Τρίτη 31 Ιανουαρίου 2023

Detect and suppress future zoonotic‐derived outbreaks: A lesson from last two decades

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Abstract

COVID-19 pandemic has revealed how vulnerable and inexperienced we are when dealing with an unprecedented global infectious threat. Looking back on the last few decades, there has been a surge in zoonotic-derived viruses globally. Notably, these outbreaks emerged as harmless zoonotic diseases within a favorable environment, then spilled over to humans and widely spread to become outbreaks. Most of these are respiratory viruses (particularly Orthomyxoviridae Orthomyxoviridae or Coronaviridae Coronaviridae family), with high transmissibility and can be easily spread. Low- and middle-income countries, particularly those with tropical climates, provide ideal environments for the growth and evolution of these zoonotic viruses. Nevertheless, a lot of our advanced centers for infectious diseases are located in high-income countries (HIC) and focus on human pathogens only (e.g., influenza, RSV, adenovirus). We should critically think about reallocating health resources in th e near-term. It is an urge for a few surveillance centers aim to detect surges in cases of respiratory pathogens or any spikes in cases, and suppress the transmission chain from an early stage. In this article, we digest lessons learned from the previous spillover pandemics and suggest actionable tactics to deal with future pandemics properly.

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Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol

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Abstract

The aim of this study was to present the diagnostic and outcome characteristics of infants with germline status of KMT2A gene (KMT2A-g) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated consistently according to the MLL-Baby protocol, a moderate-intensity protocol. Of the 139 patients enrolled in the MLL-Baby study, 100 (71.9%) carried different types of rearranged KMT2A (KMT2A-r), while the remaining 39 infants (28.1%) had KMT2A-g. KMT2A-g patients were generally older (77% older than 6 months), less likely to have a very high white blood cell count (greater than 100 × 109/L), less likely to be central nervous system (CNS)-positive, and more likely to be CD10-positive. The 6-year event-free survival and overall survival rates for all 39 patients were 0.74 (standard error [SE] 0.07) and 0.80 (SE 0.07), respectively. Relapse was the most common adverse event (n = 5), with a cumulativ e incidence of relapse (CIR) of 0.13 (SE 0.06), while the incidence of a second malignancy (n = 1) and death in remission (n = 3) was 0.03 (SE 0.04) and 0.08 (SE 0.04), respectively. None of the initial parameters, including genetics and the presence of recently described fusions of NUTM1 and PAX5 genes, was able to distinguish patients with different outcomes. Only rapidity of response, measured as minimal residual disease (MRD) by flow cytometry, showed a statistically significant impact. Moderate-intensity therapy, as used in the MLL-Baby protocol in infants with KMT2A-g BCP-ALL, yields results comparable to other infant studies. Patients with a slow multicolor flow cytometry (MFC)-MRD response should be subjected to advanced therapies, such as targeted or immunotherapies.
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Automated Creak Differentiates Adductor Laryngeal Dystonia and Muscle Tension Dysphonia

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Objective

The purpose of this study was to determine whether automated estimates of vocal creak would differentiate speakers with adductor laryngeal dystonia (AdLD) from speakers with muscle tension dysphonia (MTD) and speakers without voice disorders.

Methods

Sixteen speakers with AdLD, sixteen speakers with MTD, and sixteen speakers without voice disorders were recorded in a quiet environment reading aloud a standard paragraph. An open-source creak detector was used to calculate the percentage of creak (% creak) in each of the speaker's six recorded sentences.

Results

A Kruskal-Wallis one-way analysis of variance revealed a statistically significant effect of group on the % creak with a large effect size. Pairwise Wilcoxon tests revealed a statistically significant difference in % creak between speakers with AdLD and controls as well as between speakers with AdLD and MTD. Receiver operating characteristic curve analyses indicated that % creak differentiated AdLD from both controls and speakers with MTD with high sensitivity and specificity (area under the curve statistics of 0.94 and 0.86, respectively).

Conclusion

Percentage of creak as calculated by an automated creak detector may be useful as a quantitative indicator of AdLD, demonstrating the potential for use as a screening tool or to aid in a differential diagnosis.

Level of Evidence

3 Laryngoscope, 2023
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Use of incorrect and correct methods to account for age in studies on epigenetic accelerated aging: implications and recommendations for best practices

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Abstract
Motivated by our conduct of a literature review on social exposures and accelerated aging as measured by a growing number of epigenetic "clocks" (which estimate age via DNA methylation patterns (DNAm)), we report on three different approaches – 1 incorrect and 2 correct – in the epidemiologic literature on treatment of age in these and other studies using other common exposures (i.e., body mass index and alcohol consumption). Among the 50 empirical articles reviewed, the majority (n = 29; 58%) used the incorrect method of analyzing accelerated aging detrended for age as the outcome and did not control for age as a covariate. By contrast, only 42% used the correct methods, which are either to analyze accelerated aging detrended for age as the outcome and control for age as a covariate (n = 16; 32%), or to analyze raw DNAm age as the outcome and control for age as a covariate (n = 5; 10%). In accord with prior demonstrations of bias introdu ced by the incorrect approach, we provide simulation analyses and additional empirical analyses to illustrate how the incorrect method can lead to bias to the null, and we discuss implications for extant research and recommendations for best practices.
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Δευτέρα 30 Ιανουαρίου 2023

Risk prediction in early childhood SHH medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than two subgroups

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Abstract
Background
The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse.
Methods
Hundred-forty-four patients with DMB (n=99) or MBEN (n=45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients, were evaluated.
Results
Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs 93% [MBEN]). Patients' age >3 years was associated with more unfavorable 5y-PFS (47% [>3 years] vs 85% [<1 year] vs 84% [1-3 years]). DNA methylation profiles available (n=78) were reclassified according to the 2021 WHO classification into SHH-1 (n=39), SHH-2 (n=38), and SHH-3 (n=1). Hierarchical clustering de lineated two subgroups among SHH-2: SHH-2a (n=19) and SHH-2b (n=19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs 83% [SHH-1] vs 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using two independent cohorts (total n=188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations.
Conclusion
These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with higher risk of r elapse.
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Severe Fatigue and Persistent Symptoms at Three Months Following SARS-CoV-2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study

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ABSTRACT
Background
Most research on SARS-CoV-2 variants focuses on initial symptomatology with limited data on longer-term sequelae. We sought to characterize the prevalence and differences in prolonged symptoms at three months post SARS-CoV-2-infection across the three major variant time-periods (pre-Delta, Delta, and Omicron).
Methods
This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, individual and organ system-based symptoms, and presence of ≥3 total symptoms across variants among COVID-positive and COVID-negative participants 3 months after their initial SARS-CoV-2 diagnosis. Variant periods were defined by dates with ≥50% dominant strain. We performed a sensitivity analysis using ≥90% dominance threshold and multivariable logistic regression modeling to estimate the independent effects of each variant adjusting for socio-demographic chara cteristics, baseline health, and vaccine status.
Results
The study included 3,223 participants (2,402 COVID-positive and 821 COVID-negative). Among the COVID-positive cohort, 463 (19.3%) were pre-Delta, 1,198 (49.9%) during Delta, and 741 (30.8%) during Omicron. Prolonged severe fatigue was highest in the pre-Delta COVID-positive cohort compared with Delta and Omicron cohorts (16.7% vs 11.5% vs 12.3%, respectively; p = 0.017), as was presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; p < 0.001). No difference was seen in the COVID-negative cohort between variant time-periods. In multivariable models, there was no difference in severe fatigue between variants. There was decreased odds of having ≥3 symptoms in Omicron compared with other variants; this was not significant after adjusting for vaccination status.
Conclusions
Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during the pre-Delta period compared with Delta and Omicron periods; however, these differences were no longer significant after adjusting for vaccination status. This suggests a potential beneficial effect of vaccination on the risk of developing long-term symptoms.
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Κυριακή 29 Ιανουαρίου 2023

Novel Murine Glioblastoma Models That Reflect the Immunotherapy Resistance Profile of Human Disease

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We therefore developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and underlying mechanisms.
Methods
The differential responsiveness of QPP lines was assessed in the brain and flank in untreat ed, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8.
Results
QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector to suppressor ratios when implanted subcutaneously (sensitive), which are absent upon implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoa ntigen burden.
Conclusions
These syngeneic QPP models of glioblastoma demonstrate clinically-relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.
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68Ga-PSMA–Avid Intranasal Solitary Fibrous Tumor

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imageThe utility of molecular imaging in solitary fibrous tumors has not been fully established. We present a rare case of recurrent intranasal solitary fibrous tumor incidentally localized on 68Ga-PSMA PET/CT scan, which turned out to be metabolically inactive on 18F-FDG PET/CT.
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Interesting Findings in 68Ga-FAPI-46 PET/CT Imaging in a Patient With Glioblastoma Multiforme

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imageA 55-year-old disabled man with glioblastoma multiforme was referred to us for fibroblast activation protein inhibitor (FAPI) PET/CT imaging. 68Ga-DOTA-FAPI-46 scan revealed uptake in the primary tumor and unexpected uptakes in soft tissue, especially in periarticular regions. These latter foci were compatible with calcifications on the CT. One in the breast was compatible with fibrotic tissue, but 2 other foci, in the rectus abdominis and gallbladder wall, could not be correlated with the CT findings. In Neurogenic heterotopic ossification, hypoxia-associated oxidative stress results in the metaplastic transformation of fi broblasts. Abnormal differentiation of fibroblasts in neurogenic heterotopic ossification before ossification could explain radiolabeled FAPI avidity in the mentioned areas.
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Molecular evolution of the human monkeypox virus

alexandrossfakianakis shared this article with you from Inoreader

ABSTRACT

Background

Recently, in 2022, new cases of human monkeypox virus (hMPXV) occurred in Europe and North America. The first case was reported in Europe in May 2022, and subsequently, more than 50,000 new cases were confirmed in 100 countries. Currently, the classification of hMPXV according to the nextstrain occurs in five big clades (1A, A.1, A.2, A.1.1, and B.1).

Aims

According to the resurgence of smallpox-like disease caused by hMPXV and the spread of the virus to the European and American continents, in the present study, we review and summarize the molecular evolution of the hMPXV, determining the molecular evolution of the main clades.

Methods

A total of 442 hMPXV whole-genome sequences (WGS) with available information from the country and sampling date (between October 2017 and 2022), were obtained and evaluated using the Bayesian method.

Results

The clade B.1 which is currently circulating was the most frequent (n=415; 93.9%). The other clades presented the following frequencies: 1A (n=13; 2.9%), A.1 (n=10; 2.3%), A.2 (n=3; 0.7%) and A.1.1 (n=1; 0.2%) The overall nucleotide divergence of hMPXV was 5,590e-5. The 1A clade was detected between 2017 and 2020. A.1 was observed, and between 2019 and 2022 some A.2 sequences were detected. In 2022, the great predominance of B.1 was observed. The common ancestor of the hMPXV belongs to the clade 1A and the time to the Most Recent Common Ancestor (tMRCA) was 2017-04-04 (Highest Posterior Density 95% (HPD95%): 2017-03-09; 2017-08-04) on the West African continent. The tMRCA of A.1 was 2018-05-21 (HPD95%: 2018-05-20; 2018-07-04) with divergence of 6.885e-5 substitutions per site per year (ssy). This clade was of West African origin but was eventually detected in European countries. Also, A.2 was detected with sequences of North America and showed tMRCA of 2019-07-15 (HPD95%: 2018-11- 18; 2020-02-24). A.1.1 showed tMRCA from 2021-06-05 (HPD95%: 2021-06-05; 2021-11-26) and this clade was detected in North America and was the precursor for the globally spreading B.1 which tMRCA was 2022-04-26 (HPD95%: 2022-02-27; 2022-04-26). hMPXV has been spread from West Africa to the United Kingdom, Israel, Singapore, the USA, Canada, Portugal, Spain, Ireland, France, Belgium, the Netherlands, Switzerland, Germany, Italy, Slovenia, Austria, the Republic Czech, Sweden, and Finland. hMPXV also reached countries such as Brazil, Mexico, Australia, and Taiwan.

Conclusion

The common ancestor of the hMPXV belongs to the clade 1A with origin in the West African continent. Clade B.1 was responsible for the recent widespread worldwide. Immunization to prevent the spread of hMPXV is not yet available to the public, future studies should focus on the development of effective vaccines to contain the spread of this virus.

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