The Milnor-Witt motivic ring spectrum and its associated theories

We build a ring spectrum representing Milnor-Witt motivic cohomology, as well as its \'etale local version and show how to deduce out of it three other theories: Borel-Moore homology, cohomology with compact support and homology. These theories, as well as the usual cohomology, are defined for singular schemes and satisfy the properties of their motivic analog (and more), up to considering more general twists. In fact, the whole formalism of these four theories can be functorially attached to any ring spectrum, giving finally maps between the Milnor-Witt motivic ones to the classical motivic ones.Comment: 28 pages. Comments welcom

Biomarkers of transfusion transmitted occult hepatitis B virus infection: Where are we and what next?

Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a complex entity to detect using surrogate blood biomarkers for intrahepatic viral transcriptional activity, requiring a continually refined battery of tests utilised for screening. This review aims to critically evaluate the latest advances in the current blood biomarkers to guide the identification of OBI donors and discuss novel HBV markers that could be introduced in future diagnostic practice. Challenges in detecting low HBV surface antigen levels, mutants, and complexes necessitate ultrasensitive multivalent dissociation assays, whilst HBV DNA testing requires improved sensitivity but worsens inaccessibility. Anti-core antibody assays defer almost all potentially infectious donations but have low specificity, and titres of anti-surface antibodies that prevent infectivity are poorly defined with suboptimal sensitivity. The challenges associated with these traditional blood HBV markers create an urgent need for alternative biomarkers that would help us better understand the OBI. Emerging viral biomarkers, such as pre-genomic RNA and HBV core-related antigen, immunological HBV biomarkers of T-cell reactivity and cytokine levels, and host biomarkers of microRNA and human leucocyte antigen molecules, present potential advances to gauge intrahepatic activity more accurately. Further studies on these markers may uncover an optimal diagnostic algorithm for OBI using quantification of various novel and traditional blood HBV markers. Addressing critical knowledge gaps identified in this review would decrease the residual risk of transfusion-transmitted HBV infection without compromising the sustainability of blood supplies

Increasing Awareness and Use of Iodised Salt in a Marginalised Community Setting in North-West Pakistan

Iodine deficiency is still prevalent in parts of Pakistan, despite the introduction of a national Iodine Deficiency Disorder Control Programme in 1994. The purpose of this study was to gain an understanding of the knowledge, attitudes and practice regarding the use of iodised salt in a brick kiln community, and to use this information to design an intervention to increase its consumption. A cross-sectional survey was used to assess the use of iodised salt and focus group discussions explored the attitudes and barriers to its use. Thematically analysed transcripts informed the design of a 4-month intervention. Iodised salt sales and urine iodine concentration (UIC) were monitored to assess the effectiveness of the intervention. At baseline, 2.6% of households reported use of iodised salt and barriers included its higher cost and belief about a negative impact on reproduction. During the intervention, sales of salt labelled as iodised increased by 45%, however this was not reflected in an increase in UIC. This study highlighted the positive impact of education and awareness raising on iodised salt consumption in a hard to reach, marginalised community. However, issues regarding adequate iodisation by local producers and appropriate storage also need to be urgently addressed at a provincial level

A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection - A systematic review

Background: Stigma, poverty, and lack of knowledge present barriers to the diagnosis and treatment of chronic infection, especially in resource-limited settings. Chronic Hepatitis B virus (HBV) infection is frequently asymptomatic, but accounts for a substantial long-term burden of morbidity and mortality. In order to improve the success of diagnostic, treatment and preventive strategies, it is important to recognise, investigate and tackle stigma. We set out to assimilate evidence for the nature and impact of stigma associated with HBV infection, and to suggest ways to tackle this challenge. Methods: We carried out a literature search in PubMed using the search terms ‘hepatitis B’, ‘stigma’ to identify relevant papers published between 2007 and 2017 (inclusive), with a particular focus on Africa. Results: We identified a total of 32 articles, of which only two studies were conducted in Africa. Lack of knowledge of HBV was consistently identified, and in some settings there was no local word to describe HBV infection. There were misconceptions about HBV infection, transmission and treatment. Healthcare workers provided inaccurate information to individuals diagnosed with HBV, and poor understanding resulted in lack of preventive measures. Stigma negatively impacted on help-seeking, screening, disclosure, prevention of transmission, and adherence to treatment, and had potential negative impacts on mental health, wellbeing, employment and relationships. Conclusion: Stigma is a potentially major barrier to the successful implementation of preventive, diagnostic and treatment strategies for HBV infection, and yet we highlight a ‘blind spot’, representing a lack of data and limited recognition of this challenge. There is a need for more research in this area, to identify and evaluate interventions that can be used effectively to tackle stigma, and to inform collaborative efforts between patients, clinical services, policy makers, traditional healers, religious leaders, charity organisations and support groups.</ns4:p

Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity

<p>Abstract</p> <p>Background</p> <p>Mutations in the substrate of HIV-1 protease, especially changes in the NC/p1 cleavage site, can directly contribute to protease inhibitor (PI) resistance and also compensate for defects in viral replicative capacity (RC) due to a drug resistant protease. These NC/p1 changes are known to enhance processing of the Gag protein. To investigate the capacity of HIV-1 to modulate Gag cleavage and its consequences for PI resistance and RC, we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2^431V, HXB2^436E+437T, HXB2^437Tand HXB2^437V).</p> <p>Results</p> <p>Here, we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance did not show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, demonstrated a clear reduction in RC. Cleavage analysis showed that a tridecameric NC/p1 peptide representing the double NC/p1 mutant was cleaved in two specific ways instead of one.</p> <p>The observed decrease in RC for the double NC/p1 mutant (HXB2^436E+437T) could (partially) be restored by either reversion of the 436E change or by acquisition of additional changes in the NC/p1 cleavage site at codon 435 or 438 as was revealed during <it>in vitro </it>evolution experiments. These changes not only restored RC but also reduced PI resistance levels. Furthermore these changes normalized Gag processing efficiency and obstructed the novel secondary cleavage site observed for the double NC/p1 mutant.</p> <p>Conclusions</p> <p>The results of this study clearly demonstrate that HIV-1 can modulate Gag processing and thereby PI resistance. Distinct increases in Gag cleavage and PI resistance result in a reduced RC that can only be restored by amino acid changes in NC/p1 which reduce Gag processing to an optimal rate.</p

Re-valuation of annual cytology using HPV self-sampling to upgrade prevention (REACH UP): A feasibility study in women living with HIV in the UK

Introduction: Current UK guidelines for cervical cancer screening are based on the assumption that most women living with HIV (WLWH) are also high-risk (HR) human papillomavirus (HPV)-positive. We aimed to provide data on prevalence of HR-HPV in WLWH in the UK and to assess feasibility and acceptability of HR-HPV self-sampling in this group. // Methods: Women living with HIV attending six HIV services in London/south of England, with no history of cervical cancer, were enrolled. Participants self-collected a vaginal swab for the detection of HR-HPV, completed a survey about sexual/gynaecological history, attitudes towards annual screening and perception of HR-HPV self-sampling, and were asked to have their annual cervical smear. // Results: In all, 67 women were included: 86.5% were of black ethnicity, the median (range) age was 47 (24–60) years, median CD4 T-cell count was 683 cells/µL [interquartile range (IQR): 527–910], and 95.4% had viral load ≤ 50 copies/mL. All performed the vaginal swab. Eighteen (27%) had no cervical smear results; none of these women attended HIV services where this was routinely offered. No cervical samples were positive for HR-HPV. Three-quarters (75.8%) of participants reported adherence to annual screening, with only one woman (1.5%) attending irregularly. On visual analogue scales (from 0 to 100), median (IQR) acceptability and necessity of smear tests were 100 (75–100) and 100 (85–100), respectively. // Conclusions: Our results suggest that the prevalence of HR-HPV in WLWH in the UK may be low. Self-sampling seems to be acceptable, suggesting, if validated, its potential role in supporting less frequent smear testing and improving screening uptake in WLW

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups

Background and Objectives: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti‐HBc) prevents transfusion‐transmitted HBV infection but can lead to significant donor loss. As isolated anti‐HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti‐HBc testing and the representation of rare blood groups in anti‐HBc‐positive donors. Materials and Methods: Three hundred ninety‐seven HBV surface antigen‐negative and anti‐HBc initially reactive blood donor samples were tested by five different anti‐HBc assays. Results: Eighty percentage of samples reactive in Architect anti‐HBc assay were positive by the Murex assay and anti‐HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty‐eight percentage of anti‐HBc‐positive donors identified as minority ethnic groups compared with 11% representation in anti‐HBc‐negative donors (p < 0.0001); the frequency of the Ro blood group in anti‐HBc‐positive donors was 18 times higher in non‐white ethnic groups. Conclusion: Using two anti‐HBc assays effectively enabled the identification of HBV‐exposed and potentially infectious donors, their deferral and potential clinical follow‐up. However, the exclusion of confirmed anti‐HBc‐positive donors will still impact the supply of rare blood such as Ro

Where do those data go? Reuse of screening results from clinical trials to estimate population prevalence of HBV infection in adults in Kilifi, Kenya

Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6-4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4-6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity

The plasmidome associated with Gram-negative bloodstream infections: a large-scale observational study using complete plasmid assembliess

Plasmids carry genes conferring antimicrobial resistance and other clinically important traits, and contribute to the rapid dissemination of such genes. Previous studies using complete plasmid assemblies, which are essential for reliable inference, have been small and/or limited to plasmids carrying antimicrobial resistance genes (ARGs). In this study, we sequenced 1,880 complete plasmids from 738 isolates from bloodstream infections in Oxfordshire, UK. The bacteria had been originally isolated in 2009 (194 isolates) and 2018 (368 isolates), plus a stratified selection from intervening years (176 isolates). We demonstrate that plasmids are largely, but not entirely, constrained to a single host species, although there is substantial overlap between species of plasmid gene-repertoire. Most ARGs are carried by a relatively small number of plasmid groups with biological features that are predictable. Plasmids carrying ARGs (including those encoding carbapenemases) share a putative ‘backbone’ of core genes with those carrying no such genes. These findings suggest that future surveillance should, in addition to tracking plasmids currently associated with clinically important genes, focus on identifying and monitoring the dissemination of high-risk plasmid groups with the potential to rapidly acquire and disseminate these genes