Κυριακή 19 Ιουνίου 2022

Clinical Significance and Molecular Annotation of Cellular Morphometric Subtypes in Lower Grade Gliomas discovered by Machine Learning

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Abstract
BACKGROUND
Lower grade gliomas (LGG) are heterogenous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes.
METHODS
Cellular morphometric biomarkers (CMBs) were identified with artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5- year overall survival (OS) of LGG patients. Tumor mutational burden (TMB), and immune cell infiltration between subtypes were analyzed using the Mann-Whitney test. The double-blinded validation for important immunotherapy-related biomarkers were executed using immunohistochemistry (IHC).
RESULTS
We developed a mac hine learning pipeline to extract CMBs from whole slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multi-center cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by immunohistochemical staining. In addition, the subtypes learned from LGG demonstrates translational impact on glioblastoma (GBM).
CONCLUSIONS
We developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune micro-environment, prognosis, and treatment response.
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Effect of new biological patch in repairing intrauterine adhesion and improving clinical pregnancy outcome in infertile women: study protocol for a randomized controlled trial

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Endometrial fibrosis caused by intrauterine adhesion (IUA) can lead to hypomenorrhea, amenorrhea, and even infertility and abortion. The postoperative recurrence rate of severe IUA remains high, giving rise to...
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Can the prophylactic administration of tranexamic acid reduce the blood loss after robotic-assisted radical prostatectomy? Robotic Assisted Radical Prostatectomy with tranEXamic acid (RARPEX): study protocol for a randomized controlled trial

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The prophylactic administration of tranexamic acid reduces blood loss during procedures at high risk of perioperative bleeding. Several studies in cardiac surgery and orthopedics confirmed this finding. The ai...
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Merits of the free periosteal femoral condyle flap in the management of advanced mandibular osteoradionecrosis

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The management of advanced mandibular osteoradionecrosis (ORN) is poorly codified and requires repeated time-consuming, morbid surgical procedures. The free periosteal medial femoral condyle flap could be used for the management of extensive mandibular ORN with fracture, to avoid non-conservative surgery such as mandibulectomy. The purpose of this study was to report the authors ' experience using periosteal flaps for advanced ORN and to assess the therapeutic effectiveness of these flaps in this context. (Source: International Journal of Oral and Maxillofacial Surgery)
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Old age amyotrophic lateral sclerosis and limbic TDP‐43 pathology

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Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology

Regional pTDP-43 lesion burden in young-ALS and old-ALS box plots shows regional TDP-43 burden in young-, middle-, and old-ALS. The line in box plots represents the median. Old-ALS cases had greater TDP-43 burden in amygdala (p < 0.001), dentate gyrus (p < 0.05), CA1 (p < 0.01), subiculum (p < 0.01), and entorhinal cortex (p < 0.01) compared with young-ALS and middle-ALS. There is no difference between the three groups in the middle frontal cortex and white matter of the parahippocampal gyrus. ***p < 0.001, **p < 0.05, *p < 0.01. p Values are from one-way ANOVA


Abstract

This study aimed to assess and compare the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate-to-severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old-ALS, n = 8), 64–74 years (middle-ALS, n = 23), and 63 years or younger (young-ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS-CBS), were summarized. Sections of paraffin-embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho-TDP-43 immunohistochemist ry. The burden of TDP-43 pathology was analyzed using digital image analysis. The TDP-43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old-ALS than in young-ALS and middle-ALS. TDP-43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS-CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP-43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change.

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Prevalence, outcome, and prevention of congenital cytomegalovirus infection in neonates born to women with preconception immunity (CHILd study).

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Abstract
Background
Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disabilities. We designed a prospective study to investigate the rate, outcome and risk factors of congenital cytomegalovirus infection (cCMV) in neonates born to immune women, and the potential need and effectiveness of hygiene recommendations in this population.
Methods
The study (NCT03973359) was composed of 2 sequential parts: an epidemiology (Part 1) and a prevent ion (Part 2) study. Performance of Part 2 depended upon a cCMV rate > 0.4%. Women enrolled in Part 1 did not receive hygiene recommendations. Newborns were screened by HCMV DNA testing in saliva and cCMV was confirmed by urine testing.
Results
Saliva swabs were positive for HCMV DNA in 45/9661 newborns and cCMV was confirmed in 18 cases. The rate of cCMV was 0.19% (95% CI: 0.11-0.29%), and three out of 18 infants with cCMV had symptoms of CMV at birth. Age, nationality, occupation and contact with children were similar between mothers of infected and non-infected newborns. Twin pregnancy (OR: 7.2; 95% CI 1.7-32.2; p = 0.037) and maternal medical conditions (OR: 3.9; 95% CI: 1.5-10.1; p = 0.003) appeared associated with cCMV. Given the rate of cCMV lower than expected, the prevention part of the study was cancelled.
Conclusion
Newborns from women with preconception immunity have a low rate of cCMV, which appears to be mostly due to reactivation of the latent virus. Therefore, serological screening in childbearing age would be pivotal to identify HCMV-seropositive women, whose newborns have a low risk of cCMV.
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Life-Threatening Complications of Influenza versus COVID-19 in U.S. Children

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ABSTRACT
Background
Clinical differences between critical illness from influenza infection versus coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.
Methods
We compared U.S. children (8 months to 17 years) admitted to the intensive care or high acuity unit with influenza (17 hospitals, 12/19/2019–3/9/2020) or COVID-19 (52 hospitals, 3/15/2020–12/31/2020). We compared demographics, underlying conditions, clinical prese ntation, severity, and outcomes. Using mixed-effects models, we assessed the odds of death or requiring life-support for influenza versus COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.
Results
Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median 5.2 vs. 13.8 years), less likely to be non-Hispanic black (14.5% vs. 27.6%) or Hispanic (24.0% vs. 36.2%), and less likely to have ≥1 underlying condition (66.4% vs. 78.5%) or be obese (21.4% vs. 42.2%). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life-support in children with influenza vs. COVID-19 were s imilar (adjusted odds ratio, 1.30 [95% CI: 0.78–2.15; P = 0.32]). Median duration of hospital stay was shorter for influenza than COVID-19 (5 versus 7 days).
Conclusions
Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.
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