Viral load decrease in SARS‐CoV‐2 BA.1 and BA.2 Omicron sublineages infection after treatment with monoclonal antibodies and direct antiviral agents

alexandrossfakianakis shared this article with you from Inoreader Viral load decrease in SARS‐CoV‐2 BA.1 and BA.2 Omicron sublineages infection after treatment with monoclonal antibodies and direct antiviral agents via Journal of Medical Virology ABSTRACT Background The efficacy on the Omicron variant of the approved early- coronavirus disease 2019 (COVID-19) therapies, especially monoclonal antibodies, has been challenged by in vitro neutralization data, while data on in vivo antiviral activity are lacking. Materials and methods We assessed potential decrease from day1 to day7 viral load (VL) in nasopharyngeal swabs of outpatients receiving Sotrovimab, Molnupiravir, Remdesivir, or Nirmatrelvir/ritonavir for mild-to-moderate COVID-19 due to sublineages BA.1 or BA.2, and average treatment effect (ATE) by weighted marginal linear regression models. Results A total of 521 patients [378 BA.1 (73%),143 (27%) BA.2] received treatments (Sotrovimab 202, Molnupiravir 117, Nirmatrelvir/ritonavir 84, and Remdesivir 118): median age 66 years, 90% vaccinated, median time from symptoms onset 3 days. Day1 mean viral load was 4.12 log2 (4.16 for BA.1 and 4.01 for BA.2). The adjusted analysis showed that Nirmatrelvir/ritonavir significantly reduced VL compared to all the other drugs, except vs. Molnupiravir in BA.2. Molnupiravir was superior to Remdesivir in both BA.1 and BA.2, and to Sotrovimab in BA.2. Sotrovimab had better activity than Remdesivir only against BA.1. Conclusions Nirmatrelvir/ritonavir showed the greatest antiviral activity against Omicron variant, comparable to Molnupiravir only in the BA.2 subgroup. VL decrease could be a valuable surrogate of drug activity in the context of the high prevalence of vaccinated people and low probability of hospital admission. This article is protected by copyright. All rights reserved. View on Web

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Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study

alexandrossfakianakis shared this article with you from Inoreader Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study via International Journal of Epidemiology - Advance Access Abstract Background Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. Methods We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768). Results Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6); P = 0.13] and UKB [–28 g (95% CI: –31, –25); P = 1.8 × 10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10–22], consistent with that previously published in women and men. Conclusion The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweigh t. Maternal urate levels are unlikely to be an important contributor to offspring birthweight. View on Web

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CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers

alexandrossfakianakis shared this article with you from Inoreader CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers via # Neuro-Oncology Current Issue Abstract AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Ro le Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers' daily lives. View on Web

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Hull’s Magic Box: Keeping Brain Tumour Biopsies “Alive” in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour

alexandrossfakianakis shared this article with you from Inoreader Hull's Magic Box: Keeping Brain Tumour Biopsies "Alive" in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour via # Neuro-Oncology Current Issue Abstract AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecular level, including RNA and protein modifications. METHOD GBM biopsies are received from Hull Royal Infirmary and maintained on-chip for 8-days. They are perfused with media, at a rate of 3 μl/min, mimicking the in vivo environment and allowing real-time analysis of tumour behaviour. PRMT inhibitors, such as GSK3368715, are added to the media, in conjunction with TMZ, to determine their efficacy ex vivo using a range of techniques, such as: immunohistochemistry, cell viability assays, protein analysis and RNA-sequencing. RESULTS We show that PRMT inhibition increases apoptos is five-fold above the control, untreated GBM-on-chip samples. This is compounded by cell viability assays, which have indicated that cell viability in these post-chip tissues is reduced by 30% upon treatment with 1μM GSK3368715. Additionally, western blot analysis has indicated that PRMT inhibition with GSK3368715 appears to switch the methylation status of fused-in-sarcoma (FUS) protein in GBM biopsies. CONCLUSION These results indicate that PRMT inhibition may not only be a viable target for GBM therapy, but could also highlight a mechanism for re-sensitising MGMT-negative GBM to TMZ. This data produces an exciting argument for further research into the use of this novel inhibitor for improving prognosis for patients diagnosed with this devastating disease. View on Web

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Multifocal and Multicentric Glioblastomas: A 10 Year Single Centre Experience

alexandrossfakianakis shared this article with you from Inoreader Multifocal and Multicentric Glioblastomas: A 10 Year Single Centre Experience via # Neuro-Oncology Current Issue Abstract AIMS The aims of this study are to share our experience of a large series of multifocal/multicentric glioblastomas (mGBM) and analyse the clinical, histological/molecular and neuroimaging characteristics as well as the outcomes of the patients in order to inform and contribute to future patient care. METHOD We conducted a retrospective single centre study of all multifocal/multicentric glioblastomas treated at our institution over a 10 year period. Data was collected from electronic patient records including patient demographics, clinical presentation, diagnostic imaging, treatment plans and histopathology/molecular findings. Time to recurrence/progression and overall survival was assessed. RESULTS 1158 glioblastomas were treated surgically over this time period of which 121 multifocal/multicentric tumours were identified (10.4%). The median age at diagnosis was 63 years with a slight male predominance (54.5%). Half of all patients (61/121) presented with focal neurological deficits. 69% of patients underwent a craniotomy for diagnosis/debulking of the larger enhancing component of the tumour whilst 31% underwent only a biopsy. The median time to recurrence/progression was 154 days. Median length of survival was 269 days. Those who underwent craniotomy had significantly prolonged survival compared to biopsy alone 301 vs 198 days (p= 0.027) as did those who had a near total resection 401 vs 269 for subtotal resection (P=0.006) and those < 60 years (p=< 0.001). 88% of patients were IDH1 wildtype. Radiotherapy and chemotherapy confer a significant survival advantage when compared with no further treatment (p<0.001). CONCLUSION Near total resection of the larger enhancing component and post-operative chemo/radiotherapy can offer prolonged survival in patients with mGBM. View on Web

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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

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First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project

alexandrossfakianakis shared this article with you from Inoreader First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project via # Neuro-Oncology Current Issue Abstract AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present detailed analysis of first-line treatments of adult glioblastoma (GBM) patients. METHOD We identified all adults patients diagnosed with a GBM. We focused on the first line of treatment and we defined 'maximal' first-line treatment as surgical resection followed by chemo-radiotherapy with 59-60 Gy and with at least one cycle of adjuvant chemotherapy Temozolomide. RESULTS 15,294 patients were diagnosed with a glioblastoma (60% male) with a median age of 66. 79% of patients received some treatment, with younger patients more likely to be treated (>90%, 18 - 59; < 30%, > 80). 54% underwent debulking surgery; 23%, biopsy. 14% received 'maximal' treatment and 21%, none. Patients who had no treatment had a median survival of 2 months whereas patient s who received 'maximal' treatment had a median survival of 16 months. CONCLUSION Most adult patients with a GBM in England have a histological diagnosis, and some oncological treatment. However, only 14% receive 'maximal' treatment. Of the 3222 patients who received none, some of these may have had purely private treatment; however, our dataset includes any private sector work undertaken in NHS hospitals. Survival remains poor, but outcomes in those receiving maximal treatment match those from clinical trials. However, most patients do not receive maximal treatment, and so the easiest route to improving outcomes may be optimise delivery of treatment in the 65% of patients who receive sub-maximal treatment. More information on https://blogs.imperial.ac.uk/gliocova View on Web

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