Experimental and computational evaluation of anti-malarial and antioxidant potential of transition metal (II) complexes with tridentate schiff base derived from pyrrolopyrimidine.

In the twenty-first century, we are experiencing persistent waves of diverse pathogen variations, contributing significantly to global illness and death rates. Within this varied spectrum of illnesses, malaria and oxidative damage emerge as prominent obstacles that have persistently affected human health. The motivation for exploring the antioxidant potential of transition metal (II) complexes with tridentate Schiff base ligands is driven by the need for effective treatments against malaria and oxidative stress-related conditions. Both malaria and oxidative damage are significant global health concerns. Transition metal complexes can potentially offer enhanced anti-malarial and antioxidant activities, providing a dual benefit. To explore the aforementioned facts and examine the therapeutic potential, the previously synthesized pyrrolopyrimidinehydrazide-3-chlorobenzaldehyde, such as HPPHmCB ligand(1)andtheirMn(II),Fe(II),Co(II),Ni(II), Pd(II),Cu(II),Zn(II),Cd(II),Hg(II)complexes(2-10) of benzaldehydes and pyrrolopyrimidinehydrazide were proposed for in vitro anti-malarial and antioxidant investigation. These compounds were assessed for their anti-malarial efficacy against Plasmodium falciparum using a micro assay protocol, with IC50 values indicating the concentration required to inhibit parasite maturation by 50%. The Hg(II) complex displays pronounced antimalarial activity with an IC50 value of 1.98 ± 0.08 µM, closely aligning with the efficacy of quinine, whereas Zn(II), Cu(II), Pd(II) complexes demonstrates most significant anti-malarial activity, with IC50 values close to the reference compound quinine. The antioxidant activity of the compounds was evaluated using the DPPH assay, with several metal complexes such as Cu(II)and Zn(II) showing strong potential in neutralizing oxidative stress. Furthermore, molecular docking simulations were conducted to explore the binding interactions of the compounds with PfNDH2, providing insights into their pharmacological potential. The study also examined the electronic properties, solubility, and potential hepatotoxicity of the compounds. The findings suggest that the metal complexes could be promising candidates for further development as anti-malarial agents, offering enhanced potency compared to the base compound.

Cardiovascular Disease Risk Stratification Using Hybrid Deep Learning Paradigm: First of Its Kind on Canadian Trial Data.

BACKGROUND: The risk of cardiovascular disease (CVD) has traditionally been predicted via the assessment of carotid plaques. In the proposed study, AtheroEdge™ 3.0HDL (AtheroPoint™, Roseville, CA, USA) was designed to demonstrate how well the features obtained from carotid plaques determine the risk of CVD. We hypothesize that hybrid deep learning (HDL) will outperform unidirectional deep learning, bidirectional deep learning, and machine learning (ML) paradigms. METHODOLOGY: 500 people who had undergone targeted carotid B-mode ultrasonography and coronary angiography were included in the proposed study. ML feature selection was carried out using three different methods, namely principal component analysis (PCA) pooling, the chi-square test (CST), and the random forest regression (RFR) test. The unidirectional and bidirectional deep learning models were trained, and then six types of novel HDL-based models were designed for CVD risk stratification. The AtheroEdge™ 3.0HDL was scientifically validated using seen and unseen datasets while the reliability and statistical tests were conducted using CST along with p-value significance. The performance of AtheroEdge™ 3.0HDL was evaluated by measuring the p-value and area-under-the-curve for both seen and unseen data. RESULTS: The HDL system showed an improvement of 30.20% (0.954 vs. 0.702) over the ML system using the seen datasets. The ML feature extraction analysis showed 70% of common features among all three methods. The generalization of AtheroEdge™ 3.0HDL showed less than 1% (p-value < 0.001) difference between seen and unseen data, complying with regulatory standards. CONCLUSIONS: The hypothesis for AtheroEdge™ 3.0HDL was scientifically validated, and the model was tested for reliability and stability and is further adaptable clinically.

Box-Behnken design (BBD) for optimization and simulation of biolubricant production from biomass using aspen plus with techno-economic analysis.

The growing concern and limitations for existing lubricants have driven the need for biolubricants, extensively proposed as the most suitable and sustainable lubricating oils. Biolubricant refers to lubricants that quickly biodegrade and are non-toxic to humans and aquatic habitats. Over the last decade, there has been a significant increase in the production of biolubricants due to the rising demand for replacing petroleum-based lubricants with those derived from renewable sources like vegetable oils and lipase that are used in various applications. In this study biodiesel (FAME) produced from blending animal fats and waste cooking was used as a raw material with ethylene glycol for biolubricant production using a transesterification reaction in the presence of calcium oxide which considers the newest and novel part as there is no production of biolubricant from animal fats and waste cooking oil in previous researches. The reaction parameters of biolubricant production were optimized using response surface methodology (RSM) with the aid of Box Behnken Design (BBD) to study the effect of independent variables on the yield of biolubricant. These variables are temperature ranging from (100-150 °C), reaction time ranging from 1 to 4 h, and FAME (Fatty Acid Methyl Ester) to alcohol molar ratio ranging from (2:1) to (4:1). The highest biolubricant yield is 91.56% at a temperature of 141 °C, a FAME/alcohol molar ratio of 2:1, and 3.3 h. Various analyses were performed on the produced biolubricant at the optimum conditions. The results include a pour point of -9 °C, a flash point of 192 °C, a kinematic viscosity at 40 °C of 10.35 cSt, a viscosity index of 183.6, an ash content of 0.76 wt.%, and a carbon residue of 1.5 wt.%, comparing favorably with the ISO VG 10 standard. The production process of biolubricant was simulated with Aspen Plus version 11 using a Non-Random Two-Liquid (NRTL) fluid package. The simulation results indicated that the production process can be applied on an industrial scale. Economic analysis was performed on the biolubricants production plant. The total capital investment was $12.7 M with a payback period of 1.48 years and an internal rate of return (IRR) of 67.5% indicating the suitability and profitability of the biolubricant production.

Aplastic anemia in association with multiple myeloma: clinical and pathophysiological insights.

We investigated immune cytopenia in multiple myeloma (MM) patients with concurrent acquired aplastic anemia (AA), focusing on three clinical cases treated with plasma cell-directed therapy. All three patients achieved partial response in MM and one patient experienced complete resolution of AA. Two patients had partial improvement in transfusion requirement but continued to suffer from severe AA, leading to immunosuppressive therapy (IST) with improvement of transfusion requirement in both patients. In vitro serum testing of these patients demonstrated platelet mitochondrial dysfunction and platelet apoptosis but did not show sera-specific inhibition of erythroid colony formation in progenitor cells. The levels of IL8 and IL15 were elevated in MM patients with AA, implicating their potential roles in this co-occurrence. Response to IST points to the possibility of myeloma-dysregulated immune system leading to autoreactive T-cell destruction of hematopoietic stem and progenitor cells, offering insights for developing new treatment for cytopenia in MM.

Identification of potential NUDT5 inhibitors from marine bacterial natural compounds via molecular dynamics and free energy landscape analysis.

NUDIX hydrolase 5 (NUDT5) is an enzyme involved in the hydrolysis of nucleoside diphosphates linked to other moieties, such as ADP-ribose. This cofactor is vital in redox reactions and is essential for the activity of sirtuins and poly(ADP-ribose) polymerases, which are involved in DNA repair and genomic stability. It has been shown that NUDT5 activity can also influence NAD+ homeostasis, thereby affecting cancer cell metabolism and survival. In this regard, the discovery of NUDT5 inhibitors has emerged as a potential therapeutic approach in cancer treatment. In this study, we conducted a high-throughput virtual screening of marine bacterial compounds against the NUDT5 enzyme and four molecules were selected based on their docking scores. These compounds established strong interactions within the NUDT5 active site, with molecular analysis highlighting the key role of Trp28A and Trp46B residues. Molecular dynamics simulations over 200 ns indicated a stable behavior, in association with root mean square deviation values always below 3 Å, suggesting conformational stability. Free energy landscape analysis further supported their potential as NUDT5 inhibitors, offering avenues for novel therapeutic strategies against NUDT5-associated breast cancer.

Computational exploration and molecular dynamic simulation for the discovery of antiviral agents targeting Newcastle disease virus.

Newcastle disease virus (NDV) is a highly infectious viral disease that impacts birds globally, especially domestic poultry. NDV is a type of avian paramyxovirus which poses a major threat to the poultry industry due to its ability to inflict significant economic damage. The membrane protein, Hemagglutinin-Neuraminidase (HN) of NDV is an attractive therapeutic candidate. It contributes to pathogenicity through various functions, such as promoting fusion and preventing viral self-agglutination, which allows for viral spread. In this study, we used pharmacophore modeling to identify natural molecules that can inhibit the HN protein of NDV. Physicochemical characteristics and phylogenetic analysis were determined to elucidate structural information and phylogeny of target protein across different species as well as members of the virus family. For structural analysis, the missing residues of HN target protein were filled and the structure was evaluated by PROCHECK and VERIFY 3D. Moreover, shape and feature-based pharmacophore model was employed to screen natural compounds' library through numerous scoring schemes. Top 48 hits with 0.8860 pharmacophore fit score were subjected towards structure-based molecular docking. Top 9 compounds were observed witihin the range of -8.9 to -7.5 kcal/mol binding score. Five best-fitting compounds in complex with HN receptor were subjected to predict biological activity and further analysis. Top two hits were selected for MD simulations to validate binding modes and structural stability. Finally, upon scrutinization, A1 (ZINC05223166) emerges as potential HN inhibitor to treat NDV, necessitating further validation via clinical trials.

Patients' perspectives on oral decitabine/cedazuridine for the treatment of myelodysplastic syndromes/neoplasms.

Background: Hypomethylating agents (HMAs) are guideline-recommended treatment for higher-risk myelodysplastic syndromes/neoplasms (MDS). However, a prior survey of patients with MDS reported challenges with intravenous (IV) and subcutaneous (SC) HMA therapies, including pain related to treatment administration and interference with daily activities; most patients also indicated a preference to switch to an oral therapy if one were available. Objectives: This study evaluated the perspectives of US patients with MDS receiving oral decitabine/cedazuridine (DEC-C), an alternative to IV/SC HMAs. Methods: An online survey was conducted among adult patients with MDS in the United States (10 November 2022 to 5 December 2022) who had filled a prescription for oral DEC-C between 2021 and 2022. Results: A total of 150 patients completed the survey; 61% were aged ⩾60 years and 63% were male. Of these, 123 (82%) were still receiving oral DEC-C, and 27 (18%) had stopped oral DEC-C treatment. Half (50%) of patients had received oral DEC-C for ⩾6 months. The majority reported that treatment was convenient (83%) and that they were satisfied with treatment (86%). Most patients also reported very little/no interference with regular daily activities (82%), social activities (78%), and productivity (78%). When queried about negative impacts on quality of life (QOL), treatment side effects were the most commonly reported (30% of respondents). Among patients who had previously received IV/SC HMAs (n = 91), most agreed that oral DEC-C interfered less with daily life (91%) and had experienced improvement in QOL (85%) compared with previous treatment; 91% reported that oral DEC-C reduced the number of times they needed to travel to a healthcare facility. Conclusion: Survey results suggest very little/no impact on regular daily activities and improved QOL with oral DEC-C relative to IV/SC HMAs, highlighting the potential for oral DEC-C to reduce the treatment burden associated with parenteral HMA therapy.

Enhancing tomato plant immune responses to Fusarium wilt disease by red seaweed Jania sp.

The novelty of this study lies in demonstrating a new approach to control wilt diseases using Jania ethyl acetate extract. In the current investigation, the potential impacts of Jania sp. ethyl acetate extract (JE) on Tomato Fusarium oxysporum wilt (FOW) have been studied. The in vitro antifungal potential of JE against F. oxysporum (FO) was examined. GC-MS investigation of the JE revealed that, the compounds possessing fungicidal action were Phenol,2-methoxy-4-(2-propenyl)-,acetate, Eugenol, Caryophyllene oxide, Isoespintanol, Cadinene, Caryophylla-4(12),8(13)-dien-5à-ol and Copaen. Jania sp. ethyl acetate extract exhibited strong antifungal potential against FO, achieving a 20 mmzone of inhibition. In the experiment, two different methods were applied: soil irrigation (SI) and foliar application (FS) of JE. The results showed that both treatments reduced disease index present DIP by 20.83% and 33.33% respectively. The findings indicated that during FOW, proline, phenolics, and the antioxidant enzymes activity increased, while growth and photosynthetic pigments decreased. The morphological features, photosynthetic pigments, total phenol content, and antioxidant enzyme activity of infected plants improved when JE was applied through soil or foliar methods. It is interesting to note that the application of JE had a substantially less negative effect on the isozymes peroxidase and polyphenol oxidase in tomato plants, compared to FOW. These reactions differed depending on whether JE was applied foliarly or via the soil. Finally, the use of Jania sp. could be utilized commercially as an ecologically acceptable method to protect tomato plants against FOW.

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial.

BACKGROUND: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. METHODS: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). FINDINGS: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. INTERPRETATION: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. FUNDING: Celgene and Acceleron Pharma.

Mediation Analysis of Acute Carotid Stenting in Tandem Lesions: Effect on Functional Outcome in a Multicenter Registry.

BACKGROUND AND OBJECTIVES: Current evidence suggests that acute carotid artery stenting (CAS) for cervical lesions is associated with better functional outcomes in patients with acute stroke with tandem lesions (TLs) treated with endovascular therapy (EVT). However, the underlying causal pathophysiologic mechanism of this relationship compared with a non-CAS strategy remains unclear. We aimed to determine whether, and to what degree, reperfusion mediates the relationship between acute CAS and functional outcome in patients with TLs. METHODS: This subanalysis stems from a multicenter retrospective cohort study across 16 stroke centers from January 2015 to December 2020. Patients with anterior circulation TLs who underwent EVT were included. Successful reperfusion was defined as a modified Thrombolysis in Cerebral Infarction scale ≥2B by the local team at each participating center. Mediation analysis was conducted to examine the potential causal pathway in which the relationship between acute CAS and functional outcome (90-day modified Rankin Scale) is mediated by successful reperfusion. RESULTS: A total of 570 patients were included, with a median age (interquartile range) of 68 (59-76), among whom 180 (31.6%) were female. Among these patients, 354 (62.1%) underwent acute CAS and 244 (47.4%) had a favorable functional outcome. The remaining 216 (37.9%) patients were in the non-CAS group. The CAS group had significantly higher rates of successful reperfusion (91.2% vs 85.1%; p = 0.025) and favorable functional outcomes (52% vs 29%; p = 0.003) compared with the non-CAS group. Successful reperfusion was a strong predictor of functional outcome (adjusted common odds ratio [acOR] 4.88; 95% CI 2.91-8.17; p < 0.001). Successful reperfusion partially mediated the relationship between acute CAS and functional outcome, as acute CAS remained significantly associated with functional outcome after adjustment for successful reperfusion (acOR 1.89; 95% CI 1.27-2.83; p = 0.002). Successful reperfusion explained 25% (95% CI 3%-67%) of the relationship between acute CAS and functional outcome. DISCUSSION: In patients with TL undergoing EVT, successful reperfusion predicted favorable functional outcomes when CAS was performed compared with non-CAS. A considerable proportion (25%) of the treatment effect of acute CAS on functional outcome was found to be mediated by improvement of successful reperfusion rates.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Ketamine in the effective management of chronic pain, depression, and posttraumatic stress disorder for Veterans: A meta-analysis and systematic review.

Introduction: Ketamine has emerged as a promising treatment alternative for the management of chronic pain. Despite encouraging findings in civilian populations, and favourable results from trials examining its efficacy in military populations, there is still a dearth of information pointing to optimal specifications related to ketamine administration for pain, depression, and posttraumatic stress disorder (PTSD) in military populations. This meta-analysis and systematic review synthesised available evidence on the effectiveness, tolerability, and feasibility of ketamine in the management of chronic pain and mental health conditions in military populations. Methods: This review followed the Cochrane's Guide for systematic reviews of interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as frameworks for data collection and synthesis. Results: A total of 11 studies and 22 independent samples were retained for data analyses. Across samples, improvements in pain, depression, and PTSD outcomes were evident, with the use of ketamine leading to significant reductions, g = 1.76, SE = 0.19, 95% CI (1.39, 2.13), Z = 9.26, p <.001. These effect sizes were robust with moderate-to-large effects. In addition, the reductions in symptoms were observed in both active-duty and Veteran groups, and for different routes of ketamine administration, frequencies of ketamine administration, duration of ketamine treatments, dosage, study design, and allowance for concurrent treatments. Discussion: This review provides a preliminary synthesis of available evidence which suggests that ketamine may be a potential option for the treatment of depression, PTSD, and chronic pain in military populations. The viability of ketamine as an alternative treatment may be particularly impactful for those who are treatment resistant, experience chronic symptoms, and/or have exhausted conventional treatments. More research is warranted in order verify the findings presented in this review.

Optimizing open-angle glaucoma risk assessment in patients with retinal vein occlusions.

PURPOSE: To evaluate factors associated with the diagnosis of open-angle glaucoma (OAG) after a retinal vein occlusion (RVO). DESIGN: Retrospective, cross-sectional study. METHODS: Patients diagnosed with OAG after RVO were matched 2:1 with RVO patients without prior glaucoma. Logistic regression identified factors linked to OAG diagnosis. RESULTS: Of 1178 RVO patients without initial OAG, 51 (4.5%) were later diagnosed with OAG after an average of 5.5 ± 6.1 years. Screening tests for OAG were performed at a higher frequency in patients diagnosed with OAG compared with patients who never received this diagnosis (visual field [VF] testing 21.6% versus 10.8% (P = 0.073) and retinal nerve fiber layer [RNFL] imaging 52.9% versus 27.4% (P = 0.002), respectively). At the time of the first VF obtained after RVO, mean deviation averaged -10.3 dB in the affected eyes, compared with -5.0 dB in the fellow eyes (P < 0.001); in contrast, RNFL thickness was similar between eyes at the time of OAG diagnosis (72 µm versus 74 µm, P = 0.290). Predictive factors for OAG diagnosis included higher intraocular pressure (IOP) and cup-to-disc ratio (CDR) in the unaffected eye, and the absence of macular edema in the RVO-affected eye (R2 = 0.375, P < 0.001). CONCLUSIONS: OAG is a significant risk factor for RVO. Our study reveals a reciprocal relationship between RVO and the development of OAG, highlighting the need for glaucoma risk assessment in all patients with RVOs to avoid delays in diagnosis and vision loss from glaucoma.

Carotid Plaque Score is Associated with 10-year Major Adverse Cardiovascular Events in Low-Intermediate Risk Patients Referred to a General Cardiology Community Clinic.

AIMS: Atherosclerotic carotid plaque assessments have not been integrated into routine clinical practice due to the time-consuming nature of both imaging and measurements. Plaque score, Rotterdam method, is simple, quick, and only requires 4-6 B-mode ultrasound images. The aim was to assess the benefit of plaque score in a community cardiology clinic to identify patients at risk for major adverse cardiovascular events (MACE). METHODS AND RESULTS: Patients ≥40 years presenting for risk assessment were given a carotid ultrasound. Exclusions included a history of vascular disease or MACE and being >75 years. Kaplan-Meier curves and hazard ratios were performed. The left and right common carotid artery (CCA), bulb, and internal carotid artery (ICA) were given 1 point per segment if plaque present (plaque score 0 to 6). Administrative data holdings at ICES were used for 10-year event follow-up. Of 8,472 patients, 60% were females (n = 5,121). Plaque was more prevalent in males (64% vs 53.9%; P <0.0001). The 10-year MACE cumulative incidence estimate was 6.37% with 276 events (males 6.9 % vs females 6.0%; P = 0.004). Having both maximal CCA IMT <1.00 mm and plaque score = 0, was associated with less events. A plaque score <2 was associated with a low 10-year event rate (4.1%) compared to 2-4 (8.7%) and 5-6 (20%). CONCLUSION: A plaque score ≥2 can re-stratify low-intermediate risk patients to a higher risk for events. Plaque score may be used as a quick assessment in a cardiology office to guide treatment management of patients.

Acute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome.

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by diverse genetic alterations, each with distinct clinical implications. Chromosome 3 inversion (inv(3)) is a rare genetic anomaly found in approximately 1.4-1.6% of AML cases, which profoundly affects prognosis. This review explores the pathophysiology of inv(3) AML, focusing on fusion genes like GATA2::EVI1 or GATA2::MECOM. These genetic rearrangements disrupt critical cellular processes and lead to leukemia development. Current treatment modalities, including intensive chemotherapy (IC), hypomethylating agents (HMAs) combined with venetoclax, and allogeneic stem cell transplantation are discussed, highlighting outcomes achieved and their limitations. The review also addresses subgroups of inv(3) AML, describing additional mutations and their impact on treatment response. The poor prognosis associated with inv(3) AML underscores the urgent need to develop more potent therapies for this AML subtype. This comprehensive overview aims to contribute to a deeper understanding of inv(3) AML and guide future research and treatment strategies.

Enhanced Antitumor Activity by the Combination of Dasatinib and Selinexor in Chronic Myeloid Leukemia.

BACKGROUND: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. METHODS: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. RESULTS: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. CONCLUSIONS: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

Photoactivated rose bengal-doped TiO2 nanoparticles modified fifth-generation adhesive on the survival rate of Streptococcus mutants and mechanical properties of tooth-colored restorative material to carious dentin.

Assessment of the antimicrobial, micro tensile bond strength (µTBS), and degree of conversion (DC) of fifth-generation adhesive modified using photoactivated 0.5% rose bengal (RB) and photoactivated RB-doped titanium dioxide nanoparticles (TiO2NPs) in different concentrations (2% and 5%) as compared with the unmodified adhesive bonded to the carious affected dentin (CAD). Forty mandibular molars with caries progression up to the middle third of the dentin, as per the International Caries Detection and Assessment System (ICDAS) score of 4 and 5 were included. Specimens were divided into four groups based on etch and rinse adhesive (ERA) modification group 1: unmodified ERA, group 2: photoactivated 0.5% RB photosensitizer (PS) modified ERA, group 3: photoactivated RB-doped 2 wt% TiO2NPs adhesive, group 4: photoactivated RB-doped 5 wt% TiO2NPs adhesive. Followed by adhesive and composite restoration on the CAD surface. All the specimens were thermocycled and an assessment of µTBS and failure pattern analysis was performed. The antibacterial potency of RB and RB-doped TiO2NPs (2% and 5%) followed by their activation using visible light against Streptococcus mutans (S.mutans) were tested. The survival rate of S.mutans was assessed using the Kruskal-Wallis test. The analysis of µTBS involved the use of ANOVA, followed by a post-hoc Tukey honestly significant difference (HSD) multiple comparisons test. Group 1 (Unmodified ERA) (0.52 ± 0.31 CFU/mL) treated samples unveiled the highest means of bacterial survival and lowest µTBS (11.32 ± 0.63 MPa). Nevertheless, group 4: photoactivated RB-doped 5 wt% TiO2NPs adhesive displayed the lowest outcomes of S.mutans survival (0.11 ± 0.02 CFU/mL) and highest bond strength (18.76 ± 1.45 MPa). The photoactivated RB-doped 2 wt% TiO2NPs in adhesive demonstrated promising enhancements in both µTBS and antibacterial efficacy against S.mutans. However, it is noteworthy that this modification led to a decrease in the DC of the adhesive. RESEARCH HIGHLIGHTS: Unmodified ERA-treated samples unveiled the highest bacterial survival and the lowest µTBS. Photoactivated RB-doped 5 wt% TiO2NPs adhesive displayed the lowest S.mutans survival rate and highest bond strength. DC decreased with an increase in concentration of TiO2.

UltraAIGenomics: Artificial Intelligence-Based Cardiovascular Disease Risk Assessment by Fusion of Ultrasound-Based Radiomics and Genomics Features for Preventive, Personalized and Precision Medicine: A Narrative Review.

Cardiovascular disease (CVD) diagnosis and treatment are challenging since symptoms appear late in the disease's progression. Despite clinical risk scores, cardiac event prediction is inadequate, and many at-risk patients are not adequately categorised by conventional risk factors alone. Integrating genomic-based biomarkers (GBBM), specifically those found in plasma and/or serum samples, along with novel non-invasive radiomic-based biomarkers (RBBM) such as plaque area and plaque burden can improve the overall specificity of CVD risk. This review proposes two hypotheses: (i) RBBM and GBBM biomarkers have a strong correlation and can be used to detect the severity of CVD and stroke precisely, and (ii) introduces a proposed artificial intelligence (AI)-based preventive, precision, and personalized ( aiP 3 ) CVD/Stroke risk model. The PRISMA search selected 246 studies for the CVD/Stroke risk. It showed that using the RBBM and GBBM biomarkers, deep learning (DL) modelscould be used for CVD/Stroke risk stratification in the aiP 3 framework. Furthermore, we present a concise overview of platelet function, complete blood count (CBC), and diagnostic methods. As part of the AI paradigm, we discuss explainability, pruning, bias, and benchmarking against previous studies and their potential impacts. The review proposes the integration of RBBM and GBBM, an innovative solution streamlined in the DL paradigm for predicting CVD/Stroke risk in the aiP 3 framework. The combination of RBBM and GBBM introduces a powerful CVD/Stroke risk assessment paradigm. aiP 3 model signifies a promising advancement in CVD/Stroke risk assessment.

Parental Knowledge, Attitudes, and Practices Towards Pediatric Ear Infections in the Makkah Region of Saudi Arabia: A Cross-Sectional Study.

BACKGROUND:  Pediatric ear infections constitute a significant public health concern worldwide, adversely impacting children's health and well-being. Parents play a crucial role in prevention, ensuring timely healthcare access, and therefore minimizing potential complications. This study aims to assess parental knowledge, attitudes, and practices towards pediatric ear infections in Makkah region. METHODOLOGY:  A descriptive cross-sectional study was conducted among Saudi parents who were ≥18 years old and lived in Makkah region. Convenience sampling was used to recruit 319 participants through social media platforms; data were collected from June to September 2023 via an online self-administered questionnaire. The questionnaire assessed sociodemographic characteristics, along with knowledge, attitudes, and practices related to pediatric ear infections. RESULTS:  A total of 319 parents were included in the study. The majority of the participants were female 228 (71.5%), and 208 (65.2%) had a university education level. The most common age groups were 18-30 years and 31-40 years. More than half of the participants (167, 52.4%) demonstrated adequate knowledge regarding pediatric ear infections. Positive attitudes and practices were reported by 183 (57.4%) and 285 (89.3%) of participants, respectively. Adequate knowledge was significantly higher among participants with younger ages (p<0.05). It was found that having a younger age (18-30 years) was an independent predictor of good knowledge (OR: 1.26 (1.96-3.65), p=0.009) and positive practice (OR: 1.53 (1.01-2.33), p=0.045). CONCLUSION:  We found that the majority of parents in Makkah region had a good level of knowledge regarding childhood ear infections, with an overall positive attitude and practice. The study revealed that younger parents had superior knowledge and younger age was an independent predictor for good knowledge and positive attitude.