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Κυριακή 20 Νοεμβρίου 2022

Inverted repeats in the monkeypox virus genome are hot spots for mutation

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Abstract

The current monkeypox virus (MPXV) strain differs from the strain arising in 2018 by 50+ single nucleotide polymorphisms (SNPs) and is mutating much faster than expected. The cytidine deaminase apolipoprotein B mRNA editing enzyme, catalytic subunit B (APOBEC3) was hypothesised to be driving this increased mutation. APOBEC has recently been identified to preferentially mutate cruciform DNA secondary structures formed by inverted repeats (IRs). IRs were recently identified as hot spots for mutation in SARS-CoV-2, and we aimed to identify whether IRs were also hot spots for mutation within MPXV genomes. We found that MPXV genomes were replete with IR sequences. Of the 50+ SNPs identified in the 2022 outbreak strain, 63.9% of these were found to have arisen within IR regions in the 2018 reference strain (MT903344.1). Notably, IR sequences found in the 2018 reference strain were significantly lost over time, with an average of 32.5% of these sequences being cons erved in the 2022 MPXV genomes. This evidence was highly indicative that mutations were arising within IRs. This data provides further support to the hypothesis that APOBEC may be driving MPXV mutation and highlights the necessity for greater surveillance of IRs of MPXV genomes to detect new mutations.

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STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA

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Abstract
Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the 'invading edge'. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival.
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18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment

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Abstract

Background

Tumor-specific molecular imaging in head and neck squamous cell carcinoma (HNSCC) is not well established. Somatostatin receptors (SSTRs) are found in solid tumors, including HNSCC. 68Ga-DOTATATE, a commercially available radionuclide that binds SSTRs, may have utility in imaging HNSCC.

Methods

Patients with HNSCC received pretreatment imaging with 18F-FDG-PET/CT and 68Ga-DOTATATE. Imaging was compared for concordance. When available, surgical resection specimens were compared to pretreatment imaging findings. Historic HNSCC tumor specimens were assessed for both SSTR and p16/human papilloma virus (HPV) expression.

Results

Twenty patients were imaged. Fifteen had oropharyngeal cancer. Primary tumor site was concordant between imaging modalities for all patients. One of 45 lymph nodes was discordant. Retrospective specimen review showed a significant correlation with SSTR expression and HPV/p16 expression. No adverse events occurred.

Conclusions

68Ga-DOTATATE imaging is safe and effective in HNSCC. SSTR expression may be increased in HPV-mediated tumors. Targeted therapies to SSTR should be explored.

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Παρασκευή 18 Νοεμβρίου 2022

Emergence of recombinant norovirus GII.12[P16] and predominance of GII.3[P12] strains in pediatric patients with acute gastroenteritis in Thailand, 2019‐2020

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ABSTRACT

Norovirus (NoV) and sapovirus (SaV) are important pathogens that cause acute gastroenteritis (AGE) in all age groups, commonly in children worldwide. Recently, a number of studies have reported a wide variety of NoV recombinant strains. This study aimed to investigate the distribution of NoV and SaV recombinant strains circulating in Chiang Mai, Thailand during 2019-2020. One hundred and twenty-four NoV and seven SaV strains detected in children admitted to the hospital with AGE were included in this study. The partial RdRp/VP1 regions of these NoV and SaV strains were analyzed by phylogenetic analysis, Simplot and RDP softwares. Overall, eight recombination patterns of NoV were detected. NoV GII.4[P16] was the most common strain detected (39.1%), followed by GII.3[P12] (25.0%), GII.4[P31] (17.2%), and other recombinant strains were detected at lower rate. NoV GII.12[P16] strains were detected for the first time in Thailand. For SaV, none of the recombinant strains was detected. All SaV strains, GI.1/GI.1, GI.2/GI.2, and GII.5/GII.5, exhibited VP1 genotype corresponded to RdRp genotype. In conclusion, this study demonstrates the distribution and diversity of NoV and SaV recombinant strains circulating in pediatric patients with AGE in Chiang Mai, Thailand during 2019-2020 with the emergence of NoV GII.3[P12] and GII.12[P16].

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Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration

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Abstract

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

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Dental implant failure rates with low insertion torque with a nonsubmerged surgical approach: A retrospective clinical study

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Abstract

Background

It is currently unclear if a low insertion torque (IT) should prompt a clinician to submerge the dental implant at time of placement.

Purpose

This study aimed to analyze implant failure rates and marginal bone loss (MBL) as a function of IT and surgical approach.

Materials and Methods

A total of 197 patients who had received 295 Mozo Grau (MG) implants were included in this study. The healing of submerged or nonsubmerged implants was evaluated in regular IT (≥20–25 Ncm) or low IT (<20–25 Ncm) cases. Implant failure and MBL were evaluated before prosthesis placement and at 6 and 12 months after functional loading with generalized estimating equations.

Results

The overall 12-month implant failure rate was 4.8% (95% confidence interval [CI]: 2.7%–8.2%). When successful at 12 months, dental implants placed with low IT and nonsubmerging had the same MBL as implants dental implants placed with other approaches (mean difference = −0.02 mm; 95% CI −0.05 to 0.02). Low IT combined with nonsubmerging of the dental implant was associated with a 30-fold increased odds for dental implant failure (95% CI: 3.8–236.6).

Conclusion

low IT and nonsubmerged healing was associated with a high failure rate.

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The Effect of Hyperosmolar Water-Soluble Contrast for the Management of Adhesive Small Bowel Obstruction: A Systematic Review and Meta-Analysis

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imageObjective: To better understand the efficacy of water-soluble contrast (WSC) in the treatment of adhesive small bowel obstruction (SBO). Background: Guidelines recommend using WSC to treat adhesive SBO nonoperatively by acting as a cathartic agent. The evidence supporting this practice is mixed. Methods: A systematic review and meta-analysis of published articles describing the effect of WSC compared with control treatments was performed for the period of January 1, 1990 to November 1, 2021. Study quality was assessed using the Cochrane risk-of-bias and the Newcastle-Ottawa tools. The therapeutic effect of WSC was assessed by operative rates and hospital length of stay (HLOS) in nonsurgical patients. Results: The initial search yielded 4879 articles, of which, 28 were selected for full text review. We identified 11 eligible randomized controlled trials (RCTs) which included 817 patients and 9 observational studies of 3944 patients. HLOS in nonsurgical patients decreased by 1.95 days (95% confidence interval: 0.56–3.3) in the RCTs and could not be assessed in the observational studies. WSC did not significantly affect operative rates in the RCTs (19.8% vs. 21.4%) but did reduce rates in the observational studies (11% vs. 16%, risk ratio: 0.56, 95% confidence interval: 0.39–0.82). Conclusion: WSC studies may reduce HLOS for patients who have SBO and do not require surgery. However, the current literature is heterogenous with considerable design limitations. High-quality RCTs are needed using standardized protocols to determine the full benefit of WSC for the management of SBO.
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Πέμπτη 17 Νοεμβρίου 2022

Τετάρτη 16 Νοεμβρίου 2022

Cardiovascular outcomes after tixagevimab and cilgavimab use for pre-exposure prophylaxis against COVID-19: a population-based propensity-matched cohort study

alexandrossfakianakis shared this article with you from Inoreader

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Abstract
Tixagevimab and cilgavimab treatment was associated with higher rates of cardiovascular events in a post-hoc analysis of a phase 3 trial. In this large population-based propensity-matched study, we found no increased risk of cardiovascular events up to 90 days after tixagevimab and cilgavimab administration, including in patients with pre-existing cardiovascular disease.
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Chickenpox and multiple sclerosis: A Mendelian randomization study

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

Observational studies have suggested a suspected association between varicella-zoster virus (VZV) infection and multiple sclerosis (MS), but the connection has remained unclear. The aim of the present study is to evaluate the causal relationship between chickenpox which is caused by VZV infection and MS.

Methods

We performed a two‑sample Mendelian randomization analysis to investigate the association of chickenpox with MS using summary statistics from genome‑wide association studies (GWAS). The GWAS summary statistics data for chickenpox was from the 23andMe cohort including 107,769 cases and 15,982 controls. A large summary of statistical data from the International Multiple Sclerosis Genetics Consortium (IMSGC) was used as the outcome GWAS data set, including 14,802 MS cases and 26,703 controls.

Results

We found evidence of a significant association between genetically predicted chickenpox and risk of MS (odds ratio [OR] = 35.27 , 95% confidence interval [CI] = 22.97–54.17, P = 1.46E-59).

Conclusions

Our findings provided evidence indicating a causal effect of chickenpox on MS. Further elucidations of this association and underlying mechanisms are needed for identifying feasible interventions to promote MS prevention.

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Τρίτη 15 Νοεμβρίου 2022

High cytomegalovirus viral load is associated with 182-day all-cause mortality in hospitalized people with human immunodeficiency virus (PWH)

alexandrossfakianakis shared this article with you from Inoreader

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Abstract
Background
Cytomegalovirus (CMV) infection is associated with increased mortality in PWH. It is less clear whether CMV infection is still associated with mortality when routinely screened and adequately treated.
Methods
This retrospective cohort study recruited 1003 hospitalized HIV-infected adults with CD4 cell counts of less than 200 cells/μL from 2017-2021. Blood CMV DNA was routinely measured and CMV DNAemia was treated if end-organ disease occurre d. CMV viral load was categorized into below the limit of quantification (BLQ;  < 500 IU/mL), low viral load (LVL; 500-10000 IU/mL), and high viral load (HVL;  ≥ 10000 IU/mL) groups. We compared the 182-day all-cause mortalities among different groups.
Results
The median CD4 cell count of the patients was 33 cells/μL (IQR, 13-84). The prevalence of CMV DNAemia was 39.8% (95%CI, 36.7%-42.9%) and was significantly associated with CD4 cell count. The 182-day all-cause mortality was 9.9% (95%CI, 8.0%-11.7%). Univariable analysis showed that, compared to BLQ, LVL and HVL were associated with 1.73-fold and 3.81-fold increased risks of mortality, respectively (P = 0.032 and P < 0.001). After adjustment for pre-defined confounding factors, HVL but not LVL was still associated increased risk of mortality (adjusted hazard ratio 2.63; 95%CI, 1.61-4.29; P < 0.001). However, for patients on effective anti-retroviral therapy, the impact of HVL on 182-day mortality was not statistically significant (P = 0.713).
Conclusions
High CMV viral load in hospitalized PWH was associated with higher mortality, even when early identified by screening. Optimalization of the management for those patients needs to be explored in future studies.
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