Predicting global invasion risks: a management tool to prevent future introductions

Predicting regions at risk from introductions of non-native species and the subsequent invasions is a fundamental aspect of horizon scanning activities that enable the development of more effective preventative actions and planning of management measures. The Asian cyprinid fish topmouth gudgeon Pseudorasbora parva has proved highly invasive across Europe since its introduction in the 1960s. In addition to direct negative impacts on native fish populations, P. parva has potential for further damage through transmission of an emergent infectious disease, known to cause mortality in other species. To quantify its invasion risk, in regions where it has yet to be introduced, we trained 900 ecological niche models and constructed an Ensemble Model predicting suitability, then integrated a proxy for introduction likelihood. This revealed high potential for P. parva to invade regions well beyond its current invasive range. These included areas in all modelled continents, with several hotspots of climatic suitability and risk of introduction. We believe that these methods are easily adapted for a variety of other invasive species and that such risk maps could be used by policy-makers and managers in hotspots to formulate increased surveillance and early-warning systems that aim to prevent introductions and subsequent invasions

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Case-finding for common mental disorders of anxiety and depression in primary care: an external validation of routinely collected data

Background The robustness of epidemiological research using routinely collected primary care electronic data to support policy and practice for common mental disorders (CMD) anxiety and depression would be greatly enhanced by appropriate validation of diagnostic codes and algorithms for data extraction. We aimed to create a robust research platform for CMD using population-based, routinely collected primary care electronic data. Methods We developed a set of Read code lists (diagnosis, symptoms, treatments) for the identification of anxiety and depression in the General Practice Database (GPD) within the Secure Anonymised Information Linkage Databank at Swansea University, and assessed 12 algorithms for Read codes to define cases according to various criteria. Annual incidence rates were calculated per 1000 person years at risk (PYAR) to assess recording practice for these CMD between January 1st 2000 and December 31st 2009. We anonymously linked the 2799 MHI-5 Caerphilly Health and Social Needs Survey (CHSNS) respondents aged 18 to 74 years to their routinely collected GP data in SAIL. We estimated the sensitivity, specificity and positive predictive value of the various algorithms using the MHI-5 as the gold standard. Results The incidence of combined depression/anxiety diagnoses remained stable over the ten-year period in a population of over 500,000 but symptoms increased from 6.5 to 20.7 per 1000 PYAR. A ‘historical’ GP diagnosis for depression/anxiety currently treated plus a current diagnosis (treated or untreated) resulted in a specificity of 0.96, sensitivity 0.29 and PPV 0.76. Adding current symptom codes improved sensitivity (0.32) with a marginal effect on specificity (0.95) and PPV (0.74). Conclusions We have developed an algorithm with a high specificity and PPV of detecting cases of anxiety and depression from routine GP data that incorporates symptom codes to reflect GP coding behaviour. We have demonstrated that using diagnosis and current treatment alone to identify cases for depression and anxiety using routinely collected primary care data will miss a number of true cases given changes in GP recording behaviour. The Read code lists plus the developed algorithms will be applicable to other routinely collected primary care datasets, creating a platform for future e-cohort research into these conditions. Keyword

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Genetic and environmental aetiologies of associations between dispositional mindfulness and ADHD traits: a population-based twin study

© The Author(s) 2019. To get additional insight into the phenotype of attentional problems, we examined to what extent genetic and environmental factors explain covariation between lack of dispositional mindfulness and attention-deficit/hyperactivity disorder (ADHD) traits in youth, and explored the incremental validity of these constructs in predicting life satisfaction. We used data from a UK population-representative sample of adolescent twins (N = 1092 pairs) on lack of dispositional mindfulness [Mindful Attention Awareness Scale (MAAS)], ADHD traits [Conners’ Parent Rating Scale-Revised (CPRS-R): inattentive (INATT) and hyperactivity/impulsivity (HYP/IMP) symptom dimensions] and life satisfaction (Students’ Life Satisfaction Scale). Twin model fitting analyses were conducted. Phenotypic correlations (rp) between MAAS and CPRS-R (INATT: rp = 0.18, HYP/IMP: rp = 0.13) were small, but significant and largely explained by shared genes for INATT (% rp INATT–MAAS due to genes: 93%, genetic correlation rA = 0.37) and HYP/IMP (% rp HYP/IMP–MAAS due to genes: 81%; genetic correlation rA = 0.21) with no significant contribution of environmental factors. MAAS, INATT and HYP/IMP significantly and independently predicted life satisfaction. Lack of dispositional mindfulness, assessed as self-reported perceived lapses of attention (MAAS), taps into an aspect of attentional functioning that is phenotypically and genetically distinct from parent-rated ADHD traits. The clinically relevant incremental validity of both scales implicates that MAAS could be used to explore the underlying mechanisms of an aspect of attentional functioning that uniquely affects life satisfaction and is not captured by DSM-based ADHD scales. Further future research could identify if lack of dispositional mindfulness and high ADHD traits can be targeted by different therapeutic approaches resulting in different effects on life satisfactio

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century