Uncovering the potential role of oxidative stress in the development of periodontitis and establishing a stable diagnostic model via combining single-cell and machine learning analysis

BackgroundThe primary pathogenic cause of tooth loss in adults is periodontitis, although few reliable diagnostic methods are available in the early stages. One pathological factor that defines periodontitis pathology has previously been believed to be the equilibrium between inflammatory defense mechanisms and oxidative stress. Therefore, it is necessary to construct a model of oxidative stress-related periodontitis diagnostic markers through machine learning and bioinformatic analysis.MethodsWe used LASSO, SVM-RFE, and Random Forest techniques to screen for periodontitis-related oxidative stress variables and construct a diagnostic model by logistic regression, followed by a biological approach to build a Protein-Protein interaction network (PPI) based on modelled genes while using modelled genes. Unsupervised clustering analysis was performed to screen for oxidative stress subtypes of periodontitis. we used WGCNA to explore the pathways correlated with oxidative stress in periodontitis patients. Networks. Finally, we used single-cell data to screen the cellular subpopulations with the highest correlation by scoring oxidative stress genes and performed a proposed temporal analysis of the subpopulations.ResultsWe discovered 3 periodontitis-associated genes (CASP3, IL-1β, and TXN). A characteristic line graph based on these genes can be helpful for patients. The primary hub gene screened by the PPI was constructed, where immune-related and cellular metabolism-related pathways were significantly enriched. Consistent clustering analysis found two oxidative stress categories, with the C2 subtype showing higher immune cell infiltration and immune function ratings. Therefore, we hypothesized that the high expression of oxidative stress genes was correlated with the formation of the immune environment in patients with periodontitis. Using the WGCNA approach, we examined the co-expressed gene modules related to the various subtypes of oxidative stress. Finally, we selected monocytes for mimetic time series analysis and analyzed the expression changes of oxidative stress genes with the mimetic time series axis, in which the expression of JUN, TXN, and IL-1β differed with the change of cell status.ConclusionThis study identifies a diagnostic model of 3-OSRGs from which patients can benefit and explores the importance of oxidative stress genes in building an immune environment in patients with periodontitis

Machine learning to construct sphingolipid metabolism genes signature to characterize the immune landscape and prognosis of patients with uveal melanoma

BackgroundUveal melanoma (UVM) is the most common primary intraocular malignancy in adults and is highly metastatic, resulting in a poor patient prognosis. Sphingolipid metabolism plays an important role in tumor development, diagnosis, and prognosis. This study aimed to establish a reliable signature based on sphingolipid metabolism genes (SMGs), thus providing a new perspective for assessing immunotherapy response and prognosis in patients with UVM.MethodsIn this study, SMGs were used to classify UVM from the TCGA-UVM and GEO cohorts. Genes significantly associated with prognosis in UVM patients were screened using univariate cox regression analysis. The most significantly characterized genes were obtained by machine learning, and 4-SMGs prognosis signature was constructed by stepwise multifactorial cox. External validation was performed in the GSE84976 cohort. The level of immune infiltration of 4-SMGs in high- and low-risk patients was analyzed by platforms such as CIBERSORT. The prediction of 4-SMGs on immunotherapy and immune checkpoint blockade (ICB) response in UVM patients was assessed by ImmuCellAI and TIP portals.Results4-SMGs were considered to be strongly associated with the prognosis of UVM and were good predictors of UVM prognosis. Multivariate analysis found that the model was an independent predictor of UVM, with patients in the low-risk group having higher overall survival than those in the high-risk group. The nomogram constructed from clinical characteristics and risk scores had good prognostic power. The high-risk group showed better results when receiving immunotherapy.Conclusions4-SMGs signature and nomogram showed excellent predictive performance and provided a new perspective for assessing pre-immune efficacy, which will facilitate future precision immuno-oncology studies

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Molecular Mechanism of Calcium Release Activation and Termination

It is now well established that sarcoplasmic reticulum (SR) Ca2+ release in cardiac muscle is triggered via a mechanism termed Ca2+-induced Ca2+ release (CICR). It is unknown, however, how the SR Ca2+ release is terminated. The overall objective of the current study is to understand the mechanisms of activation and termination of SR Ca2+ release mediated by the cardiac ryanodine receptor (RyR2) and their roles in the pathogenesis of cardiac disease. A simple HEK293 cell expression system was established to assess the impact of RyR2 mutations on both Ca2+ release activation and termination. We found that mutations in the pore-forming region of RyR2 affected either the activation or the termination of Ca2+ release or both, indicating that the pore-forming region is a major determinant of Ca2+ release termination. Two additional regions, the N-terminal region and the calmodulin binding domain (CaMBD) of RyR2, were also found to be important for the termination of Ca2+ release. These results demonstrate that RyR2 itself controls the termination of Ca2+ release. RyR2 and its numerous modulators together form a macromolecular complex. Whether these modulators regulate the activation or termination of Ca2+ release is largely unknown. Our results show that both the 12.6 kDa FK506 binding protein (FKBP12.6) and calmodulin (CaM) facilitate the termination of Ca2+ release, but have little effect on Ca2+ release activation. On the other hand, cytosolic Ca2+ affects both the activation and termination of Ca2+ release, whereas CaM-dependent protein kinase II (CaMKII) only alters the activation of Ca2+ release. These data indicate that Ca2+ release termination is a common target of RyR2 regulation. RyR2 modulators are believed to exert their impact on channel function by inducing conformational changes in the channel, but these ligand-induced conformational changes and their functional correlation have yet to be demonstrated. Using a novel fluorescence resonance energy transfer (FRET)-based conformational probe, we assessed conformational changes in the “clamp” region near the corners of the square-shaped three-dimensional structure of RyR2 upon activation by a number of ligands. Our data demonstrate that conformational changes in the clamp region of RyR2 are ligand dependent, and suggest that RyR2 possesses multiple ligand-dependent gating mechanisms associated with distinct conformational changes. Enhanced luminal Ca2+ activation has been recognized as a common defect of RyR2 mutations linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). However, why some CPVT mutations are also associated with cardiomyopathies is unknown. Single cell luminal Ca2+ imaging revealed that RyR2 mutations that are associated with dilated cardiomyopathy (DCM) or arrhythmogenic right ventricular dysplasia type 2 (ARVD2) markedly reduced the threshold for Ca2+ release termination and increased the fractional Ca2+ release. In contrast, a RyR2 mutation associated with hypertrophic cardiomyopathy (HCM) increased the threshold for Ca2+ release termination and reduced the fractional Ca2+ release. These results provide the first evidence that abnormal fractional Ca2+ release attributable to aberrant termination of Ca2+ release is a common defect in RyR2-associated cardiomyopathies. Overall, these findings provide novel and important insights into the molecular basis and regulation of Ca2+ release activation and termination, and their roles in the genesis of cardiac arrhythmias and cardiomyopathies.2 year