Acceptability and Feasibility of Universal Offer of Rapid Point of Care Testing for HIV in an Acute Admissions Unit: Results of the RAPID Project

UK guidance recommend all acute medical admissions be offered an HIV test. Our aim was to determine whether a dedicated staff member using a multimedia tool, a model found to be effective in the USA, is an acceptable, feasible, and cost-effective model when translated to a UK setting

What can they expect? Decreased quality of life and increased postoperative complication rate in patients with a fracture-related infection

Background: By gaining insight into the Quality of Life (QoL) status and occurrence of complications, critical facets in the care for patients with Fracture-Related Infection (FRI) can be mitigated and measures can be taken to improve their outcome. Therefore, the aims of this study were to 1) determine the QoL in FRI patients in comparison to non-FRI patients and 2) describe the occurrence of other complications in both FRI and non-FRI patients. Methods: An ambidirectional cohort study was conducted in a level 1 trauma centre between January 1st 2016 and November 1st 2021. All patients who underwent surgical stabilisation of an isolated long bone fracture were eligible for inclusion. To avoid confounding, only patients with an Injury Severity Score (ISS) <16 were included. Data regarding patient demographics, fracture characteristics, treatment, follow-up and complications were collected of both non-FRI and FRI patients. QoL was assessed through the use of five-level EuroQol five-dimension (EQ-5D-5L) questionnaires twelve months post-injury. Results: A total of 134 patients were included in this study, of whom 38 (28%) FRI patients and 96 (72%) non-FRI patients. In comparison to non-FRI patients, FRI patients scored significantly worse on the QoL assessment regarding the index value (p = 0.012) and the domains mobility (p<0.001), usual activities (p = 0.010) and pain/discomfort (p = 0.009). Other postoperative complications were more often reported (p<0.001) in FRI patients (66%, n = 25/38) compared to non-FRI patients (27%, n = 26/96). During the median follow-up of 14.5 months (interquartile range (IQR) 9.5–26.5), 25 FRI patients developed a total of 49 distinctive complications besides FRI. The complications nonunion (18%, n = 9/49), infection other than FRI (e.g. line infection, urinary tract infection, pneumonia) (18%, n = 9/49) and implant failure (14%, n = 7/49) were the most frequently described in the FRI group. Conclusion: Patients who suffered from an FRI have a decreased QoL in comparison to those without an FRI. Moreover, patients with an FRI have a higher rate of additional complications. These findings can help in patient counselling regarding the potential physical and mental consequences of having a complicated course of recovery due to an infection

the CUTHIVAC-001 randomized trial

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers

The Safety and Immunogenicity of GTU®MultiHIV DNA Vaccine Delivered by Transcutaneous and Intramuscular Injection With or Without Electroporation in HIV-1 Positive Subjects on Suppressive ART

International audiencePrevious studies have shown targeting different tissues via the transcutaneous (TC) and intramuscular injection (IM) with or without electroporation (EP) has the potential to trigger immune responses to DNA vaccination. The CUTHIVTHER 001 Phase I/II randomized controlled clinical trial was designed to determine whether the mode of DNA vaccination delivery (TC+IM or EP+IM) could influence the quality and function of induced cellular immune responses compared to placebo, in an HIV positive clade B cohort on antiretroviral therapy (ART). The GTU®MultiHIV B DNA vaccine DNA vaccine encoded a MultiHIV B clade fusion protein to target the cellular response. Overall the vaccine and regimens were safe and well-tolerated. There were robust pre-vaccination IFN-γ responses with no measurable change following vaccination compared to placebo. However, modest intracellular cytokine staining (ICS) responses were seen in the TC+IM group. A high proportion of individuals demonstrated potent viral inhibition at baseline that was not improved by vaccination. These results show that HIV positive subjects with nadir CD4+ counts ≥250 on suppressive ART display potent levels of cellular immunity and viral inhibition, and that DNA vaccination alone is insufficient to improve such responses. These data suggest that more potent prime-boost vaccination strategies are likely needed to improve pre-existing responses in similar HIV-1 cohorts (This study has been registered at http://ClinicalTrials.gov under registration no. NCT02457689)

Genetic and cellular aspects of the establishment of histocompatible stem cells: information gained from an animal model

The establishment of patient-specific histocompatible stem cells may be an alternative for overcoming current limitations in stem cell engineering. We are developing an animal model to assist the establishment of histocompatible, autologous stem cells. In this process, we obtained valuable information on establishing and characterizing stem cells. As an initial step, we succeeded in establishing histocompatible stem cells using preantral follicle cultures and subsequent parthenogenetic activation. The gene expression profile of the established stem cells was similar to that of embryonic stem cells (ESCs) derived from normal fertilization. On the other hand, we propose a way to derive histocompatible, ESC-like cells by co-culturing ovarian stromal cells with feeder fibroblasts, which may allow the derivation of stem cells from somatic tissue. However, more progress regarding the establishment and elucidation on origination of established cell lines is necessary to use this genetic manipulation-free procedure. Nevertheless, relevant information on the process will help to stimulate preclinical research on cell transformation into differentiated, undifferentiated, and even cancerous cells, as well as clinical studies on the application of induced pluripotent cells

Association of iron overload based quantitative T2* MRI technique and carotid intima-media thickness in patients with beta-thalassemia: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Body iron status has been implicated in atherosclerotic cardiovascular disease. The main hypothesis is that high iron status is associated with increased risk of atherosclerosis. We investigated the potential role of iron as an additional risk factor promoting atherosclerosis among beta-thalassemic patients.</p> <p>Methods</p> <p>In this cross-sectional study, the liver iron load was assessed by quantitative T2* MRI technique and intima-media thickness (IMT) of the common carotid artery by high-resolution ultrasound among 119 patients (62 male, 57 female) with beta-thalassemia (major and intermediate) whose age ranged from 10 to 50 years with a mean of 25.6 years. The patients were divided into three groups according to the severity of iron loading, obtained by T2*MRI technique: group I (normal), group II (mild) and group III (moderate and severe) iron load.</p> <p>For elimination of the effect of age on carotid IMT values, the patients also were divided into four age groups (10-19 y, 20-29 y, 30-39 y and 40-50 y). Mean carotid IMT based on the severity of iron loading were compared at different age groups, using one way ANOVA analysis for assessing the effect of iron loading on carotid IMT. Pearson's coefficient of correlation were used to assess the degree of correlation between studied variables (liver T2*, IMT, age).</p> <p>Results</p> <p>There were significant differences in mean carotid IMT based on the severity of iron loading at different age groups, with P = 0.003 at 20-29 y, P = 0.006 at 30-39 y and p = 0.037 at 40-50 y. Age (p = 0.001) and liver T2*(p = 0.003) had significant correlation with mean carotid IMT independently.</p> <p>At the age group of 10-19 years, there were not significant differences in mean carotid IMT based on the liver iron loading (p = 0.661).</p> <p>No significant differences also are seen in mean carotid IMT between male and female (p = 0.41).</p> <p>Conclusions</p> <p>This study identified a relationship between body iron status and carotid IMT. This relationship support to the hypothesis of a link between body iron load and atherosclerosis.</p

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

Plasma triglyceride and high density lipoprotein cholesterol are poor surrogate markers of pro-atherogenic chylomicron remnant homeostasis in subjects with the metabolic syndrome

Background: Subjects with metabolic syndrome (MetS) exhibit impaired lipoprotein metabolism and have an increased risk of cardiovascular disease. Although the risk is attributed primarily to the risk associated with individual components, it is also likely affected by other associated metabolic defects. Remnants of postprandial lipoproteins show potent atherogenicity in cell and animal models of insulin resistance and in pre-diabetic subjects with postprandial dyslipidemia. However, few studies have considered regulation of chylomicron remnant homeostasis in MetS per se. This study measured the plasma concentration in Caucasian men and women of small dense chylomicrons following fasting and explored associations with metabolic and anthropometric measures. Methods: A total of 215 Australian Caucasian participants (me dianage62years) were investigated. Of them, 40 participants were classified as having MetS. Apolipoprotein (apo) B-48, an exclusive marker of chylomicrons, metabolic markers and anthropometric measures were determined following an overnight fast.Results: The fasting apo B-48 concentration was 40 % higher in subjects with MetS than those without MetS. In all subjects, triglyceride ( r =0.445, P < 0.0005), non-HDL cholesterol ( r =0.28, P < 0.0005) and HDL cholesterol concentration ( r = − 0.272, P < 0.0005) were weakly associated with apo B-48 concentration. In subjects with MetS, the association of apo B-48 with triglyceride and non-HDL cholesterol was enhanced, but neither were robust markers of elevated apo B-48 in MetS (r = 0.618 and r = 0.595 respectively). There was no association between apo B-48 and HDL cholesterol in subjects with MetS. Conclusion: This study demonstrates a substantial accumulation of pro-atherogenic remnants in subjects with MetS. We have shown that in a Caucasian cohort, the fasting plasma concentration of triglyceride or HDL/non-HDL cholesterol serves as poor surrogate markers of atherogenic chylomicron remnants. These findings suggest that subjects with MetS exhibit a chronic defect in chylomicron metabolism that is likely to contribute to their increased CV risk