Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Genomic Characterization of Aggressive Breast Cancer in Younger Women
No full textPURPOSEAlthough breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women. METHODSClinicopathologic, molecular, and genomic differences across age groups ( 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups. RESULTSSurvival analysis showed that women 60 years. Molecular subtypes in the METABRIC cohort showed women 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001). CONCLUSIONSBCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment
Assessing plate reconstruction models using plate driving force consistency tests
No full textPlate reconstruction models are constructed to fit constraints such as magnetic anomalies, fracture zones, paleomagnetic poles, geological observations and seismic tomography. However, these models do not consider the physical equations of plate driving forces when reconstructing plate motion. This can potentially result in geodynamically-implausible plate motions, which has implications for a range of work based on plate reconstruction models. We present a new algorithm that calculates time-dependent slab pull, ridge push (GPE force) and mantle drag resistance for any topologically closed reconstruction, and evaluates the residuals—or missing components—required for torques to balance given our assumed plate driving force relationships. In all analyzed models, residual torques for the present-day are three orders of magnitude smaller than the typical driving torques for oceanic plates, but can be of the same order of magnitude back in time—particularly from 90 to 50 Ma. Using the Pacific plate as an example, we show how our algorithm can be used to identify areas and times with high residual torques, where either plate reconstructions have a high degree of geodynamic implausibility or our understanding of the underlying geodynamic forces is incomplete. We suggest strategies for plate model improvements and also identify times when other forces such as active mantle flow were likely important contributors. Our algorithm is intended as a tool to help assess and improve plate reconstruction models based on a transparent and expandable set of a priori dynamic constraints
Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays for dementia research
No full textBackground
DNA methylation (DNAm) has been implicated in many diseases including dementia. Array-based technologies offer a cost-effective and comprehensive approach for measuring DNAm on a genome-wide scale. However, the accuracy of DNAm measurements obtained using Illumina arrays can vary across different probes. Previous research has focused primarily on assessing the reliability of DNAm in younger subjects, and have compared duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on EPIC-EPIC comparisons.
Methods
We conducted a comprehensive assessment of probe reliability on the Illumina EPIC arrays using 138 duplicated blood DNAm samples from subjects older than 65 years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. To assess the reliability of each probe, we computed intraclass correlations (ICCs) for each probe. Both the magnitude and patterns of reliability in the EPIC-EPIC comparison were assessed. Furthermore, we also investigated the impact of probe reliability on the analyses of epigenome-wide association studies (EWAS).
Results
Our findings revealed the reliability of probes on the EPIC arrays is higher than those of previous studies involving duplicate measurements on 450k-EPIC or 450k-450k arrays. Consistent with earlier research, we observed increased reliability in probes with substantial between-subject variances or average methylation beta values ranging from 0.2 to 0.8. Lower reliability was observed in type I probes or probes located within the promoter and CpG island regions. In addition, we found some probes can yield high ICC values despite significant disagreement in duplicate measurements, primarily due to their relatively high between-subject variance. To account for such discrepancies explicitly, we introduced a novel statistical measure called the modified ICC, which penalizes the ICC based on the half-width of the 95% confidence limits of agreement. Importantly, we found probe reliability has significant implications in various downstream analyses of EWAS, such as meta-analysis, differentially methylated regions analysis, and integrative analyses within the cross-tissue or multi-omics contexts.
Conclusion
We developed a valuable resource for dementia research, providing crucial reliability information for probes on the EPIC array. This resource can be utilized to identify and prioritize high-quality probes, thereby minimizing the potential for false discoveries and maximizing the potential of EWAS
Genome wide association study of neuropathic ocular pain
No full textPurpose: To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development. Design: Prospective study of individuals with NOP. Participants: Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic. Methods: The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 x 10(-5)), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 x 10(-4)), CTC-487M23.8 (P = 1.79 x 10(-4)), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 x 10(-4)), and signal recognition particle-19 (SRP19) (P = 2.56 x 10(-4)). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 x 10(-3)) and olfactory signaling (false discovery rate = 1.63 x 10(-2)) pathways were enriched with the most significant genes. Conclusions: Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better under-standing of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments.</p
SF2Former: Amyotrophic lateral sclerosis identification from multi-center MRI data using spatial and frequency fusion transformer
No full textAmyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by motor neuron degeneration. Significant research has begun to establish brain magnetic resonance imaging (MRI) as a potential biomarker to diagnose and monitor the state of the disease. Deep learning has emerged as a prominent class of machine learning algorithms in computer vision and has shown successful applications in various medical image analysis tasks. However, deep learning methods applied to neuroimaging have not achieved superior performance in classifying ALS patients from healthy controls due to insignificant structural changes correlated with pathological features. Thus, a critical challenge in deep models is to identify discriminative features from limited training data. To address this challenge, this study introduces a framework called SF2Former, which leverages the power of the vision transformer architecture to distinguish ALS subjects from the control group by exploiting the long-range relationships among image features. Additionally, spatial and frequency domain information is combined to enhance the network’s performance, as MRI scans are initially captured in the frequency domain and then converted to the spatial domain. The proposed framework is trained using a series of consecutive coronal slices and utilizes pre-trained weights from ImageNet through transfer learning. Finally, a majority voting scheme is employed on the coronal slices of each subject to generate the final classification decision. The proposed architecture is extensively evaluated with multi-modal neuroimaging data (i.e., T1-weighted, R2*, FLAIR) using two well-organized versions of the Canadian ALS Neuroimaging Consortium (CALSNIC) multi-center datasets. The experimental results demonstrate the superiority of the proposed strategy in terms of classification accuracy compared to several popular deep learning-based techniques.
•We propose a novel vision transformer-based deep model to classify ALS subjects from the healthy control group.•We analyze two independent and extensive MRI datasets of 120 and 232 scans of ALS and healthy control subjects.•To evaluate the effectiveness of our proposed framework, we leverage multi-center and multi-modal neuroimaging data, including T1-weighted, R2*, and FLAIR images.•Our results demonstrate superior classification accuracy when compared to various state-of-the-art deep learning-based techniques
GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice
No full textBackground:
Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain’s inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found inhibition of GSDMD activation attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.
Methods:
Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal day 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1), a marker of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.
Results:
Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure failed to increase either AIF1+ or TUNEL+ cell numbers, nor decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air- exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, and core development pathways hypoxia-induced factor 1, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.
Conclusion:
GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants
The clinical impact and cost-effectiveness of clinic-based cognitive behavioral therapy for people with HIV, depression, and virologic failure in South Africa
No full textDepression affects 25-30% of people with HIV (PWH) in South Africa (RSA) and is associated with both antiretroviral therapy (ART) nonadherence and increased mortality. We evaluated the cost-effectiveness of task-shifted, cognitive behavioral therapy (CBT) for PWH with diagnosed depression and virologic failure from a randomized trial in RSA.RSA.Using the Cost-Effectiveness of Preventing AIDS Complications model, we simulated both trial strategies: Enhanced treatment as usual (ETAU) and ETAU plus CBT for ART adherence and depression (CBT-AD; eight sessions plus two follow-ups). In the trial, viral suppression at one year was 20% with ETAU and 32% with CBT-AD. Model inputs included mean initial age (39 years) and CD4 count (214/μL), ART costs (29/session). We projected 5- and 10-year viral suppression, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs: 2,545/QALY [0.5x per-capita GDP]). In sensitivity analyses, we determined how input parameter variation affected cost-effectiveness.Model-projected 5- and 10-year viral suppression were 18.9% and 8.7% with ETAU and 21.2% and 9.7% with CBT-AD. Compared with ETAU, CBT-AD would increase discounted life expectancy from 4.12 to 4.68 QALYs and costs from 6,670/person (ICER: 70/session and simultaneously improved one-year viral suppression by ≤4% compared with ETAU.Cognitive behavioral therapy for PWH with depression and virologic failure in RSA could improve life expectancy and be cost-effective. Such targeted mental health interventions should be integrated into HIV care
Cancer Patients' Unmet Needs in Three Low- to Middle- Income Countries: Perspectives from Health Care Providers
No full textWe sought to determine differences by low- and middle- income countries (Brazil, Romania, and Turkiye) on the degree to which health care providers (HCPs) note unmet needs among patients with cancer ( = 741). HCPs endorsed sexuality/intimacy and financial concerns as the most common. Investigating age differences in unmet needs between Brazil and Turkiye, were that should be targeted by. Results revealed that unmet needs to manage emotional distress were higher among older patients in Turkiye, whereas unmet needs to manage insomnia/fatigue were higher among pediatric patients in Brazil. Findings may guide the development of programs to address unmet needs among patients
Monodactylous Longitudinal Melanonychia in Pediatric Skin of Color: A Case Series and Review
No full textIntroduction: Longitudinal melanonychia, a pigmented longitudinal streak on the nail, is a common clinical finding that may be associated with subungual melanoma with varying presentation depending on race and skin tone. It has been long reported that darker skinned ethnicities have a higher prevalence of longitudinal melanonychia in the US population (e.g., African Americans with 77% prevalence) [Indian J Dermatol. 2021;66(4):445], but unfortunately, there are limited studies exclusively looking at longitudinal melanonychia in pediatric patients of color. Case Presentation: In this case series, we review the current literature and report the findings of 8 cases of longitudinal melanonychia in children with skin types IV or greater. Out of the 8 cases identified, only 4 returned to the clinic for monitoring (n = 4), and there was an average of 20.8 months between the initial and final visits. Of the patients that returned for follow-up, 2 showed no relevant changes in the nail pigmentation, 1 showed fading of the band, and 1 patient showed enlargement of the band to involve the whole nail. Conclusion: Although many sources recommend a conservative approach to treatment that involves monitoring and follow-up, our findings indicate that a wait-and-see method cannot be applied to all cases in the pediatric population due to disruptions in continuity of care. An individualized approach considering such factors should be employed for each patient, and certain high-risk features of the ABCDEF nail melanoma model may be relevant in pediatric cases