Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.publishedVersio

TiSA: TimeSeriesAnalysis - A pipeline for the analysis of longitudinal transcriptomics data

Improved transcriptomic sequencing technologies now make it possible to perform longitudinal experiments, thus generating a large amount of data. Currently, there are no dedicated or comprehensive methods for the analysis of these experiments. In this article, we describe our TimeSeries Analysis pipeline (TiSA) which combines differential gene expression, clustering based on recursive thresholding, and a functional enrichment analysis. Differential gene expression is performed for both the temporal and conditional axes. Clustering is performed on the identified differentially expressed genes, with each cluster being evaluated using a functional enrichment analysis. We show that TiSA can be used to analyse longitudinal transcriptomic data from both microarrays and RNA-seq, as well as small, large, and/or datasets with missing data points. The tested datasets ranged in complexity, some originating from cell lines while another was from a longitudinal experiment of severity in COVID-19 patients. We have also included custom figures to aid with the biological interpretation of the data, these plots include Principal Component Analyses, Multi Dimensional Scaling plots, functional enrichment dotplots, trajectory plots, and complex heatmaps showing the broad overview of results. To date, TiSA is the first pipeline to provide an easy solution to the analysis of longitudinal transcriptomics experiments.publishedVersio

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age

Correlates between CD4 reconstitution in HIV patients on suppressive HAART and soluble markers of inflammation and apoptosis

Highly active antiretroviral therapy successfully suppresses viral replication and increases CD4+ T cell counts in most patients with HIV infection. However, there is a group of patients which exhibits discordant treatment responses, with poor CD4 reconstitution despite successful viral suppression. The clinical consequences of such immunological failure are significant, including both AIDS-related and non-AIDS-related pathology, yet the group is poorly characterised. Little is known about why certain patients do not gain the full benefit of HAART, and there are consequently few therapeutic options currently available to improve their care. To investigate relevant aspects of the immunopathology of HIV infection in patients on HAART, we have 124 selected patients with persistent viral suppression after 3-9 months of HAART and degrees of CD4 reconstitution ranging from no gains at all to normal CD4 levels. A range of soluble markers of inflammation and apoptosis will be quantified by ELISA technique, in serum samples from each patient from before HAART initiation, and at 6, 12, 24 and 36 months of HAART. We will seek correlates between rates of CD4 gain and measured levels of cytokines and soluble membrane proteins, during the first 36 months of HAART. Hopefully, the discovery of such relationships may further elucidate the mechanisms underlying discordant treatment responses in HIV patients, and contribute to improved disease management

Vaginal vask før keisersnitt for å forebygge postoperativ endometritt

Keisersnitt er den viktigste risikofaktoren for å utvikle postpartum endometritt, en komplikasjon som forlenger den postoperative tilhelingen og kan forstyrre etableringen av mor-barn-relasjonen i nyfødtperioden, samt i noen tilfeller ha et alvorlig forløp. Cochrane-samarbeidet har publisert systematiske oversikter som anbefaler antibiotikaprofylakse og vaginal desinfeksjon som infeksjonsforebyggende tiltak ved keisersnitt. Mens profylaktisk bruk av antibiotika er i varierende grad av bruk i norsk klinisk praksis, er det liten oppmerksomhet rundt preoperativ vaginal desinfeksjon. Vi tok for oss innføring av sistnevnte som kvalitetsforbedring

Immune activation and regulation in chronic HIV infection: Implications for immune reconstitution and therapeutic strategies

Chronic HIV infection is characterised by a generalised hyperactivation of the immune system, which drives disease progression towards AIDS and increases the risk of non-AIDS morbidity such as cardiovascular disease. This immune hyperactivation persists to some degree despite antiretroviral therapy, and may contribute to impaired regeneration of the immune system in a subset of treated patients. The aim of this thesis was to further explore the implications of HIV-associated immune activation on immune function. To his end, three studies were performed. The first study analysed plasma markers of inflammation in 112 patients initiating antiretroviral therapy, and identified elevated plasma levels of the chemokine MIP-1β as a putative biomarker predictive of poor CD4 gain, or so-called immunological non-response. Elevated MIP-1β may represent a facet of HIV-associated immunopathology contributing to immunological non-response. The second study explored an in vitro assay to quantify the effect of inhibitory signalling molecules IL-10, TGF-β, PD-1 and CD160 on HIV peptide-induced CD8+ T cell proliferation. These signalling pathways attenuated HIV-specific T cell function with a high degree of inter-individual variability. An assay such as this may be of use in predicting response to immunotherapies targeting these pathways. The third and final study was an exploratory clinical trial to determine the immunomodulatory effects of cyclooxygenase 2 inhibitor etoricoxib in HIV-infected patients. Etoricoxib reduced immune activation and coagulation parameters in antiretroviral therapy-naïve HIV-infected patients, but this effect was modest and may not be sufficient to improve clinical endpoints. Etoricoxib had no appreciable effect in patients on stable antiretroviral therapy. These results indicate a limited role for cyclooxygenase inhibitors as immunotherapeutic adjuvant agents in HIV-infected patients

'Interaktivitet' og publikumsdeltakelse i NRK fjernsynet

Dette prosjektet er utført som en casestudie av prosjektfasen til debattprogrammet Standpunkt. Hensikten med prosjektet er å undersøke hvordan begrepet interaktivitet har fått en dominerende posisjon i programproduserende og programsettende miljøer i NRK. Jeg argumenterer for at interaktivitet har et sett av samlende og positive konnotasjoner og at disse kan bidra til å legitimere tjenester for publikumsdeltakelse. Jeg viser med støtte i relevant teori at interaktivitet er et begrep det er vanskelig å definere og argumenterer for at det er fruktbart å undersøke det som et emisk begrep i NRK. I analysen av programprosjekteringen undersøker jeg hvordan prosjektgruppen utformet de konkrete tjenestene for publikumsdeltakelse under merkelappen interaktivitet . Jeg fokuserer både på de konkrete tjenestene og de manifeste motivene prosjektgruppen jobbet etter

Regulation of Gag- and Env-specific CD+ T cell responses in ART-naïve HIV-infected patients: Potential implications for individualized immunotherapy

Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways. Peripheral blood mononuclear cells from 26 asymptomatic HIV-infected, antiretroviral therapy-naïve patients were stimulated with Gag and Env overlapping peptide panels for 5 days. Monoclonal antibodies (mAbs) blocking inhibitory mediators interleukin (IL) 10, transforming growth factor (TGF) β, programmed death ligand (PD–L) 1 and herpes virus entry mediator (HVEM) were added to parallel cultures. Functional T cell regulation (FTR) was defined as the difference in proliferation between stimulated cultures with and without blocking mAbs. FTR was detected in 54% of patients. Blockade of IL-10/PD-L1 and IL10/TGF-β detected all cases with Gag- and Env-associated FTR, respectively. In accordance with previous findings, isolated Env FTR was associated with higher plasma HIV RNA and lower CD4 counts, while patients with both Gag and Env FTR also had higher Gag- and Env-specific proliferative CD8+ T cell responses. There was no association between FTR and frequencies of activated regulatory T cells. In conclusion, we observed substantial heterogeneity in FTR between patients, inhibitory pathways and HIV antigens. FTR may help to individualize immunomodulation and warrants further assessment in clinical immunotherapy trials

Sars-cov-2 viremia is associated with inflammatory, but not cardiovascular biomarkers, in patients hospitalized for covid-19

Background COVID‐19 may present with a variety of cardiovascular manifestations, and elevations of biomarkers reflecting myocardial injury and stress are prevalent. SARS‐CoV‐2 has been found in cardiac tissue, and myocardial dysfunction post‐COVID‐19 may occur. However, the association between SARS‐CoV‐2 RNA in plasma and cardiovascular biomarkers remains unknown. Methods and Results COVID MECH (COVID‐19 Mechanisms) was a prospective, observational study enrolling consecutive, hospitalized patients with laboratory‐confirmed infection with SARS‐CoV‐2 and symptoms of COVID‐19. Biobank plasma samples used to measure SARS‐CoV‐2 RNA and cardiovascular and inflammatory biomarkers were collected in 123 patients at baseline, and in 96 patients (78%) at day 3. Patients were aged 60±15 (mean ± SD) years, 71 (58%) were men, 68 (55%) were White, and 31 (25%) received mechanical ventilation during hospitalization. SARS‐CoV‐2 RNA was detected in plasma from 48 (39%) patients at baseline. Patients with viremia were more frequently men, had more diabetes mellitus, and lower oxygen saturation. Patients with viremia had higher concentrations of interleukin‐6, C‐reactive protein, procalcitonin, and ferritin (all <0.001), but comparable levels of cTnT (cardiac troponin T; P=0.09), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; P=0.27) and D‐dimer (P=0.67) to patients without viremia. SARS‐CoV‐2 RNA was present in plasma at either baseline or day 3 in 50 (52%) patients, and these patients experienced increase from baseline to day 3 in NT‐proBNP and D‐dimer concentrations, while there was no change in cTnT. Conclusions SARS‐CoV‐2 viremia was associated with increased concentrations of inflammatory, but not cardiovascular biomarkers. NT‐proBNP and D‐dimer, but not cTnT, increased from baseline to day 3 in patients with viremia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232

SARS‐CoV‐2 Viremia is Associated With Inflammatory, But Not Cardiovascular Biomarkers, in Patients Hospitalized for COVID‐19

Background COVID‐19 may present with a variety of cardiovascular manifestations, and elevations of biomarkers reflecting myocardial injury and stress are prevalent. SARS‐CoV‐2 has been found in cardiac tissue, and myocardial dysfunction post‐COVID‐19 may occur. However, the association between SARS‐CoV‐2 RNA in plasma and cardiovascular biomarkers remains unknown. Methods and Results COVID MECH (COVID‐19 Mechanisms) was a prospective, observational study enrolling consecutive, hospitalized patients with laboratory‐confirmed infection with SARS‐CoV‐2 and symptoms of COVID‐19. Biobank plasma samples used to measure SARS‐CoV‐2 RNA and cardiovascular and inflammatory biomarkers were collected in 123 patients at baseline, and in 96 patients (78%) at day 3. Patients were aged 60±15 (mean ± SD) years, 71 (58%) were men, 68 (55%) were White, and 31 (25%) received mechanical ventilation during hospitalization. SARS‐CoV‐2 RNA was detected in plasma from 48 (39%) patients at baseline. Patients with viremia were more frequently men, had more diabetes mellitus, and lower oxygen saturation. Patients with viremia had higher concentrations of interleukin‐6, C‐reactive protein, procalcitonin, and ferritin (all &lt;0.001), but comparable levels of cTnT (cardiac troponin T; P =0.09), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; P =0.27) and D‐dimer ( P =0.67) to patients without viremia. SARS‐CoV‐2 RNA was present in plasma at either baseline or day 3 in 50 (52%) patients, and these patients experienced increase from baseline to day 3 in NT‐proBNP and D‐dimer concentrations, while there was no change in cTnT. Conclusions SARS‐CoV‐2 viremia was associated with increased concentrations of inflammatory, but not cardiovascular biomarkers. NT‐proBNP and D‐dimer, but not cTnT, increased from baseline to day 3 in patients with viremia. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04314232. </jats:sec