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Τετάρτη 5 Οκτωβρίου 2022

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

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

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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.
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Oral biofilm dysbiosis during experimental periodontitis

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Abstract

Objectives

We have previously characterized the main osteoimmunological events that occur during ligature periodontitis. This study aims to determine the polymicrobial community shifts that occur during disease development.

Methods

Periodontitis was induced in C57BL/6 mice using the ligature-induced periodontitis model. Healthy oral mucosa swabs and ligatures were collected every 3-days from 0 to 18 days post-ligature placement. Biofilm samples were evaluated by 16SrRNA gene sequencing (Illumina MiSeq) and QIIME. Timecourse changes were determined by relative abundance, diversity, and rank analyses (PERMANOVA, Bonferroni-adjusted).

Results

Microbial differences between health and periodontal inflammation were observed at all phylogenic levels. An evident microbial community shift occurred in 25 genera during the advancement of "gingivitis" (3-6d) to periodontitis (9-18d). From day 0–18, dramatic changes were identified Streptococcus levels, with an overall decrease (54.04-0.02%) as well an overall increase of Enterococcus and Lactobacillus (23.7-73.1% and 10.1%-70.2%, respectively). Alpha-diversity decreased to its lowest at 3d, followed by an increase in diversity as disease advancement. Beta-diversity increased after ligature placement, indicating that bone loss develops in response to a greater microbial variability (p = 0.001). Levels of facultative and strict anaerobic bacteria augmented over the course of disease progression, with a total of 8 species significantly different during the 18-day period.

Conclusion

The data supports that murine gingival inflammation and alveolar bone loss develop in response to microbiome shifts. Bacterial diversity increased during progression to bone loss. These findings further support the utilization of the periodontitis ligature model for microbial shift analysis under different experimental conditions.

This article is protected by copyright. All rights reserved
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Τρίτη 4 Οκτωβρίου 2022

Immunomodulatory effect of IL‐1RA in LPS activated macrophage/dental pulp stem cells co‐culture

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Abstract

Aims:

Lipopolysaccharides (LPS) activated human dental pulp stem cells (hDPSCs) and macrophage co-cultures showed downregulated TNF-α secretion that is modulated by hDPSCs through IDO axis, whereas the secretory levels of IL-1β remained unchanged. Therefore, sustained production of IL-1β could contribute to progressive dental pulp inflammation. However, the role of IL-1 receptor antagonists (IL-1RA) in downregulating the secretion of IL-1β and TNF-α in LPS activated M0/M1/M2 macrophage and hDPSCs co-culture has not been studied yet. Therefore, the aim of the present study is to determine the immunomodulatory role of blocking IL-1 receptors in DPSCs macrophage co-culture activated with LPS.

Methodology:

Human monocytic cell line THP-1 was polarised to M0, M1, and M2 macrophages and co-cultured with hDPSCs. The viability of the co-cultured cells was assessed by apoptosis assay. Co-cultures were activated with LPS followed by the assessment of gene expression and protein levels of IL-1β and TNF-α with and without IL-1RA blocking via qRT-PCR and cytokine flex assay by flow cytometry. Data from three separate experiments was analysed using One-way ANOVA followed by Tukey's Post-hoc test and a p value of <0.05 was considered statistically significant.

Results:

THP-1 derived M0, M1, and M2 macrophages co-cultured with hDPSCs showed spindle and round-shaped cells, with > 90% viability when assessed by apoptosis assay. Inflammatory TNF-α and IL-1β profile in stimulated co-cultures showed upregulated IL-1β whereas TNF-α was downregulated (p< 0.05). Anti-inflammatory gene expression levels of IL-10, TGF-β were downregulated (p< 0.05). Blocking with IL-1RA resulted in remarkable decrease of IL-1β at the gene expression and protein production levels while TNF-α levels remained low (p< 0.05). Levels of anti-inflammatory cytokine IL-10 showed no significant difference.

Conclusion:

Blocking the IL-1 receptor in hDPSCs and macrophage (M0, M1, M2) co-cultures activated with LPS resulted in down regulation of inflammatory cytokines IL-1β and TNF-α. These findings highlight the immunomodulatory effect of IL-1RA in inflammatory conditions of dental pulp infections.
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Magnetic Resonance Imaging Directed Surgical Decision Making for Lateral Pelvic Lymph Node Dissection in Rectal Cancer After Total Neoadjuvant Therapy (TNT)

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imageObjective: Lateral pelvic lymph node (LPLN) metastases are an important cause of preventable local failure in rectal cancer. The aim of this study was to evaluate clinical and oncological outcomes following magnetic resonance imaging (MRI)-directed surgical selection for lateral pelvic lymph node dissection (LPLND) after total neoadjuvant therapy (TNT). Methods: A retrospective consecutive cohort analysis was performed of rectal cancer patients with enlarged LPLN on pretreatment MRI. Patients were categorized as LPLND or non-LPLND. The main outcomes were lateral local recurrence rate, perioperative and oncological outcomes and factors associated with decision making for LPLND. Results: A total of 158 patients with enlarged pretreatment LPLN and treated with TNT were identified. Median follow-up was 20 months (interquartile range 10–32). After multidisciplinary review, 88 patients (56.0%) underwent LPLND. Mean age was 53 (SD±12) years, and 54 (34.2%) were female. Total operative time (509 vs 429 minutes; P=0.003) was greater in the LPLND group, but median blood loss (P=0.70) or rates of major morbidity (19.3% vs 17.0%) did not differ. LPLNs were pathologically positive in 34.1%. The 3-year lateral local recurrence rates (3.4% vs 4.6%; P=0.85) did not differ between groups. Patients with LPLNs demonstrating pretreatment heterogeneity and irregular margin (odds ratio, 3.82; 95% confidence interval: 1.65–8.82) or with short-axis ≥5 mm post-TNT (odds ratio 2.69; 95% confidence interval: 1.19–6.08) were more likely to undergo LPLND. Conclusions: For rectal cancer patients with evidence of LPLN metastasis, the appropriate selection of patients for LPLND can be facilitated by a multidisciplinary MRI-directed approach with no significant difference in perioperative or oncologic outcomes.
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Polyethylenglycol – Freund oder Feind?

alexandrossfakianakis shared this article with you from Inoreader

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Laryngorhinootologie 2022; 101: 784-786
DOI: 10.1055/a-1861-7047

Anaphylaktische Reaktionen nach Impfungen sind selten. Zwei Fälle von Reaktionen nach der Pfizer-BioNTech-Covid-19-Vakzine, BNT162b2, wurden aus dem UK berichtet, weitere 19 aus den USA. Als möglicher Auslöser wurde Polyethylenglycol (PEG) angeschuldigt. Pegylierung ist ein üblicher Vorgang in der Impfstoffherstellung, um die Substanzen vor schnellem immunologischem Abbau zu schützen. PEG ist ein Polyether (Synonyme z. B. Laureth-9, Polidocanol, Thesit, Macrogol) und findet sich in Kosmetika, Körperpflegeprodukten, Nahrungsmitteln, Liposomen und Nanopartikeln als Drug-Delivery-Systeme für Medikamente und als osmotisches Laxans vor Gastro-/Koloskopien. IgM-Antikörper auf PEG werden bei 70% der Bevölkerung nachgewiesen. Bei 2 Fällen von Soforttyp-Reaktionen auf PEG fanden sich IgE-Antiköper, bei anderen Medikamentengaben mit PEG geht man von pseudoallergischen Reaktionen über die Komplement-Aktivierungs-related Pseudoallergie (CARPA) aus. In Relation zum weit verbreiteten Einsatz von PEG sind die Impfreaktionen sehr selten und aktuell kein Grund, Allergiker oder Menschen mit Anaphylaxien bei entsprechenden Vorsichtsmaßnahmen auf bekannte Auslöser auszuschließen. Aufgrund der Meldepflicht (Gesundheitsamt und Arzneimittelkommission der deutschen Ärzteschaft) ist bald mit weiteren Erkenntnissen zu rechnen.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text
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Δευτέρα 3 Οκτωβρίου 2022

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

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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.
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Κυριακή 2 Οκτωβρίου 2022

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

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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.
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Stereotactic Radiosurgery for Brainstem Metastases

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Abstract
AIMS
Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes.
METHOD
Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist.
RESULTS
41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had p revious WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06).
CONCLUSION
Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.
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Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes

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Abstract

The first aim was to define the oncologic outcomes of open partial laryngectomy (OPL) in naïve pT3 laryngeal cancer. The second aim was to analyze the outcomes after OPL versus total laryngectomy (TL). A literature search was conducted in three databases (MEDLINE, EMBASE, and Cochrane Library) until January 2022. In 805 patients treated with OPL, 5-year OS, DSS, DFS and LFS were 80.5% (95% CI 70.6–87.6), 83.4% (95% CI 75.7–89), 77.4% (95% CI 66.3–85.7) and 77.9% (95% CI 68.7–85), respectively. Three articles compared TL versus OLP: 5-year OS, DSS and DFS risk difference were 0.100 (95% CI −0.092 to 0.291), 0.067 (95% CI −0.085 to 0.220) and 0.018 (95% CI −0.164 to 0.201) respectively. OPL for selected pT3 laryngeal cancer is able to guarantee a high percentage of oncological success. Accurate patient selection is of utmost importance to differentiate advanced disease amenable to conservative surgery.
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