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Frontiers in Neuroanatomy 2024Literature suggests a common pathophysiological ground between carotid atherosclerosis (CAS) and white matter alterations in the brain. However, the association between...
INTRODUCTION
Literature suggests a common pathophysiological ground between carotid atherosclerosis (CAS) and white matter alterations in the brain. However, the association between carotid intima-media thickness (CIMT) and white matter hyperintensities (WMH) has not been conclusively reported. The current systematic review explores and reports the relationship between CIMT and WMH among asymptomatic/non-stroke adults.
METHODS
A recent literature search on PubMed, SCOPUS, and Web of Science databases was conducted in compliance with the PRISMA protocol. The pre-defined Population-Intervention-Comparison-Outcome-Study (PICOS) criteria included observational studies investigating the CIMT-WMH association among non-stroke adults undergoing magnetic resonance imaging and carotid ultrasound.
RESULTS
Out of 255 potential results, 32 studies were critically assessed for selection, and finally, 10 articles were included, comprising 5,116 patients (females = 60.2%; males = 39.8%) aged between 36-71 years. The included studies earned high quality ratings (6-9) based on the Newcastle-Ottawa-Scale criteria. Qualitative synthesis showed a significantly parallel relationship between increased CIMT and greater WMH burden in 50% of the studies. In addition, significant risk factors related to the CIMT-WMH association included older age, hypertension, depression, migraine, Hispanic ethnicity, and apolipoprotein E (ɛ4) in postmenopausal women.
CONCLUSION
Overall, the cumulative evidence showed a consistent CIMT-WMH association in asymptomatic middle-aged and older non-stroke adults, indicating that CAS may contribute to the progression of pathologically hyperintense white matter in the brain. However, further research is warranted to infer the plausible relationship between CIMT and WMH in the absence of stroke.
PubMed: 38903057
DOI: 10.3389/fnana.2024.1394766 -
BMC Geriatrics Jun 2024Upper gastrointestinal bleeding (UGIB) in older patients is associated with substantial in-hospital morbidity and mortality. This study aimed to develop and validate a... (Comparative Study)
Comparative Study
BACKGROUND
Upper gastrointestinal bleeding (UGIB) in older patients is associated with substantial in-hospital morbidity and mortality. This study aimed to develop and validate a simplified risk score for predicting 30-day in-hospital mortality in this population.
METHODS
A retrospective analysis was conducted on data from 1899 UGIB patients aged ≥ 65 years admitted to a single medical center between January 2010 and December 2019. An additional cohort of 330 patients admitted from January 2020 to October 2021 was used for external validation. Variable selection was performed using five distinct methods, and models were generated using generalized linear models, random forest, support vector machine, and k-nearest neighbors approaches. The developed score, "ABCAP," incorporated Albumin < 30 g/L, Blood Urea Nitrogen (BUN) > 7.5 mmol/L, Cancer presence, Altered mental status, and Pulse rate > 100/min, each assigned a score of 1. Internal and external validation procedures compared the ABCAP score with the AIMS65 score.
RESULTS
In internal validation, the ABCAP score demonstrated robust predictive capability with an area under the curve (AUC) of 0.878 (95% CI: 0.824-0.932), which was significantly better than the AIMS65 score (AUC: 0.827, 95% CI: 0.751-0.904), as revealed by the DeLong test (p = 0.048). External validation of the ABCAP score resulted in an AUC of 0.799 (95% CI: 0.709-0.889), while the AIMS65 score yielded an AUC of 0.743 (95% CI: 0.647-0.838), with no significant difference between the two scores based on the DeLong test (p = 0.16). However, the ABCAP score at the 3-5 score level demonstrated superior performance in identifying high-risk patients compared to the AIMS65 score. This score exhibited consistent predictive accuracy across variceal and non-variceal UGIB subgroups.
CONCLUSIONS
The ABCAP score incorporates easily obtained clinical variables and demonstrates promising predictive ability for 30-day in-hospital mortality in older UGIB patients. It allows effective mortality risk stratification and showed slightly better performance than the AIMS65 score. Further cohort validation is required to confirm generalizability.
Topics: Humans; Aged; Male; Female; Retrospective Studies; Hospital Mortality; Aged, 80 and over; Risk Assessment; Gastrointestinal Hemorrhage; Geriatric Assessment
PubMed: 38902633
DOI: 10.1186/s12877-024-04971-w -
Scientific Reports Jun 2024Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small...
Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFCs. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.
Topics: Humans; Cleft Palate; Cleft Lip; Female; Ghana; Male; Mice; Genetic Predisposition to Disease; Animals; Nigeria; Ethiopia; Black People; Child
PubMed: 38902479
DOI: 10.1038/s41598-024-65151-9 -
ELife Jun 2024Brain structural circuitry shapes a richly patterned functional synchronization, supporting for complex cognitive and behavioural abilities. However, how coupling of...
Brain structural circuitry shapes a richly patterned functional synchronization, supporting for complex cognitive and behavioural abilities. However, how coupling of structural connectome (SC) and functional connectome (FC) develops and its relationships with cognitive functions and transcriptomic architecture remain unclear. We used multimodal magnetic resonance imaging data from 439 participants aged 5.7-21.9 years to predict functional connectivity by incorporating intracortical and extracortical structural connectivity, characterizing SC-FC coupling. Our findings revealed that SC-FC coupling was strongest in the visual and somatomotor networks, consistent with evolutionary expansion, myelin content, and functional principal gradient. As development progressed, SC-FC coupling exhibited heterogeneous alterations dominated by an increase in cortical regions, broadly distributed across the somatomotor, frontoparietal, dorsal attention, and default mode networks. Moreover, we discovered that SC-FC coupling significantly predicted individual variability in general intelligence, mainly influencing frontoparietal and default mode networks. Finally, our results demonstrated that the heterogeneous development of SC-FC coupling is positively associated with genes in oligodendrocyte-related pathways and negatively associated with astrocyte-related genes. This study offers insight into the maturational principles of SC-FC coupling in typical development.
Topics: Humans; Connectome; Young Adult; Male; Adolescent; Female; Brain; Magnetic Resonance Imaging; Child; Child, Preschool; Adult; Nerve Net
PubMed: 38900563
DOI: 10.7554/eLife.93325 -
Journal of Cellular and Molecular... Jun 2024The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for...
The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions.
Topics: Humans; DNA Methylation; Trophoblasts; Oxidative Stress; Transcriptome; Cell Hypoxia; Cell Line; Female; Pregnancy; Gene Expression Profiling; Gene Expression Regulation; Phosphofructokinase-2
PubMed: 38899809
DOI: 10.1111/jcmm.18469 -
Epigenetics Dec 2024This research investigates the intricate dynamics of DNA methylation in the hours following CD8+ T cell activation, during a critical yet understudied temporal window....
This research investigates the intricate dynamics of DNA methylation in the hours following CD8+ T cell activation, during a critical yet understudied temporal window. DNA methylation is an epigenetic modification central to regulation of gene expression and directing immune responses. Our investigation spanned 96-h post-activation and unveils a nuanced tapestry of global and site-specific methylation changes. We identified 15,626 significant differentially methylated CpGs spread across the genome, with the most significant changes occurring within the genes , , and . While many changes had modest effect sizes, approximately 120 CpGs exhibited a logFC above 1.5, with cell activation and proliferation pathways the most affected. Relatively few of the differentially methylated CpGs occurred along adjacent gene regions. The exceptions were seven differentially methylated gene regions, with the Human T cell Receptor Alpha Joining Genes demonstrating consistent methylation change over a 3kb window. We also investigated whether an inflammatory environment could alter DNA methylation during activation, with proliferating cells exposed to the oxidant glycine chloramine. No substantial differential methylation was observed in this context. The temporal perspective of early activation adds depth to the evolving field of epigenetic immunology, offering insights with implications for therapeutic innovation and expanding our understanding of epigenetic modulation in immune function.
Topics: DNA Methylation; CD8-Positive T-Lymphocytes; Lymphocyte Activation; Humans; Cell Proliferation; CpG Islands; Epigenesis, Genetic; ADAM10 Protein; Membrane Proteins
PubMed: 38899429
DOI: 10.1080/15592294.2024.2367385 -
Molecular Oncology Jun 2024The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology.... (Review)
Review
The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E-mutated GBM benefit from BRAF/MEK-inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (< 10%) of targeted treatments. Efficacy was observed in one-third and currently appears to be limited to BRAF-, VEGFR-, and mTOR-directed treatments. Advancing precision oncology for GBM requires consideration of pathways instead of single alterations, new trial concepts enabling rapid and adaptive drug evaluation, a focus on drugs with sufficient bioavailability in the CNS, and the extension of target discovery and validation to the tumor microenvironment, tumor cell networks, and their interaction with immune cells and neurons.
PubMed: 38899374
DOI: 10.1002/1878-0261.13678 -
Frontiers in Endocrinology 2024Metabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for...
BACKGROUND
Metabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for metabolic abnormalities and OC lacks consistency.
METHOD
The Mendelian randomization (MR) approach is a widely used methodology for determining causal relationships. Our study employed summary statistics from the genome-wide association studies (GWAS), and we used inverse variance weighting (IVW) together with MR-Egger and weighted median (WM) supplementary analyses to assess causal relationships between exposure and outcome. Furthermore, additional sensitivity studies, such as leave-one-out analyses and MR-PRESSO were used to assess the stability of the associations.
RESULT
The IVW findings demonstrated a causal associations between 10 metabolic factors and an increased risk of OC. Including "Basal metabolic rate" (OR= 1.24, = 6.86×10); "Body fat percentage" (OR= 1.22, = 8.20×10); "Hip circumference" (OR= 1.20, = 5.92×10); "Trunk fat mass" (OR= 1.15, = 1.03×10); "Trunk fat percentage" (OR= 1.25, = 8.55×10); "Waist circumference" (OR= 1.23, = 3.28×10); "Weight" (OR= 1.21, = 9.82×10); "Whole body fat mass" (OR= 1.21, = 4.90×10); "Whole body fat-free mass" (OR= 1.19, = 4.11×10) and "Whole body water mass" (OR= 1.21, = 1.85×10).
CONCLUSION
Several metabolic markers linked to altered fat accumulation and distribution are significantly associated with an increased risk of OC.
Topics: Humans; Mendelian Randomization Analysis; Female; Ovarian Neoplasms; Genome-Wide Association Study; Risk Factors; Polymorphism, Single Nucleotide
PubMed: 38899007
DOI: 10.3389/fendo.2024.1401648 -
BMC Musculoskeletal Disorders Jun 2024Spinal fractures in patients with ankylosing spondylitis (AS) mainly present as instability, involving all three columns of the spine, and surgical intervention is often...
BACKGROUND
Spinal fractures in patients with ankylosing spondylitis (AS) mainly present as instability, involving all three columns of the spine, and surgical intervention is often considered necessary. However, in AS patients, the significant alterations in bony structure and anatomy result in a lack of identifiable landmarks, which increases the difficulty of pedicle screw implantation. Therefore, we present the clinical outcomes of robotic-assisted percutaneous fixation for thoracolumbar fractures in patients with AS.
METHODS
A retrospective review was conducted on a series of 12 patients diagnosed with AS. All patients sustained thoracolumbar fractures between October 2018 and October 2022 and underwent posterior robotic-assisted percutaneous fixation procedures. Outcomes of interest included operative time, intra-operative blood loss, complications, duration of hospital stay and fracture union. The clinical outcomes were assessed using the visual analogue scale (VAS) and Oswestry Disability Index (ODI). To investigate the achieved operative correction, pre- and postoperative radiographs in the lateral plane were analyzed by measuring the Cobb angle.
RESULTS
The 12 patients had a mean age of 62.8 ± 13.0 years and a mean follow-up duration of 32.7 ± 18.9 months. Mean hospital stay duration was 15 ± 8.0 days. The mean operative time was 119.6 ± 32.2 min, and the median blood loss was 50 (50, 250) ml. The VAS value improved from 6.8 ± 0.9 preoperatively to 1.3 ± 1.0 at the final follow-up (P < 0.05). The ODI value improved from 83.6 ± 6.1% preoperatively to 11.8 ± 6.6% at the latest follow-up (P < 0.05). The average Cobb angle changed from 15.2 ± 11.0 pre-operatively to 8.3 ± 7.1 at final follow-up (P < 0.05). Bone healing was consistently achieved, with an average healing time of 6 (5.3, 7.0) months. Of the 108 screws implanted, 2 (1.9%) were improperly positioned. One patient experienced delayed nerve injury after the operation, but the nerve function returned to normal upon discharge.
CONCLUSION
Posterior robotic-assisted percutaneous internal fixation can be used as an ideal surgical treatment for thoracolumbar fractures in AS patients. However, while robot-assisted pedicle screw placement can enhance the accuracy of pedicle screw insertion, it should not be relied upon solely.
Topics: Humans; Spinal Fractures; Male; Middle Aged; Thoracic Vertebrae; Female; Retrospective Studies; Spondylitis, Ankylosing; Lumbar Vertebrae; Robotic Surgical Procedures; Fracture Fixation, Internal; Treatment Outcome; Aged; Operative Time; Length of Stay; Pedicle Screws; Adult; Blood Loss, Surgical; Follow-Up Studies
PubMed: 38898448
DOI: 10.1186/s12891-024-07597-6 -
Nature Communications Jun 2024Cytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the...
Cytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the plasma membrane by spatially distinct β- and γ-actin networks. These networks are generated by the formin family of actin nucleators, DIAPH3 and DIAPH1 respectively. Here we show that β- and γ-actin perform specialized and non-redundant roles in cytokinesis and cannot substitute for one another. Expression of hybrid DIAPH1 and DIAPH3 proteins with altered actin isoform specificity relocalized cytokinetic actin isoform networks within the cell, causing cytokinetic failure. Consistent with this we show that β-actin networks, but not γ-actin networks, are required for the maintenance of non-muscle myosin II and RhoA at the cytokinetic furrow. These data suggest that independent and spatially distinct actin isoform networks form scaffolds of unique interactors that facilitate localized biochemical activities to ensure successful cell division.
Topics: rhoA GTP-Binding Protein; Cytokinesis; Formins; Actins; Humans; Myosin Type II; Adaptor Proteins, Signal Transducing; HeLa Cells; Animals; Protein Isoforms
PubMed: 38897998
DOI: 10.1038/s41467-024-49427-2