μουσειοσκευής "Ένας Αρχαίος Ναός" για προβολή στην τάξη
Kiloparsec-scale AGN outflows and feedback in merger-free galaxies
No full textRecent observations and simulations have challenged the long-held paradigm that mergers are the dominant mechanism driving the growth of both galaxies and supermassive black holes (SMBH), in favour of non-merger (secular) processes. In this pilot study of merger-free SMBH and galaxy growth, we use Keck Cosmic Web Imager spectral observations to examine four low-redshift (0.043 < z < 0.073) disc-dominated ‘bulgeless’ galaxies hosting luminous active galactic nucleus (AGN), assumed to be merger-free. We detect blueshifted broadened [O III] emission from outflows in all four sources, which the [OIII]/Hβ ratios reveal are ionized by the AGN. We calculate outflow rates in the range 0.12−0.7 M⊙ yr−1, with velocities of 675−1710 km s−1, large radial extents of 0.6−2.4 kpc, and SMBH accretion rates of 0.02−0.07 M⊙ yr−1. We find that the outflow rates, kinematics, and energy injection rates are typical of the wider population of low-redshift AGN, and have velocities exceeding the galaxy escape velocity by a factor of ∼30, suggesting that these outflows will have a substantial impact through AGN feedback. Therefore, if both merger-driven and non-merger-driven SMBH growth lead to co-evolution, this suggests that co-evolution is regulated by feedback in both scenarios. Simulations find that bars and spiral arms can drive inflows to galactic centers at rates an order of magnitude larger than the combined SMBH accretion and outflow rates of our four targets. This work therefore provides further evidence that non-merger processes are sufficient to fuel SMBH growth and AGN outflows in disc galaxies
Beyond individual triage: regional allocation of life-saving resources such as ventilators in public health emergencies
No full textIn the first wave of the COVID-19 pandemic, healthcare workers in some countries were forced to make distressing triaging decisions about which individual patients should receive potentially life-saving treatment. Much of the ethical discussion prompted by the pandemic has concerned which moral principles should ground our response to these individual triage questions. In this paper we aim to broaden the scope of this discussion by considering the ethics of broader structural allocation decisions raised by the COVID-19 pandemic. More specifically, we consider how nations ought to distribute a scarce life-saving resource across healthcare regions in a public health emergency, particularly in view of regional differences in projected need and existing capacity. We call this the regional triage question. Using the case study of ventilators in the COVID-19 pandemic, we show how the moral frameworks that we might adopt in response to individual triage decisions do not translate straightforwardly to this regional-level triage question. Having outlined what we take to be a plausible egalitarian approach to the regional triage question, we go on to propose a novel way of operationalising the ‘save the most lives’ principle in this context. We claim that the latter principle ought to take precedence in the regional triage question, but also note some important limitations to the extent of the influence that it should have in regional allocation decisions
Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate
No full textCellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the leucine-rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF-κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues
Protocol for the development of the Wales Multimorbidity e-Cohort (WMC): data sources and methods to construct a population-based research platform to investigate multimorbidity
No full textIntroduction Multimorbidity is widely recognised as the presence of two or more concurrent long-term conditions, yet remains a poorly understood global issue despite increasing in prevalence.
We have created the Wales Multimorbidity e-Cohort (WMC) to provide an accessible research ready data asset to further the understanding of multimorbidity. Our objectives are to create a platform to support research which would help to understand prevalence, trajectories and determinants in multimorbidity, characterise clusters that lead to highest burden on individuals and healthcare services, and evaluate and provide new multimorbidity phenotypes and algorithms to the National Health Service and research communities to support prevention, healthcare planning and the management of individuals with multimorbidity.
Methods and analysis The WMC has been created and derived from multisourced demographic, administrative and electronic health record data relating to the Welsh population in the Secure Anonymised Information Linkage (SAIL) Databank. The WMC consists of 2.9 million people alive and living in Wales on the 1 January 2000 with follow-up until 31 December 2019, Welsh residency break or death. Published comorbidity indices and phenotype code lists will be used to measure and conceptualise multimorbidity.
Study outcomes will include: (1) a description of multimorbidity using published data phenotype algorithms/ontologies, (2) investigation of the associations between baseline demographic factors and multimorbidity, (3) identification of temporal trajectories of clusters of conditions and multimorbidity and (4) investigation of multimorbidity clusters with poor outcomes such as mortality and high healthcare service utilisation.
Ethics and dissemination The SAIL Databank independent Information Governance Review Panel has approved this study (SAIL Project: 0911). Study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals
