Lessons learnt from a 2017 Irish national clinical claims review: a retrospective observational study.

Objective: Learning from adverse outcomes in health and social care is critical to advancing a culture of patient safety and reducing the likelihood of future preventable harm to service users. This review aims to present an overview of all clinical claims finalised in one calendar year involving publicly funded health and social care providers in Ireland.

Design: This is a retrospective observational study.

A VRC13-like bNAb response is associated with complex escape pathways in HIV-1 envelope.

The rational design of HIV-1 immunogens to trigger the development of broadly neutralizing antibodies (bNAbs) requires understanding the viral evolutionary pathways influencing this process. An acute HIV-1-infected individual exhibiting >50% plasma neutralization breadth developed neutralizing antibody specificities against the CD4-binding site (CD4bs) and V1V2 regions of Env gp120. Comparison of pseudoviruses derived from early and late autologous sequences demonstrated the development of >2 log resistance to VRC13 but not to other CD4bs-specific bNAbs.

Validation of dried blood spots for capturing hepatitis C virus diversity for genomic surveillance.

Dried blood spots (DBS) have emerged as a promising alternative to traditional venous blood for hepatitis C virus (HCV) testing. However, their capacity to accurately reflect the genetic diversity of HCV remains poorly understood. We employed deep sequencing and advanced phylogenetic analyses on paired plasma and DBS samples from two common subtypes to evaluate the suitability of DBS for genomic surveillance.

Validation of Dried Blood Spots for Capturing Hepatitis C Virus Diversity for Genomic Surveillance.

Dried blood spots (DBS) have emerged as a promising alternative to traditional venous blood for HCV testing. However, their capacity to accurately reflect the genetic diversity of HCV remains poorly understood. We employed deep sequencing and advanced phylogenetic analyses on paired plasma and DBS samples to evaluate the suitability of DBS for genomic surveillance.

Functional impairment of HIV-specific CD8 T cells precedes aborted spontaneous control of viremia.

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8 T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control.

Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection.

Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1-specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice.

Hepatitis C Virus Transmission Clusters in Public Health and Correctional Settings, Wisconsin, USA, 2016-2017.

Ending the hepatitis C virus (HCV) epidemic requires stopping transmission among networks of persons who inject drugs. Identifying transmission networks by using genomic epidemiology may inform community responses that can quickly interrupt transmission. We retrospectively identified HCV RNA-positive specimens corresponding to 459 persons in settings that use the state laboratory, including correctional facilities and syringe services programs, in Wisconsin, USA, during 2016-2017.

Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo.

An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4 T cell loss after the discontinuation of antiretroviral therapy.

Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein.

The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma.

Immunization of BLT Humanized Mice Redirects T Cell Responses to Gag and Reduces Acute HIV-1 Viremia.

BLT (bone marrow-liver-thymus) humanized mice, which reconstitute a functional human immune system, develop prototypic human virus-specific CD8 T cell responses following infection with human immunodeficiency virus type 1 (HIV-1). We explored the utility of the BLT model for HIV-1 vaccine development by immunizing BLT mice against the conserved viral Gag protein, utilizing a rapid prime-boost protocol of poly(lactic-co-glycolic) acid microparticles and a replication-defective herpes simplex virus (HSV) recombinant vector. After HIV-1 challenge, the mice developed broad, proteome-wide gamma interferon-positive (IFN-γ) T cell responses against HIV-1 that reached magnitudes equivalent to what is observed in HIV-1-infected individuals.

Structural topology defines protective CD8 T cell epitopes in the HIV proteome.

Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen () class I alleles.

Development of a novel bedside index for the early identification of severe maternal infection.

Objectives: International consensus reports have recently recommended that the Systemic Inflammatory Response Syndrome (SIRS) criteria for the diagnosis of sepsis should cease and that new bedside criteria need to be developed to improve prevention, early diagnosis and treatment. The aim of this retrospective audit was to evaluate a suite of four bedside clinical criteria, called the Early Maternal Infection Prompts (EMIP), in helping to identify women with a suspected severe infection who were admitted to a High Dependency Unit (HDU) in a large tertiary referral stand-alone maternity hospital.

Study Design: The four EMIP criteria were decided based on existing national obstetric guidelines and a review of the recent literature on maternal critical illnesses.

HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission.

HIV-1 primarily infects T lymphocytes and uses these motile cells as migratory vehicles for effective dissemination in the host. Paradoxically, the virus at the same time disrupts multiple cellular processes underlying lymphocyte motility, seemingly counterproductive to rapid systemic infection. Here we show by intravital microscopy in humanized mice that perturbation of the actin cytoskeleton via the lentiviral protein Nef, and not changes to chemokine receptor expression or function, is the dominant cause of dysregulated infected T cell motility in lymphoid tissue by preventing stable cellular polarization required for fast migration.

High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease.

Background & Aims: The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution.

Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo.

Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection.

Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome.

Evaluation of the systemic inflammatory response syndrome criteria for the diagnosis of sepsis due to maternal bacteremia.

Objective: To examine, in the setting of maternal bacteremia, the implications for the diagnosis of maternal sepsis of customizing the systemic inflammatory response syndrome (SIRS) criteria for physiologic changes of pregnancy.

Methods: Women with maternal bacteremia in a tertiary maternity hospital during 2009-2014 were identified. Records were retrospectively reviewed to determine whether they fulfilled the criteria for diagnosis of sepsis based on either the standard SIRS parameters derived from the Surviving Sepsis Campaign or SIRS parameters customized for pregnancy.

Evaluation of point-of-care maternal venous lactate testing in normal pregnancy.

Objective: There is little information about whether the established non-pregnant adult venous lactate reference range is appropriate for pregnancy. This prospective observational study examined whether the non-pregnant adult reference range is appropriate during pregnancy.

Methods: Women attending for routine prenatal appointments or elective cesarean delivery in a tertiary hospital were recruited.

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8+ T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection.

Unlabelled: Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]).

Maternal bacteremia and the Irish maternity early warning system.

Objective: To assess whether introduction of the Irish maternity early warning system (IMEWS) in 2013 has improved the recording of vital signs among women with proven maternal bacteremia.

Methods: In a mixed retrospective and prospective study at a single center in Dublin, Ireland, the patient records of all cases of maternal bacteremia between January 1, 2009, and March 31, 2014, were reviewed. The IMEWS chart was applied retrospectively to records of vital signs from January 2009 to March 2013, and prospectively from April 2013 to March 2014.

Comparative analysis of Salmonella susceptibility and tolerance to the biocide chlorhexidine identifies a complex cellular defense network.

Chlorhexidine is one of the most widely used biocides in health and agricultural settings as well as in the modern food industry. It is a cationic biocide of the biguanide class. Details of its mechanism of action are largely unknown.

A novel Tn3-like composite transposon harboring blaVIM-1 in Klebsiella pneumoniae spp. pneumoniae isolated from river water.

Objectives: We present a new plasmid (pOW16C2) with a novel Tn3-like transposon harboring blaVIM-1 from a Klebsiella pneumoniae strain isolated from river water in Switzerland.

Methods: Complete nucleotide sequence of pOW16C2 was obtained using a Pacific Biosciences SMRT sequencing approach and coding sequences were predicted.

Results: The 59,228 bp sequence included a typical IncN-like backbone and a mosaic structure with blaVIM-1, aacA4, aphA15, aadA1, catB2, qnrS1, sul1, and dfrA14 conferring resistance to carbapenems and other β-lactam antibiotics, aminoglycosides, chloramphenicol, quinolones, sulfonamides, and trimethoprim, respectively.