Κυριακή 8 Ιανουαρίου 2023

Temporal trends in the incidence of malignant and non-malignant primary brain and central nervous system tumors by method of diagnosis in England, 1993-2017

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Abstract
Background
Several studies report increasing incidence of primary CNS tumors. The reasons for this are unclear.
Methods
Data on all 188,340 individuals diagnosed with a primary CNS tumor in England (1993-2017) were obtained from the National Cancer Registry. Data on all CT head and MRI brain scans in England (2013-2017) were obtained from NHS Digital. Age-sex-standardized annual incidence rates per 100,000 population (ASR) were calculated by calendar year, tumor behavior, tumor location and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC).
Results
The ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: 1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: -0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically c onfirmed, the ASR increased modestly (AAPC: 1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those aged 65+. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013-2017, with especially large increases in 65-84 and 85+ year olds (AAPCs: 18.4% and 22.5%).
Conclusion
Increases in CNS tumor incidence in England are largely attributable to greater detection of benign tumors. This could be the result of increasing use of neuroimaging, particularly CT head scans in A&E in people aged 65+.
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Upregulation of PD‐L1 by SARS‐CoV‐2 promotes immune evasion

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Abstract

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T cell sequestration, cytokine storm and mortality. However, it remains largely unknown how SARS-CoV-2 induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network (TO-GCN) approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated NF-κB and IRF1 pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 ChIP-sequencing. Cross-referencing our transcriptomic and epigenomic datasets revealed that coupling NF-κB and IRF1 pathways mediate PD-L1 immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an earl y stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

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The third vaccine dose significantly reduces susceptibility to the B.1.1.529 (Ômicron) SARS‐CoV‐2 variant

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Abstract

The main COVID-19 vaccine formulations used today are mainly based on the wild-type SARS-CoV-2 spike glycoprotein as an antigen. However, new virus variants capable of escaping neutralization activity of serum antibodies elicited in vaccinated individuals have emerged. The Omicron (B.1.1.529) variant caused epidemics in regions of the world in which most of the population has been vaccinated. In this study, we aimed to understand what determines individual's susceptibility to Omicron in a scenario of extensive vaccination. For that purpose, we collected nasopharynx swab (n = 286) and blood samples (n = 239) from flu-like symptomatic patients, as well as their vaccination history against COVID-19. We computed the data regarding vaccine history, COVID-19 diagnosis, COVID-19 serology and viral genome sequencing to evaluate their impact on the number of infections. As main results, we showed that vaccination in general did not reduce the number of individuals infected by Omicron, even with an increased immune response found among vaccinated non-infected individuals. Nonetheless, we found that individuals who received the third vaccine dose showed significantly reduced susceptibility to Omicron infections. A relevant evidence that support this finding was the higher virus neutralization capacity of serum samples of most patients who received the third vaccine dose. In summary, this study shows that boosting immune responses after a third vaccine dose reduces susceptibility to COVID-19 caused by the Omicron variant. Results presented in this study are useful for future formulations of COVID-19 vaccination policies.

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Rapid Detection of Monkeypox Virus by Multiple Cross Displacement Amplification Combined with Nanoparticle‐based Biosensor platform

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Abstract

The current outbreak of monkeypox virus (MPXV) has become a public health emergency of international concern that highlights the need for rapid, sensitive MPXV diagnostic assays. Here, we combined isothermal multiple cross displacement amplification (MCDA) with nanoparticle-based lateral flow biosensor (LFB) to devise a diagnostic test for the diagnosis of MPXV infection (called MPXV-MCDA-LFB) and differentiation of West and Central African MPXV isolates. The MPXV-MCDA-LFB protocol conducts isothermal MCDA reaction for DNA templates followed by LFB detection of preamplification target sequences. Two MCDA primer sets were designed targeting the D41L and ATI genes of Central and West African MPXV isolates, respectively, and the optimal condition of two MCDA reactions was 64 ºC for 30 min. The two MCDA reactions were decoded by LFB, which was devised for detecting three targets, including two amplicons yielded from two MCDA reactions and a chromatography contr ol. Thus, the MPXV-MCDA-LFB assay could be completed within 50 min including rapid template preparation (15 min), MCDA reaction (30 min) and reporting of result (< 5 min). The MPXV-MCDA-LFB method is very sensitive and can detect the target genes (D14L and ATI) with as low as five copies of plasmid template per reaction and 12.5 copies of pseudovirus in human blood samples. MPXV-MCDA-LFB assay does not cross-react with non-MPXV templates, validating its specificity. Therefore, the MPXV-MCDA-LFB assay developed here is a useful tool for rapid and reliable diagnosis of MPXV infection.

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Single‐cell transcriptomics dissects epithelial heterogeneity in HPV+ cervical adenocarcinoma

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Abstract

The intra- and inter-tumoral heterogeneity of epithelial cells in human papillomavirus (HPV)+ cervical adenocarcinoma (CEAD) remains largely unknown. To investigate this issue, we performed single-cell RNA sequencing on 19,229 epithelial cells sorted from three tumor samples of three patients with HPV+ CEAD. Six epithelial subclusters (Epi1 to Epi6) were identified that showed distinct gene expression. Among these, Epi1 and Epi4 had apparent tumor hallmarks and metabolic activities. Epi1 was highly enriched in hallmarks of hypoxia, IL2/STAT5 signaling, retinol metabolism, glycolysis, and arachidonic acid metabolism, while Epi4 was highly enriched in hallmarks of G2M checkpoint, E2F targets, DNA repair, PI3K/AKT/MTOR signaling, glycolysis, fatty acid degradation, TCA cycle, and glutathione metabolism. We also investigated inter-tumoral epithelial heterogeneity and found that Patient 1 was highly enriched for KRAS signaling and angiogenesis, while Patient 2 was highly enriched for epithelial-mesenchymal transition and TGF-β signaling, and Patient 3 was highly enriched for hypoxia, DNA repair, G2M checkpoint, and E2F targets. Using single-cell RNA sequencing, we revealed the intra- and inter-tumoral heterogeneity of epithelial cells in HPV+ CEAD, providing insights into the importance of personalized treatment for patients with HPV+ CEAD.

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Τετάρτη 4 Ιανουαρίου 2023

Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: a systematic review and meta-analysis

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Abstract
Background
Optimal doses of first line drugs for drug-susceptible tuberculosis (DS-TB) treatment in children and young adolescents remain uncertain. We aimed to determine if children treated using WHO-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic exposures.
Methods
Titles, abstracts, and full-text articles were screened. We searched Pubmed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children <18 years, being treated for DS-TB with rifampicin, pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO, CRD42021274222.
Results
Of 304 studies identified, 46 studies were eligible for full-text review and 12 and 18 articles were included for the efficacy and pharmacokinetic analysis, respectively. Of 1,830 children in cluded in the efficacy analysis, 82% had favourable outcomes (range 25%-95%). At WHO-recommended doses, exposures to rifampicin, pyrazinamide, and ethambutol were lower in children as compared to adults. Children ≤6 years have 35% lower AUC than older children (14.4 (9.9-18.8) vs 22.0 (13.8-30.1) μg.h/mL) and children with HIV (CWHIV) had 35% lower rifampicin AUC than HIV negative children (17.3 (11.4-23.2) vs 26.5 (21.3-31.7) μg.h/mL). Heterogeneity and small sample sizes were major limitations.
Conclusion
There is large variability in outcomes with an average 82% favourable outcomes. Drug exposures are lower in children than in adults. Younger children and CWHIV are underexposed to rifampicin. Standardization of pharmacokinetic paediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
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Severe bacterial non-AIDS infections in persons with HIV: the epidemiology and evolution of antibiotic resistance over an 18-year period (2000–2017) in the ANRS CO3 AquiVih-Nouvelle-Aquitaine cohort

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Abstract
Background
Severe non-AIDS bacterial infections (SBIs) are one of the leading causes of hospital admissions among persons with HIV (PWH) in regions with high ART coverage.
Methods
This large prospective cohort study of PWH examined the types of infections, bacterial documentation, and evolution of antibiotic resistance among PWH hospitalized with SBIs over an 18-year period.
Results
Between 2000 and 2017, 459 PWH had at least one SBI with bacterial documentation. Among the 847 SBIs, there were 280 cases of bacteremia, 269 cases of pneumonia, and 240 urinary tract infections. The 1025 isolated bacteria included Enterobacteriaceae (n = 394; mainly Escherichia coli), Staphylococcus aureus (n = 153) and Streptococcus pneumoniae (n = 82). The proportion of S. pn eumoniae as the causative agent in pneumonia and bacteremia decreased sharply over time, from 34% to 8% and from 21 to 3%, respectively.The overall antibiotic resistance of S. aureus and S. pneumoniae decreased progressively but it increased for Enterobacteriaceae (from 24% to 48% for amoxicillin-clavulanate, from 4 to 18% for cefotaxime, and from 5% to 27% for ciprofloxacin). Cotrimoxazole prophylaxis was associated with higher nonsusceptibility of S. pneumoniae to amoxicillin and erythromycin, higher nonsusceptibility of Enterobacteriaceae to beta-lactams and fluoroquinolones, and a higher risk of extended-spectrum β-lactamase producing Enterobacteriaceae.
Conclusions
The bacterial resistance pattern among PWH between 2014 and 2017 was broadly similar to that in the general population, with the exception of a higher resistance profile of Enteroba cteriaceae to fluoroquinolones. The use of cotrimoxazole as prophylaxis was associated with an increased risk of antibiotic resistance.
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