The relationship between target joints and direct resource use in severe haemophilia

Objectives Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. Methods Data on haemophilia patients without inhibitors was drawn from the ‘Cost of Haemophilia across Europe – a Socioeconomic Survey’ (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. Results Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1–10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). Conclusions Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

Emerging infectious disease implications of invasive mammalian species : the greater white-toothed shrew (Crocidura russula) is associated with a novel serovar of pathogenic Leptospira in Ireland

The greater white-toothed shrew (Crocidura russula) is an invasive mammalian species that was first recorded in Ireland in 2007. It currently occupies an area of approximately 7,600 km2 on the island. C. russula is normally distributed in Northern Africa and Western Europe, and was previously absent from the British Isles. Whilst invasive species can have dramatic and rapid impacts on faunal and floral communities, they may also be carriers of pathogens facilitating disease transmission in potentially naive populations. Pathogenic leptospires are endemic in Ireland and a significant cause of human and animal disease. From 18 trapped C. russula, 3 isolates of Leptospira were cultured. However, typing of these isolates by standard serological reference methods was negative, and suggested an, as yet, unidentified serovar. Sequence analysis of 16S ribosomal RNA and secY indicated that these novel isolates belong to Leptospira alstonii, a unique pathogenic species of which only 7 isolates have been described to date. Earlier isolations were limited geographically to China, Japan and Malaysia, and this leptospiral species had not previously been cultured from mammals. Restriction enzyme analysis (REA) further confirms the novelty of these strains since no similar patterns were observed with a reference database of leptospires. As with other pathogenic Leptospira species, these isolates contain lipL32 and do not grow in the presence of 8-azagunaine; however no evidence of disease was apparent after experimental infection of hamsters. These isolates are genetically related to L. alstonii but have a novel REA pattern; they represent a new serovar which we designate as serovar Room22. This study demonstrates that invasive mammalian species act as bridge vectors of novel zoonotic pathogens such as Leptospira

The Canlex Project: summary and conclusions

The Canadian geotechnical engineering community has completed a major collaborative 5 year research project entitled the Canadian Liquefaction Experiment (CANLEX). The main objective of the project was to study the phenomenon of soil liquefaction, which can occur in saturated sandy soils and is characterized by a large loss of strength or stiffness resulting in substantial deformations. The intent of this paper is to compare, interpret, and summarize the large amount of field and laboratory data obtained for six sites in Western Canada as part of the CANLEX project. The sites are compared in terms of both flow-liquefaction and cyclic-softening considerations. The paper presents a number of conclusions drawn from the project as a whole, in terms of both fundamental and practical significance.published_or_final_versio

Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection.</p> <p>Methods</p> <p>A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and <it>in silico </it>mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied.</p> <p>Results</p> <p>Cross-matching of literature and <it>in silico</it>-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall category; 13% are classical vaccine candidates; 9% are categorized Conserved hypotheticals, all potentially very potent T-cell antigens.</p> <p>Conclusion</p> <p>The comprehensive literature and <it>in silico</it>-based analyses allowed for the selection of a repertoire of 189 vaccine candidates, out of the whole-genome 3989 ORF products. This repertoire, which was ranked to generate a list of 45 top-hits antigens, is a platform for selection of genes covering all stages of <it>M. tuberculosis </it>infection, to be incorporated in rBCG or subunit-based vaccines.</p

Climate change threatens the world’s marine protected areas

Marine protected areas (MPAs) are a primary management tool for mitigating threats to marine biodiversity1,2. MPAs and the species they protect, however, are increasingly being impacted by climate change. Here we show that, despite local protections, the warming associated with continued business-as-usual emissions (RCP8.5)3 will likely result in further habitat and species losses throughout low-latitude and tropical MPAs4,5. With continued business-as-usual emissions, mean sea-surface temperatures within MPAs are projected to increase 0.035 °C per year and warm an additional 2.8 °C by 2100. Under these conditions, the time of emergence (the year when sea-surface temperature and oxygen concentration exceed natural variability) is mid-century in 42% of 309 no-take marine reserves. Moreover, projected warming rates and the existing ‘community thermal safety margin’ (the inherent buffer against warming based on the thermal sensitivity of constituent species) both vary among ecoregions and with latitude. The community thermal safety margin will be exceeded by 2050 in the tropics and by 2150 for many higher latitude MPAs. Importantly, the spatial distribution of emergence is stressor-specific. Hence, rearranging MPAs to minimize exposure to one stressor could well increase exposure to another. Continued business-as-usual emissions will likely disrupt many marine ecosystems, reducing the benefits of MPAs

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC