An integrative evidence review on service user participation in the design and delivery of drug treatment, recovery and harm reduction services.

This study aims to provide an overview of what user involvement entails within the context of drug treatment services in Ireland. The objective of the study is to provide policy-makers, practitioners, researchers and service users with a clearer understanding of the challenges associated with user involvement, a fundamental paradigm or principle when seeking to develop more effective and satisfactory services. The study involved a lengthy and complex series of research tasks, including an extensive literature search, a service user consultation and discussions with a number of stakeholders. Julie Glanville was responsible for designing the literature search, Feline Engling Cardoso coordinated the stakeholder interviews and Jonathan Pratschke carried out the service user consultation, as well as analysing the interview transcripts and supervising the study. Brian Galvin from the Health Research Board provided oversight and guidance, the Royal College of Physicians of Ireland provided ethical approval for the service user consultation

Authors' response to comments from Nachman KE et al.

Abstract Authors’ response to comments letter to the editor from Nachman KE et al

Ability to Taste 6‐ n ‐Propylthiouracil and BMI in Low‐income Preschool‐aged Children

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93763/1/oby.2008.227.pd

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

BACKGROUND: Patients with antibody deficiency respond poorly to COVID-19 vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesised that immunoglobulin preparations will now contain neutralising SARS-CoV-2 spike antibodies which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralising capacity of patient samples and immunoglobulin products was assessed using in vitro pseudo-virus and live-virus neutralisation assays, the latter investigating multiple batches against current circulating omicron variants. We describe the clinical course of nine patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titre increased from 2123 to 10600 U/ml post-infusion, with corresponding increase in pseudo-virus neutralisation titres to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralisation, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside Remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum over 900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 virus at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralising anti-SARS-CoV-2 antibodies which are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity

PRISMA 2020 explanation and elaboration : updated guidance and exemplars for reporting systematic reviews

The methods and results of systematic reviews should be reported in sufficient detail to allow users to assess the trustworthiness and applicability of the review findings. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was developed to facilitate transparent and complete reporting of systematic reviews and has been updated (to PRISMA 2020) to reflect recent advances in systematic review methodology and terminology. Here, we present the explanation and elaboration paper for PRISMA 2020, where we explain why reporting of each item is recommended, present bullet points that detail the reporting recommendations, and present examples from published reviews. We hope that changes to the content and structure of PRISMA 2020 will facilitate uptake of the guideline and lead to more transparent, complete, and accurate reporting of systematic reviews

Cytotoxic T-Cells in HIV-1: "The Good" and "The Bad"

CD8+ T-cell antigen sensitivity is critical for optimal control of persistent viral infections, including HIV-1. The devastating HIV-1 pandemic may be countered by development of a cytotoxic T lymphocyte based vaccine if qualities associated with protection can be defined at the molecular level. However, the heterogeneity of the total viral-specific CTL response confounds identification of protective correlates and T-cell sensitivity is no exception and remains controversial. To address this issue we reduced the heterogeneity of the HIV-1 CTL response to single units, generating 19 CTL clones that recognise the same HIV-1 derived epitope restricted by HLA B*08. Correlation of functional assays directly with the ability of each clone to control HIV-1 replication in vitro, the “viral suppression assay,” identified antigen sensitivity as a key quality for anti-viral efficacy. Remarkably, four clones from this panel, isolated from one individual, a long-term non-progressor, all used an identical TCR yet had distinct antigen sensitivity and suppressive activity. Two of these clones were characterised in detail, and had distinct cytokine profiles, regulated by epigenetic mechanisms, and differential expression of a group of cell surface receptors with the potential to modulate the signalling threshold to antigen. Expression of the TNFα locus of the high sensitivity clone with “Good” suppression was repressed by DNA methylation. Understanding how CTL qualities required for optimal control of HIV-1 replication differentiate and are then enriched in the total CTL response, and if repression of TNFα contributes to this process, will contribute to rational vaccine design. This is the first evidence that avidity maturation in CD8+ T cells with the same TCR affinity occurs in viral infections in humans as reported in the mouse. This suggests the induction of high sensitivity CTL will be critical for an effective HIV-1 vaccine, but offers hope that this can be achieved even in individuals without protective HLA alleles, by further exploration of peripheral avidity maturation and epigenetic regulation of the HIV-1 specific CD8+ T-cell response

Cytotoxic T-Cells in HIV-1: "The Good" and "The Bad"

CD8+ T-cell antigen sensitivity is critical for optimal control of persistent viral infections, including HIV-1. The devastating HIV-1 pandemic may be countered by development of a cytotoxic T lymphocyte based vaccine if qualities associated with protection can be defined at the molecular level. However, the heterogeneity of the total viral-specific CTL response confounds identification of protective correlates and T-cell sensitivity is no exception and remains controversial. To address this issue we reduced the heterogeneity of the HIV-1 CTL response to single units, generating 19 CTL clones that recognise the same HIV-1 derived epitope restricted by HLA B*08. Correlation of functional assays directly with the ability of each clone to control HIV-1 replication in vitro, the “viral suppression assay,” identified antigen sensitivity as a key quality for anti-viral efficacy. Remarkably, four clones from this panel, isolated from one individual, a long-term non-progressor, all used an identical TCR yet had distinct antigen sensitivity and suppressive activity. Two of these clones were characterised in detail, and had distinct cytokine profiles, regulated by epigenetic mechanisms, and differential expression of a group of cell surface receptors with the potential to modulate the signalling threshold to antigen. Expression of the TNFα locus of the high sensitivity clone with “Good” suppression was repressed by DNA methylation. Understanding how CTL qualities required for optimal control of HIV-1 replication differentiate and are then enriched in the total CTL response, and if repression of TNFα contributes to this process, will contribute to rational vaccine design. This is the first evidence that avidity maturation in CD8+ T cells with the same TCR affinity occurs in viral infections in humans as reported in the mouse. This suggests the induction of high sensitivity CTL will be critical for an effective HIV-1 vaccine, but offers hope that this can be achieved even in individuals without protective HLA alleles, by further exploration of peripheral avidity maturation and epigenetic regulation of the HIV-1 specific CD8+ T-cell response.This thesis is not currently available in ORA