Rapid selection of sotrovimab escape variants in SARS-CoV-2 Omicron infected immunocompromised patients

alexandrossfakianakis shared this article with you from Inoreader Rapid selection of sotrovimab escape variants in SARS-CoV-2 Omicron infected immunocompromised patients via Clinical Infectious Diseases Advance Access Abstract Background Monoclonal antibodies (mAb) targeting SARS-CoV-2 are predominantly less effective against Omicron variants. Immunocompromised patients often experience prolonged viral shedding and are therefore at increased risk for viral escape mutations, when mAbs are used as monotherapy. Methods In an observational, prospective cohort, 57 patients infected with Omicron variants receiving sotrovimab alone or in combination with remdesivir were followed. The study endpoints were a decrease in SARS-CoV-2-RNA <106 copies/ml in nasopharyngeal swabs at day 21 and the emergence of resistance mutations at days 7, 14, and 21 after sotrovimab administration. All SARS-CoV-2 samples were analyzed by whole-genome sequencing, individual variants within the quasispecies were subsequently quantified and further characterized by a pseudovirus neutralization assay. Results 47/57 patients (82.5%) were infected with Omicron/BA .1 and 10/57 (17.5%) with Omicron/BA.2. The vast majority of patients (43/57, 75.4%) were immunodeficient, predominantly due to immunosuppression after organ transplantation or hematologic malignancies. 21 days after sotrovimab administration, 12/43 (27.9%) of immunodeficient patients had prolonged viral shedding compared to 1/14 (7.1%) immunocompetent patients (p = 0.011). Longitudinal sequencing revealed that 14/43 (32.6%) immunodeficient patients had in part Omicron-specific viral spike protein mutations (e.g., P337S and/or E340D/V) that substantially reduced susceptibility to sotrovimab in a pseudovirus neutralization assay. Combination therapy with remdesivir significantly reduced the selection of escape variants. Conclusions Immunocompromised patients face a considerable risk of prolonged viral shedding and emergence of escape mutations after early therapy with sotrovimab. These findings underscore the importance of careful monitoring and the need to conduct dedic ated clinical trials for this patient population. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Imaging of pediatric testicular tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

alexandrossfakianakis shared this article with you from Inoreader Imaging of pediatric testicular tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper via Pediatric Blood & Cancer Abstract Primary intratesticular tumors are uncommon in children, but incidence and risk of malignancy both sharply increase during adolescence. Ultrasound is the mainstay for imaging the primary lesion, and cross-sectional modalities are often required for evaluation of regional or distant disease. However, variations to this approach are dictated by additional clinical and imaging nuances. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary testicular malignancy at diagnosis and during follow-up. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods

alexandrossfakianakis shared this article with you from Inoreader Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods via Neuro-Oncology Advance Access Abstract Genomic and transcriptional heterogeneity is prevalent among the most common and aggressive primary brain tumors in children and adults. Over the past 20 years, advances in bioengineering, biochemistry and bioinformatics have enabled the development of an array of techniques to study tumor biology at single-cell resolution. The application of these techniques to study primary brain tumors has helped advance our understanding of their intra-tumoral heterogeneity and uncover new insights regarding their co-option of developmental programs and signaling from their microenvironment to promote tumor proliferation and invasion. These insights are currently being harnessed to develop new therapeutic approaches. Here we provide an overview of current single-cell techniques and discuss relevant biology and therapeutic insights uncovered by their application to primary brain tumors in children and adults. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Estimation of the time-varying incremental effect of low dose aspirin on incidence of pregnancy

alexandrossfakianakis shared this article with you from Inoreader Estimation of the time-varying incremental effect of low dose aspirin on incidence of pregnancy via Epidemiology - Published Ahead-of-Print Background. In many research settings, the intervention implied by the average causal effect of a time-varying exposure is impractical or unrealistic, and we might instead prefer a more realistic target estimand. Instead of requiring all individuals to be always exposed vs. unexposed, incremental effects quantify the impact of merely shifting each individual's probability of being exposed. Methods. We demonstrate estimation of incremental effects in the time-varying setting, using data from the Effects of Aspirin in Gestation and Reproduction trial, which assessed the effect of preconception low-dose aspirin on pregnancy outcomes. Compliance to aspirin or placebo was summarized weekly and was affected by time-varying confounders such as bleeding or nausea. We sought to estimate what the incidence of pregnancy by 26 weeks post-randomization would have been if we shifted each participant's probability of taking aspirin or placebo in each week by odds ratios (OR) between 0.30 and 3.00. Results. Under no intervention (OR=1), the incidence of pregnancy was 77% (95% CI: 74%, 80%). Decreasing women's probability of complying with aspirin had little estimated effect on pregnancy incidence. When we increased women's probability of taking aspirin, estimated incidence of pregnancy increased, from 83% (95% CI: 79%, 87%) for OR=2 to 89% (95% CI: 84%, 93%) for OR=3. We observed similar results when we shifted women's probability of complying with placebo. Conclusions. These results estimated that realistic interventions to increase women's probability of taking aspirin would have yielded little to no impact on the incidence of pregnancy, relative to similar interventions on placebo. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery

alexandrossfakianakis shared this article with you from Inoreader Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery via # Neuro-Oncology Current Issue Abstract AIMS To present and review our experience in the management of low-grade gliomas. METHOD Retrospective case note review of all patients with WHO grade 2 glioma from 2011 to 2018 (based on WHO criteria at time of diagnosis). Data collected on demographics, presentation, location, initial management, histology, treatment, progression free (PFS) and overall survival (OS). RESULTS 130 eligible patients. Median follow 4.6 years (up to 10.5). Median age 40 years (range: 18-83). There were 70 (53.8%) astrocytomas, 44 (33.8%) oligodenrogliomas, 16 (12.3%) oligoastrocytomas. 66%(n=86) presented with seizures, 10.7%(n=14) with sensory symptoms, 8.5%(n=11) with speech disturbance, 5.3%(n=4) with motor symptoms and 12.3%(n=16) were identified incidentally. 50.1%(n=65) were frontal, 27.7%(n=36) temporal and 9.2%(n=12) parietal. 1st line treatment was resection in 70.7%(n=92), biopsy in 23.8%(n=31) and observation in 4.6%(n=6). 15.4 %(n=20) received adjuvant radiotherapy alone and 6.1%(n=8) received adjuvant radiotherapy followed by chemotherapy . At first recurrence, 31.6%(n=12) received further surgery and 95%(n=38) received radiotherapy and/or chemotherapy . Median PFS from 1st line treatment 66, 44 and 33 months for gross total resection (GRT), subtotal resection (STR), and biopsy respectively. Overall survival was 95.1%, 79.3% and 69.% for GTR, STR and biopsy respectively. CONCLUSION Management of low-grade gliomas remains challenging. Extent of resection impacts prognosis but not all patients have gliomas amenable to surgery. The effects of chemoradiotherapy will be presented in future meetings as this is an ongoing project. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

alexandrossfakianakis shared this article with you from Inoreader Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome via Brain Pathology The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled). Abstract Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians

alexandrossfakianakis shared this article with you from Inoreader Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians via International Endodontic Journal Abstract Aim To investigate if there was an association between genetic polymorphisms in TNF-⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in Brazilian subjects. Methodology Patients who had pulpal necrosis and apical periodontitis installed at the time of treatment, with at least one-year of follow-up after non-surgical root canal treatment were recalled. 378 subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal–treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF-⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real-time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratio were implemented (𝛂= 5%). Results The genetic polymorphism in TNF-α (rs1800629) was associated as a protective factor for the development of PAP (p<0.05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p<0.05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B respectively) were not associated with the development of PAP (p>0.05). Conclusions The observed results demonstrate that polymorphism in TNF-α but not in its receptors is associated with PAP. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.