A multicentre retrospective cohort comparison of aetiology and survival in patients with chronic hypersensitivity pneumonitis versus idiopathic pulmonary fibrosis

This is the author accepted manuscript. The final version is available from BMJ Publishing Group via the DOI in this recordWinter Meeting of the British Thoracic Society, 5-7 December 2018, London, U

Spatial-temporal patterns of ambient fine particulate matter (PM2.5) and black carbon (BC) pollution in Accra

Background: Sub-Saharan Africa (SSA) is rapidly urbanizing, and ambient air pollution has emerged as a major environmental health concern in SSA cities. Yet, effective air quality management is hindered by limited data. We deployed robust, low-cost and low-power devices in a large-scale measurement campaign and characterized within-city variations in fine particulate matter (PM2.5) and black carbon (BC) pollution in Accra, Ghana. Methods: Between April 2019 and June 2020, we measured weekly gravimetric (filter-based) and minute-by-minute PM2.5 concentrations at 146 unique locations, comprising of 10 fixed (~1-year) and 136 rotating (7-day) sites covering a range of land-use and source influences. Filters were weighed for mass, and light absorbance (10−5m−1) of the filters was used as proxy for BC concentration. Year-long data at four fixed sites that were monitored in a previous study (2006-2007) were compared to assess change in PM2.5 concentrations. Results: The mean annual PM2.5 across the fixed sites ranged from 26 μg/m3 at a peri-urban site to 40 μg/m3 at commercial, business, and industrial (CBI) areas. CBI areas had the highest PM2.5 levels (mean: 37 μg/m3), followed by high-density residential neighborhoods (mean: 36 μg/m3), while peri-urban areas recorded the lowest (mean: 26 μg/m3). Both PM2.5 and BC levels were highest during the dry dusty Harmattan period (mean PM2.5: 89 μg/m3) compared to non-Harmattan season (mean PM2.5: 23 μg/m3). PM2.5 at all sites peaked at dawn and dusk, coinciding with morning and evening heavy traffic. We found about a ~50% reduction (71 vs 37 μg/m3) in mean annual PM2.5 concentrations when compared to measurements in 2006-2007 in Accra. Conclusion: Ambient PM2.5 concentrations in Accra may have plateaued at levels lower than those seen in large Asian megacities. However, levels are still 2- to 4-fold higher than the WHO guideline. Effective and equitable policies are needed to reduce pollution levels and protect public health

High-resolution spatiotemporal measurement of air and environmental noise pollution in sub-Saharan African cities: Pathways to Equitable Health Cities Study protocol for Accra, Ghana

Introduction: Air and noise pollution are emerging environmental health hazards in African cities, with potentially complex spatial and temporal patterns. Limited local data is a barrier to the formulation and evaluation of policies to reduce air and noise pollution. Methods and analysis: We designed a year-long measurement campaign to characterize air and noise pollution and their sources at high-resolution within the Greater Accra Metropolitan Area, Ghana. Our design utilizes a combination of fixed (year-long, n = 10) and rotating (week-long, n = ~130) sites, selected to represent a range of land uses and source influences (e.g. background, road-traffic, commercial, industrial, and residential areas, and various neighbourhood socioeconomic classes). We will collect data on fine particulate matter (PM2.5), nitrogen oxides (NOx), weather variables, sound (noise level and audio) along with street-level time-lapse images. We deploy low-cost, low-power, lightweight monitoring devices that are robust, socially unobtrusive, and able to function in the Sub-Saharan African (SSA) climate. We will use state-of-the-art methods, including spatial statistics, deep/machine learning, and processed-based emissions modelling, to capture highly resolved temporal and spatial variations in pollution levels across Accra and to identify their potential sources. This protocol can serve as a prototype for other SSA cities. Ethics and dissemination: This environmental study was deemed exempt from full ethics review at Imperial College London and the University of Massachusetts Amherst; it was approved by the University of Ghana Ethics Committee. This protocol is designed to be implementable in SSA cities to map environmental pollution to inform urban planning decisions to reduce health harming exposures to air and noise pollution. It will be disseminated through local stakeholder engagement (public and private sectors), peer-reviewed publications, contribution to policy documents, media, and conference presentations

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

ICU-acquired pneumonia in immunosuppressed patients with acute hypoxemic respiratory failure: A post-hoc analysis of a prospective international cohort study

Objective: Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure. Design: Post-hoc analysis of a multinational, prospective cohort study in 16 countries. Settings: ICU. Patients: Immunosuppressed patients with acute hypoxemic respiratory failure. Intervention: None. Measurements and main results: The original cohort had 1611 and in this post-hoc analysis a total of 1512 patients with available data on hospital mortality and occurrence of ICU-AP were included. ICU-AP occurred in 158 patients (10.4%). Hospital mortality was higher in patients with ICU-AP (14.8% vs. 7.1% p < 0.001). After adjustment for confounders and centre effect, use of vasopressors (Odds Ratio (OR) 2.22; 95%CI 1.46-.39) and invasive me-chanical ventilation at day 1 (OR 2.12 vs. high flow oxygen; 95%CI 1.07-4.20) were associated with increased risk of ICU-AP while female gender (OR 0.63; 95%CI 0.43-94) and chronic kidney disease (OR 0.43; 95%CI 0.22-0.88) were associated with decreased risk of ICU-AP. After adjustment for confounders and centre effect, ICU-AP was independently associated with mortality (Hazard Ratio 1.48; 95%CI 14.-1.91; P = 0.003). Conclusions: The attributable mortality of ICU-AP has been repetitively questioned in immunosuppressed pa-tients with acute respiratory failure. This manuscript found that ICU-AP represents an independent risk factor for hospital mortality.(c) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis

publishedVersio

Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis

Microsatellite discovery in an insular amphibian (Grandisonia alternans) with comments on cross-species utility and the accuracy of locus identification from unassembled Illumina data

The Seychelles archipelago is unique among isolated oceanic islands because it features an endemic radiation of caecilian amphibians (Gymnophiona). In order to develop population genetics resources for this system, we identified microsatellite loci using unassembled Illumina MiSeq data generated from a genomic library of Grandisonia alternans, a species that occurs on multiple islands in the archipelago. Applying a recently described method (PALFINDER) we identified 8001 microsatellite loci that were potentially informative for population genetics analyses. Of these markers, we screened 60 loci using five individuals, directly sequenced several amplicons to confirm their identity, and then used eight loci to score allele sizes in 64 G. alternans individuals originating from five islands. A number of these individuals were sampled using non-lethal methods, demonstrating the efficacy of non-destructive molecular sampling in amphibian research. Although two loci satisfied our criteria as diploid, neutrally evolving loci with the statistical power to detect population structure, our success in identifying reliable loci was very low. Additionally, we discovered some issues with primer redundancy and differences between Illumina and Sanger sequences that suggest some Illumina-inferred loci are invalid. We investigated cross-species utility for eight loci and found most could be successfully amplified, sequenced and aligned across other species and genera of caecilians from the Seychelles. Thus, our study in part supported the validity of using PALFINDER with unassembled reads for microsatellite discovery within and across species, but importantly identified major limitations to applying this approach to small datasets (ca. 1 million reads) and loci with small tandem repeat sizes