G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

BACKGROUND: G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. METHODS AND RESULTS: CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. CONCLUSIONS: Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Appropriateness of Ketoanalogues of Amino Acids, Calcium Citrate, and Inulin Supplementation for CKD Management: A RAND/UCLA Consensus.

BACKGROUND: Current treatment for chronic kidney disease (CKD) focuses on improving manifestations and delaying progression. Nutritional approaches play a crucial role in CKD management, and various supplements have become available. Ketoanalogues of amino acids (KAs), calcium citrate, and inulin have been proposed as suitable supplements, yet their widespread use has been limited due to insufficient evidence. This study aimed to generate general guidance statements on the appropriateness of these supplements through a RAND/UCLA consensus process. METHODS: A RAND/UCLA consensus panel was convened to evaluate the appropriateness of these supplements in different clinical scenarios. In this study, we present a subgroup analysis focusing on a panel of eleven clinical nephrologists from among the experts. RESULTS: Supplementation of low-protein diets (LPDs) and very low-protein diets (VLPDs) with KA was considered appropriate to reduce manifestations and delay CKD outcomes, supplementation with calcium citrate is considered appropriate to reduce CKD manifestations, and supplementation with inulin is considered appropriate to delay CKD outcomes and manage comorbidities. CONCLUSIONS: Based on a combination of clinical experience and scientific evidence, the panel reached a consensus that KA supplementation of LPD and VLPD, calcium citrate, and inulin are appropriate in patients with CKD across various scenarios.

Social media impact on students' decision-making regarding aesthetic dental treatments based on cross-sectional survey data.

This study investigated the influence of social media on patients regarding aesthetic dental treatments according to sex, type of treatment, and time since their last treatment. A cross-sectional study was conducted using a web-based survey. Participants were students over 18 years of age who were social media users and had undergone aesthetic dental treatment. 504 responses were included. Data evaluation was made using Pearson chi-square test. The level of significance was set at p < .05. 29.37% of the respondents indicated that social media influenced their decision to have their aesthetic treatment. Regarding the influence of social media, no differences were observed between males and females, nor by type of aesthetic treatment. Participants who had undergone an aesthetic dental treatment within the last year were more influenced by social media than those who had undergone it more than two years ago. Posts from dental clinics or dentists were the type of content that most influenced participants. Social media can influence some patients' decision to undergo aesthetic dental treatment, thus dental practices and dentists should consider the increasing importance of social media in their daily practice.

Neutrophil-to-Lymphocyte Ratio and Cytokine Profiling as Predictors of Disease Severity and Survival in Unvaccinated COVID-19 Patients.

BACKGROUND: During the COVID-19 pandemic, identifying reliable biomarkers for predicting disease severity and patient outcomes in unvaccinated individuals is essential. This study evaluates the efficacy of key hematological markers, including leukocyte and neutrophil counts, Neutrophil-to-Lymphocyte Ratio (NLR), and cytokine profiles (IL-6, INF-γ, TNF-α, IL-17A, CCL2, and CXCL10) for predicting the necessity for mechanical ventilation and assessing survival probabilities. METHODS: We conducted an in-depth analysis on a cohort of COVID-19 patients, emphasizing the relationship between NLR, cytokine profiles, and clinical outcomes, utilizing routine leukocyte counting and cytokine quantification by flow cytometry. RESULTS: Elevated leukocyte and neutrophil counts, increased NLR, and significant cytokine elevations such as IL-6 and IL-10 were strongly associated with the need for mechanical ventilation, reflecting a pronounced systemic inflammatory response indicative of severe disease outcomes. CONCLUSION: Integrating hematological markers, particularly NLR and cytokine profiles, is crucial in predicting mechanical ventilation needs and survival in non-vaccinated COVID-19 patients. Our findings provide critical insights into the pathophysiology of COVID-19, supporting the development of more targeted clinical interventions and potentially informing future strategies for managing infectious disease outbreaks.

Understanding the role of B cells in CAR T-cell therapy in leukemia through a mathematical model.

Chimeric antigen receptor T (CAR T) cell therapy has been proven to be successful against a variety of leukemias and lymphomas. This paper undertakes an analytical and numerical study of a mathematical model describing the competition of CAR T, leukemia, tumor, and B cells. Considering its significance in sustaining anti-CD19 CAR T-cell stimulation, a B-cell source term is integrated into the model. Through stability and bifurcation analyses, the potential for tumor eradication, contingent on the continuous influx of B cells, has been revealed, showing a transcritical bifurcation at a critical B-cell input. Additionally, an almost heteroclinic cycle between equilibrium points is identified, providing a theoretical basis for understanding disease relapse. Analyzing the oscillatory behavior of the system, the time-dependent dynamics of CAR T cells and leukemic cells can be approximated, shedding light on the impact of initial tumor burden on therapeutic outcomes. In conclusion, the study provides insights into CAR T-cell therapy dynamics for acute lymphoblastic leukemias, offering a theoretical foundation for clinical observations and suggesting avenues for future immunotherapy modeling research.

Morphological MRI features as prognostic indicators in brain metastases.

BACKGROUND: Stereotactic radiotherapy is the preferred treatment for managing patients with fewer than five brain metastases (BMs). However, some lesions recur after irradiation. The purpose of this study was to identify patients who are at a higher risk of failure, which can help in adjusting treatments and preventing recurrence. METHODS: In this retrospective multicenter study, we analyzed the predictive significance of a set of interpretable morphological features derived from contrast-enhanced (CE) T1-weighted MR images as imaging biomarkers using Kaplan-Meier analysis. The feature sets studied included the total and necrotic volumes, the surface regularity and the CE rim width. Additionally, we evaluated other nonmorphological variables and performed multivariate Cox analysis. RESULTS: A total of 183 lesions in 128 patients were included (median age 61 [31-95], 64 men and 64 women) treated with stereotactic radiotherapy (57% single fraction, 43% fractionated radiotherapy). None of the studied variables measured at diagnosis were found to have prognostic value. However, the total and necrotic volumes and the CE rim width measured at the first follow-up after treatment and the change in volume due to irradiation can be used as imaging biomarkers for recurrence. The optimal classification was achieved by combining the changes in tumor volume before and after treatment with the presence or absence of necrosis (p < < 0.001). CONCLUSION: This study demonstrated the prognostic significance of interpretable morphological features extracted from routine clinical MR images following irradiation in brain metastases, offering valuable insights for personalized treatment strategies.

The Role and Applications of Artificial Intelligence in Dental Implant Planning: A Systematic Review.

Artificial intelligence (AI) is revolutionizing dentistry, offering new opportunities to improve the precision and efficiency of implantology. This literature review aims to evaluate the current evidence on the use of AI in implant planning assessment. The analysis was conducted through PubMed and Scopus search engines, using a combination of relevant keywords, including "artificial intelligence implantology", "AI implant planning", "AI dental implant", and "implantology artificial intelligence". Selected articles were carefully reviewed to identify studies reporting data on the effectiveness of AI in implant planning. The results of the literature review indicate a growing interest in the application of AI in implant planning, with evidence suggesting an improvement in precision and predictability compared to traditional methods. The summary of the obtained findings by the included studies represents the latest AI developments in implant planning, demonstrating its application for the automated detection of bones, the maxillary sinus, neuronal structure, and teeth. However, some disadvantages were also identified, including the need for high-quality training data and the lack of standardization in protocols. In conclusion, the use of AI in implant planning presents promising prospects for improving clinical outcomes and optimizing patient management. However, further research is needed to fully understand its potential and address the challenges associated with its implementation in clinical practice.

Growth dynamics of lung nodules: implications for classification in lung cancer screening.

BACKGROUND: Lung nodules observed in cancer screening are believed to grow exponentially, and their associated volume doubling time (VDT) has been proposed for nodule classification. This retrospective study aimed to elucidate the growth dynamics of lung nodules and determine the best classification as either benign or malignant. METHODS: Data were analyzed from 180 participants (73.7% male) enrolled in the I-ELCAP screening program (140 primary lung cancer and 40 benign) with three or more annual CT examinations before resection. Attenuation, volume, mass and growth patterns (decelerated, linear, subexponential, exponential and accelerated) were assessed and compared as classification methods. RESULTS: Most lung cancers (83/140) and few benign nodules (11/40) exhibited an accelerated, faster than exponential, growth pattern. Half (50%) of the benign nodules versus 26.4% of the malignant ones displayed decelerated growth. Differences in growth patterns allowed nodule malignancy to be classified, the most effective individual variable being the increase in volume between two-year-interval scans (ROC-AUC = 0.871). The same metric on the first two follow-ups yielded an AUC value of 0.769. Further classification into solid, part-solid or non-solid, improved results (ROC-AUC of 0.813 in the first year and 0.897 in the second year). CONCLUSIONS: In our dataset, most lung cancers exhibited accelerated growth in contrast to their benign counterparts. A measure of volumetric growth allowed discrimination between benign and malignant nodules. Its classification power increased when adding information on nodule compactness. The combination of these two meaningful and easily obtained variables could be used to assess malignancy of lung cancer nodules.