Sustained intestinal epithelial monolayer wound closure after transient application of a FAK-activating small molecule.

M64HCl, which has drug-like properties, is a water-soluble Focal Adhesion Kinase (FAK) activator that promotes murine mucosal healing after ischemic or NSAID-induced injury. Since M64HCl has a short plasma half-life in vivo (less than two hours), it has been administered as a continuous infusion with osmotic minipumps in previous animal studies. However, the effects of more transient exposure to M64HCl on monolayer wound closure remained unclear. Herein, we compared the effects of shorter M64HCl treatment in vitro to continuous treatment for 24 hours on monolayer wound closure. We then investigated how long FAK activation and downstream ERK1/2 activation persist after two hours of M64HCl treatment in Caco-2 cells. M64HCl concentrations immediately after washing measured by mass spectrometry confirmed that M64HCl had been completely removed from the medium while intracellular concentrations had been reduced by 95%. Three-hour and four-hour M64HCl (100 nM) treatment promoted epithelial sheet migration over 24 hours similar to continuous 24-hour exposure. 100nM M64HCl did not increase cell number. Exposing cells twice with 2-hr exposures of M64HCl during a 24-hour period had a similar effect. Both FAK inhibitor PF-573228 (10 µM) and ERK kinase (MEK) inhibitor PD98059 (20 µM) reduced basal wound closure in the absence of M64HCl, and each completely prevented any stimulation of wound closure by M64HCl. Rho kinase inhibitor Y-27632 (20 µM) stimulated Caco-2 monolayer wound closure but no further increase was seen with M64HCl in the presence of Y-27632. M64HCl (100 nM) treatment for 3 hours stimulated Rho kinase activity. M64HCl decreased F-actin in Caco-2 cells. Furthermore, a two-hour treatment with M64HCl (100 nM) stimulated sustained FAK activation and ERK1/2 activation for up to 16 and hours 24 hours, respectively. These results suggest that transient M64HCl treatment promotes prolonged intestinal epithelial monolayer wound closure by stimulating sustained activation of the FAK/ERK1/2 pathway. Such molecules may be useful to promote gastrointestinal mucosal repair even with a relatively short half-life.

Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+ progenitors.

AIMS/HYPOTHESIS: Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6. METHODS: We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs). RESULTS: RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets. CONCLUSIONS/INTERPRETATION: These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes. DATA AVAILABILITY: RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).

In-vitro cytotoxicity of biosynthesized nanoceria using Eucalyptus camaldulensis leaves extract against MCF-7 breast cancer cell line.

Cerium oxide nanoparticles possess unique properties that make them promising candidates in various fields, including cancer treatment. Among the proposed synthesis methods for CNPs, biosynthesis using natural extracts, offers an eco-friendly and convenient approach for producing CNPs, particularly for biomedical applications. In this study, a novel method of biosynthesis using the aqueous extract of Eucalyptus camaldulensis leaves was used to synthesize CNPs. Scanning electron microscopy and Transmission electron microscopy (TEM) techniques revealed that the synthesized CNPs exhibit a flower-like morphology. The particle size of CNPs obtained using Powder X-ray diffraction peaks and TEM as 13.43 and 39.25 nm. Energy-dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy confirmed the effect of biomolecules during the synthesis process and the formation of CNPs. The cytotoxicity of biosynthesized samples was evaluated using the MTT method demonstrating the potential of these samples to inhibit MCF-7 cancerous cells. The viability of the MCF-7 cell line conducted by live/dead imaging assay confirmed the MTT cytotoxicity method and indicated their potential to inhibit cancerous cells. Furthermore, the successful uptake of CNPs by MCF-7 cancer cells, as demonstrated by confocal microscopy, provides evidence that the intracellular pathway contributes to the anticancer activity of the CNPs. In general, results indicate that the biosynthesized CNPs exhibit significant cytotoxicity against the MCF-7 cancerous cell line, attributed to their high surface area.

Analysis of potential genes, immunological and antioxidant profiles associated with trypanosomiasis susceptibility in dromedary camels.

Trypanosomiasis is associated with tissue damage and may trigger an immunological response. These tissue lesions are linked to metabolic issues and oxidative stress. The current study aimed to investigate the immunological, antioxidant, and metabolic changes that may be connected to camel trypanosomiasis. Blood samples were collected from 54 camels and allocated into two groups: The control group (35 camels) and the infected group (19 camels). The genes TLR2, TLR5, IL-17, MARCHF3, RASGRP1, EPS15L1, PPIE, ASB16, CMPK2, LPCAT1, FPGT, GPHN, TNNI3K, DIO3, keap1, and OXSR1 were significantly up-regulated in trypanosomiasis camels. However, down-regulation was observed for the genes Nrf2, PRDX6, and NDUFS5. PCR-DNA sequencing was used to identify nucleotide sequence polymorphisms in the immune (TLR2, TLR5, IL-17, MARCHF3, RASGRP1, and EPS15L1), metabolic (PPIE, ASB16, CMPK2, LPCAT1, FPGT, GPHN, TNNI3K, and DIO3), and antioxidant (Nrf2, Keap1, PRDX6, NDUFS5, and OXSR1) genes between healthy and trypanosomiasis-affected camels. Exploring the serum profile also showed a significant (P ˂ 0.05) increase in Hp, SAA, Cp, IL-1ß, IL-6, IL 10, TNF-α, and MDA, with significant (P ˂ 0.05) reduction in the serum levels of CAT, SOD, GSH, T3, and T4 in diseased camels compared with healthy ones. Our findings confirm the significance of nucleotide variations, gene expression patterns, and the biochemical profile of the investigated markers as indicators for the susceptibility of trypanosomiasis in dromedary camels and may be utilized to create management strategies.

Aflibercept or ranibizumab for diabetic macular edema.

Background: Vascular endothelial growth factor (VEGF) is the primary substance involved in retinal barrier breach. VEGF overexpression may cause diabetic macular edema (DME). Laser photocoagulation of the macula is the standard treatment for DME; however, recently, intravitreal anti-VEGF injections have surpassed laser treatment. Our aim was to evaluate the efficacy of intravitreal injections of aflibercept or ranibizumab for managing treatment-naive DME. Methods: This single-center, retrospective, interventional, comparative study included eyes with visual impairment due to treatment-naive DME that underwent intravitreal injection of either aflibercept 2 mg/0.05 mL or ranibizumab 0.5 mg/0.05 mL at Al-Azhar University Hospitals, Egypt between March 2023 and January 2024. Demographic data and full ophthalmological examination results at baseline and 1, 3, and 6 months post-injection were collected, including the best-corrected distance visual acuity (BCDVA) in logarithm of the minimum angle of resolution (logMAR) notation, slit-lamp biomicroscopy, dilated fundoscopy, and central subfield thickness (CST) measured using spectral-domain optical coherence tomography. Results: Overall, the 96 eyes of 96 patients with a median (interquartile range [IQR]) age of 57 (10) (range: 20-74) years and a male-to-female ratio of 1:2.7 were allocated to one of two groups with comparable age, sex, diabetes mellitus duration, and presence of other comorbidities (all P >0.05). There was no statistically significant difference in baseline diabetic retinopathy status or DME type between groups (both P >0.05). In both groups, the median (IQR) BCDVA significantly improved from 0.7 (0.8) logMAR at baseline to 0.4 (0.1) logMAR at 6 months post-injection (both P = 0.001), with no statistically significant difference between groups at all follow-up visits (all P >0.05). The median (IQR) CST significantly decreased in the aflibercept group from 347 (166) µm at baseline to 180 (233) µm at 6 months post-injection, and it decreased in the ranibizumab group from 360 (180) µm at baseline to 190 (224) µm at 6 months post-injection (both P = 0.001), with no statistically significant differences between groups at all follow-up visits (all P >0.05). No serious adverse effects were documented in either group. Conclusions: Ranibizumab and aflibercept were equally effective in achieving the desired anatomical and functional results in patients with treatment-naïve DME in short-term follow-up without significant differences in injection counts between both drugs. Larger prospective, randomized, double-blinded trials with longer follow-up periods are needed to confirm our preliminary results.

Numerical analysis of the impact of winding angles on the mechanical performance of filament wound type 4 composite pressure vessels for compressed hydrogen gas storage.

Transportation relies heavily on petroleum products, forcing the adoption of alternative energy sources like hydrogen. Hydrogen is considered the cleanest fuel for the twenty-first century due to its water-based combustion and no CO2 emissions. However, challenges persist in production, utilization, and storage; employing composite material-based high-pressure storage vessels is increasing in the hydrogen storage sector. The paper analyzes the impact of the winding angles on the mechanical performance of the filament wound Type 4 composite pressure vessels (CPVs) for compressed hydrogen gas storage at 70 MPa. This work examines the individual winding angles and combined angles winding patterns to promote the efficiency of Type 4 CPVs by achieving maximum burst pressure, ensuring safe burst mode, and reducing CPV weight by applying maximum principal stress theory with the aid of the Ansys ACP Prep/Post and static modules. The weight and burst pressure of CPVs are significantly influenced by fiber orientation; a combination of positive and negative helical winding angles promotes higher burst pressure at a lower weight. A hoop angle and intermediate helical angles can be combined to create high-efficiency CPVs that provide mechanical performance comparable to that of a combination of high and low helical angles. Finally, a one-factor-at-a-time (OAT) sensitivity analysis was performed to determine how the winding angle and the thicknesses of layers affect the CPVs' performance. It was found that the performance of the CPVs is significantly influenced by the thicknesses of the wound layers.

Experimental investigation of multi-step airfoils in low Reynolds numbers applications.

This study provides a detailed analysis of the aerodynamic performance of various airfoil configurations, focusing on lift coefficient, stall characteristics, and maximum lift-to-drag ratio. The investigation includes the NACA23012C profile and configurations with different step geometries, ranging from one-step to five-step designs. Experimental measurements were conducted using a well-equipped aerodynamic laboratory, Institute of Aviation Engineering and Technology (IAET), Giza, Egypt. The lab features a wind tunnel, propeller test rig, and data acquisition system. The experiments were conducted meticulously to ensure accuracy and reproducibility, with a standardized method employed for uncertainty analysis. The results reveal distinct aerodynamic behaviors among the different configurations, highlighting the significant impact of design variations on aerodynamic performance. Notably, the three-step configuration consistently exhibited high performance, with a competitive or superior lift coefficient across a range of Reynolds numbers, showing an improvement of up to 35.1 %. Similarly, the four-step configuration demonstrated substantial increases in lift-to-drag ratios, reaching up to 53.2 %, while the five-step configuration exhibited varying trends with a minimum drag coefficient. The study also investigated stall characteristics and sensitivity to Reynolds numbers, revealing the complex trade-offs inherent in airfoil design. The findings provide valuable insights into optimizing airfoil performance under different operational conditions. Additionally, the adoption of two and three stepped airfoils resulted in significant reductions in blade material and associated costs for turbine blades.

Generation of nine induced pluripotent stem cell lines from six young children with autism spectrum disorder and three matched control subjects from the Qatari population.

Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we recruited nine Qatari children of Arab ethnicity (males, aged 2-4 years), including six ASD subjects (n = 3 mild-to-moderate ASD and n = 3 severe ASD) and three control subjects. We generated induced pluripotent stem cell (iPSC) lines from PBMC samples of these subjects using non-integrating Sendai viral vectors. These iPSC lines were fully characterized and exhibited pluripotency characteristics, normal karyotypes, and trilineage differentiation potential. These iPSC lines provide valuable cell models for understanding ASD pathophysiology and developing new therapeutics for ASD.

Identifying miRNA Signatures Associated with Pancreatic Islet Dysfunction in a FOXA2-Deficient iPSC Model.

The pathogenesis of diabetes involves complex changes in the expression profiles of mRNA and non-coding RNAs within pancreatic islet cells. Recent progress in induced pluripotent stem cell (iPSC) technology have allowed the modeling of diabetes-associated genes. Our recent study using FOXA2-deficient human iPSC models has highlighted an essential role for FOXA2 in the development of human pancreas. Here, we aimed to provide further insights on the role of microRNAs (miRNAs) by studying the miRNA-mRNA regulatory networks in iPSC-derived islets lacking the FOXA2 gene. Consistent with our previous findings, the absence of FOXA2 significantly downregulated the expression of islet hormones, INS, and GCG, alongside other key developmental genes in pancreatic islets. Concordantly, RNA-Seq analysis showed significant downregulation of genes related to pancreatic development and upregulation of genes associated with nervous system development and lipid metabolic pathways. Furthermore, the absence of FOXA2 in iPSC-derived pancreatic islets resulted in significant alterations in miRNA expression, with 61 miRNAs upregulated and 99 downregulated. The upregulated miRNAs targeted crucial genes involved in diabetes and pancreatic islet cell development. In contrary, the absence of FOXA2 in islets showed a network of downregulated miRNAs targeting genes related to nervous system development and lipid metabolism. These findings highlight the impact of FOXA2 absence on pancreatic islet development and suggesting intricate miRNA-mRNA regulatory networks affecting pancreatic islet cell development.

Mortality and Morbidity in Adults With Rheumatic Heart Disease.

Importance: Rheumatic heart disease (RHD) remains a public health issue in low- and middle-income countries (LMICs). However, there are few large studies enrolling individuals from multiple endemic countries. Objective: To assess the risk and predictors of major patient-important clinical outcomes in patients with clinical RHD. Design, Setting, and Participants: Multicenter, hospital-based, prospective observational study including 138 sites in 24 RHD-endemic LMICs. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were cause-specific mortality, heart failure (HF) hospitalization, stroke, recurrent rheumatic fever, and infective endocarditis. This study analyzed event rates by World Bank country income groups and determined the predictors of mortality using multivariable Cox models. Results: Between August 2016 and May 2022, a total of 13 696 patients were enrolled. The mean age was 43.2 years and 72% were women. Data on vital status were available for 12 967 participants (94.7%) at the end of follow-up. Over a median duration of 3.2 years (41 478 patient-years), 1943 patients died (15% overall; 4.7% per patient-year). Most deaths were due to vascular causes (1312 [67.5%]), mainly HF or sudden cardiac death. The number of patients undergoing valve surgery (604 [4.4%]) and HF hospitalization (2% per year) was low. Strokes were infrequent (0.6% per year) and recurrent rheumatic fever was rare. Markers of severe valve disease, such as congestive HF (HR, 1.58 [95% CI, 1.50-1.87]; P < .001), pulmonary hypertension (HR, 1.52 [95% CI, 1.37-1.69]; P < .001), and atrial fibrillation (HR, 1.30 [95% CI, 1.15-1.46]; P < .001) were associated with increased mortality. Treatment with surgery (HR, 0.23 [95% CI, 0.12-0.44]; P < .001) or valvuloplasty (HR, 0.24 [95% CI, 0.06-0.95]; P = .042) were associated with lower mortality. Higher country income level was associated with lower mortality after adjustment for patient-level factors. Conclusions and Relevance: Mortality in RHD is high and is correlated with the severity of valve disease. Valve surgery and valvuloplasty were associated with substantially lower mortality. Study findings suggest a greater need to improve access to surgical and interventional care, in addition to the current approaches focused on antibiotic prophylaxis and anticoagulation.

Study of plasmid mediated quinolone resistance genes among Escherichia coli and Klebsiella pneumoniae isolated from pediatric patients with sepsis.

The resistance to antibiotics in Gram-negative bacilli causing sepsis is a warning sign of failure of therapy. Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) represent major Gram-negative bacilli associated with sepsis. Quinolone resistance is an emerging resistance among E. coli and K. pneumoniae. Therefore, the present study aimed to study the presence of plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, and qnrS by polymerase chain reaction (PCR) in E. coli and K. pneumoniae isolated from pediatric patients with sepsis. This was a retrospective cross-sectional study that included pediatric patients with healthcare-associated sepsis. The E. coli and K. pneumoniae isolates were identified by microbiological methods. PMQR genes namely qnrA, qnrB, and qnrS were detected in E. coli and K. pneumoniae isolates by PCR. The results were analyzed by SPPS24, and the qualitative data was analyzed as numbers and percentages and comparison was performed by Chi-square test, P was significant if < 0.05. The most prevalent gene detected by PCR was qnrA (75%), followed by qnrB (28.1%), and qnrS (25%). The most frequently detected qnr gene in E coli and K. pneumoniae was qnrA (28.8%, and 16.3% respectively). The present study highlights the high prevalence of ciprofloxacin resistance among E. coli and K. pneumoniae isolated from pediatric patients with healthcare-associated sepsis. There was a high frequency of PMQR genes in E. coli and K. pneumoniae isolated from pediatric patients. Therefore, it is important to monitor the spread of PMQR genes in clinical isolates to ensure efficient antibiotic use in those children. The finding denotes the importance of an antibiotics surveillance program.

Outcomes of Implant Exchange and Latissimus Dorsi Flap Replacement After Breast Implant Complications.

BACKGROUND: Immediate action is required to address some complications of implant-based reconstruction after mastectomy to prevent reconstruction failure. Implant exchange may be simple but poses the risk of further complications while autologous flap reconstruction seems more complex but may pose less subsequent risk. Which of these is preferable remains unclear. METHODS: We reviewed thirty-two female breast cancer patients who had serious complications with their breast implants after post-mastectomy reconstruction. Latissimus dorsi flap (LDF) patients underwent explantation and immediate reconstruction with an LDF, while implant exchange (IE) patients underwent immediate implant removal and exchange with an expander followed by delayed reconstruction with silicon or immediately with a smaller size silicone implant. RESULTS: LDF patients underwent a single operation with an average duration of care of 31 days compared to an average 1.8 procedures (p= 0.005) with an average duration of care of 129.9 days (p < 0.001) among IE patients. Seven IE (50%) had serious complications that required subsequent revision while no LDF patients required additional procedures. Patient overall satisfaction and esthetics results were also superior in the LDF group at six months. CONCLUSION: In patients who want to reconstructively rescue and salvage their severely infected or exposed breast implant, the LDF offers an entirely autologous solution. LDF reconstruction in this setting allows patients to avoid an extended duration of care, reduces their risk of complications, and preserves the reconstructive process. LEVEL OF EVIDENCE III: The journal asks authors to assign a level of evidence to each article. For a complete description of Evidence-Based Medicine ratings, see the Table of Contents or the online Instructions for Authors at www.springer.com/00266 .

Crystal structures, electron spin resonance, and thermogravimetric analysis of three mixed-valence copper cyanide polymers.

The crystal structures of three mixed-valence copper cyanide alkanolamine polymers are presented, together with thermogravimetric analysis (TGA) and electron spin resonance (ESR) data. In all three structures, a CuII moiety on a crystallographic center of symmetry is coordinated by two alkanolamines and links two CuICN chains via cyanide bridging groups to form diperiodic sheets. The sheets are linked together by cuprophilic CuI-CuI interactions to form a three-dimensional network. In poly[bis(µ-3-aminopropanolato)tetra-µ-cyanido-dicopper(I)dicopper(II)], [Cu4(CN)4(C3H8NO)2]n, 1, propanolamine bases have lost their hydroxyl H atoms and coordinate as chelates to two CuII atoms to form a dimeric CuII moiety bridged by the O atoms of the bases with CuII atoms in square-planar coordination. The ESR spectrum is very broad, indicating exchange between the two CuII centers. In poly[bis(2-aminopropanol)tetra-µ-cyanido-dicopper(I)copper(II)], [Cu3(CN)4(C3H9NO)2]n, 2, and poly[bis(2-aminoethanol)tetra-µ-cyanido-dicopper(I)copper(II)], [Cu3(CN)4(CH7NO)2]n, 3, a single CuII atom links the CuICN chains together via CN bridges. The chelating alkanolamines are not ionized, and the OH groups form rather long bonds in the axial positions of the octahedrally coordinated CuII atoms. The coordination geometries of CuII in 2 and 3 are almost identical, except that the Cu-O distances are longer in 2 than in 3, which may explain their somewhat different ESR spectra. Thermal decomposition in 2 and 3, but not in 1, begins with the loss of HCN(g), and this can be correlated with the presence of OH protons on the ligands in 2 and 3, which are not present in 1.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case­control study

BACKGROUND Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. METHODS The INTERSTROKE study is a case­control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). FINDINGS Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46­1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61­2.11) than ICH (OR 1.19 95% CI 1.00­1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24­4.10) and PAR (18.6%, 15.1­22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63­2.87) and undetermined cause (OR 1.97, 95% CI 1.55­2.50). Both filtered (OR 1.73, 95% CI 1.50­1.99) and non-filtered (OR 2.59, 95% CI 1.79­3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69­2.27), ischemic stroke (OR 1.89, 95% CI 1.59­2.24) and ICH (OR 2.00, 95% CI 1.60­2.50). INTERPRETATION There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. FUNDING The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Molecular networking-guided investigation of the secondary metabolome of four Morus species and their in vivo neuroprotective potential for the mitigation of Alzheimer's disease.

Alzheimer's Disease (AD) is a fatal age-related neurodegenerative condition with a multifactorial etiology contributing to 70% of dementia globally. The search for a multi-target agent to hit different targets involved in the pathogenesis of AD is crucial. In the present study, the neuroprotective effects of four Morus extracts were assessed in LPS-induced AD in mice. Among the studied species, M. macroura exhibited a profound effect on alleviating the loss of cognitive function, improved the learning ability, restored the acetylcholine esterase (AChE) levels to normal, and significantly reduced the tumor necrosis factor alpha (TNF-α) brain content in LPS-treated mice. To investigate the secondary metabolome of the studied Morus species, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-HRMS/MS), aided with feature-based molecular networking, was employed. Among the annotated features, aryl benzofurans and prenylated flavonoids were suggested as being responsible for the observed neuroprotective effect. Furthermore, some of the detected metabolites were proposed as new natural products such as moranoline di-O-hexoside (1), isomers of trimethoxy-dihydrochalcone-O-dihexoside (59 & 76), (hydroxy-dimethoxyphenyl)butenone-O-hexoside (82), and O-methylpreglabridin-O-sulphate (105). In conclusion, our findings advocate the potential usage of M. macroura leaves for the management of AD, yet after considering further clinical trials.

Genetic programming expressions for effluent quality prediction: Towards AI-driven monitoring and management of wastewater treatment plants.

Continuous effluent quality prediction in wastewater treatment processes is crucial to proactively reduce the risks to the environment and human health. However, wastewater treatment is an extremely complex process controlled by several uncertain, interdependent, and sometimes poorly characterized physico-chemical-biological process parameters. In addition, there are substantial spatiotemporal variations, uncertainties, and high non-linear interactions among the water quality parameters and process variables involved in the treatment process. Such complexities hinder efficient monitoring, operation, and management of wastewater treatment plants under normal and abnormal conditions. Typical mathematical and statistical tools most often fail to capture such complex interrelationships, and therefore data-driven techniques offer an attractive solution to effectively quantify the performance of wastewater treatment plants. Although several previous studies focused on applying regression-based data-driven models (e.g., artificial neural network) to predict some wastewater treatment effluent parameters, most of these studies employed a limited number of input variables to predict only one or two parameters characterizing the effluent quality (e.g., chemical oxygen demand (COD) and/or suspended solids (SS)). Harnessing the power of Artificial Intelligence (AI), the current study proposes multi-gene genetic programming (MGGP)-based models, using a dataset obtained from an operational wastewater treatment plant, deploying membrane aerated biofilm reactor, to predict the filtrated COD, ammonia (NH4), and SS concentrations along with the carbon-to-nitrogen ratio (C/N) within the effluent. Input features included a set of process variables characterizing the influent quality (e.g., filtered COD, NH4, and SS concentrations), water physics and chemistry parameters (e.g., temperature and pH), and operation conditions (e.g., applied air pressure). The developed MGGP-based models accurately reproduced the observations of the four output variables with correlation coefficient values that ranged between 0.98 and 0.99 during training and between 0.96 and 0.99 during testing, reflecting the power of the developed models in predicting the quality of the effluent from the treatment system. Interpretability analyses were subsequently deployed to confirm the intuitive understanding of input-output interrelations and to identify the governing parameters of the treatment process. The developed MGGP-based models can facilitate the AI-driven monitoring and management of wastewater treatment plants through devising optimal rapid operation and control schemes and assisting the plants' operators in maintaining proper performance of the plants under various normal and disruptive operational conditions.

Adherence to antihypertensives in the United States: A comparative meta-analysis of 23 million patients.

Adherence to antihypertensives is crucial for control of blood pressure. This study analyzed factors and interventions that could affect adherence to antihypertensives in the US. PubMed, Scopus, Web of Science, and Embase were searched on January 21, 2022 and December 25, 2023 for studies on the adherence to antihypertensives in the US. Nineteen studies and 23 545 747 patients were included in the analysis, which showed that adherence to antihypertensives was the highest among Whites (OR: 1.47, 95% CI 1.34-1.61 compared to African Americans). Employment status and sex were associated with insignificant differences in adherence rates. In contrast, marital status yielded a significant difference where unmarried patients demonstrated low adherence rates compared to married ones (OR: 0.8, 95% CI 0.67-0.95). On analysis of comorbidities, diabetic patients reported lower adherence to antihypertensives (OR: 0.95, 95% CI 0.92-0.97); furthermore, patients who did not have Alzheimer showed higher adherence rates. Different BMIs did not significantly affect the adherence rates. Patients without insurance reported significantly lower adherence rates than insured patients (OR: 3.93, 95% CI 3.43-4.51). Polypill users had higher adherence rates compared with the free-dose combination (OR: 1.21, 95% CI 1.2-1.21), while telepharmacy did not prove to be as effective. Lower adherence rates were seen among African Americans, uninsured, or younger patients. Accordingly, interventions such as fixed-dose combinations should be targeted at susceptible groups. Obesity and overweight did not affect the adherence to antihypertensives.

Clinical and Radiographic Outcomes of Autogenous Inlay Graft vs Autogenous Onlay Graft for Anterior Maxillary Horizontal Ridge Augmentation: A Randomized Control Clinical Study.

AIM: This study aimed to compare the efficacy of autogenous onlay and inlay grafts for anterior maxillary horizontal ridge augmentation. MATERIALS AND METHODS: This randomized clinical trial was performed on 14 patients with a deficient partially edentulous anterior maxillary ridge (3-5 mm in width). Patients were randomized and grouped into two equal groups: Group A was treated with symphyseal autogenous bone block, which was placed and fixed buccally as an onlay graft, and group B: was treated with symphyseal autogenous bone block, which was interpositioned and fixed in space created between buccal and lingual cortex as inlay graft. Patients were evaluated clinically and radiographically to evaluate the increase of bone width at [Baseline, immediate postoperative (T0)] and six months post-graft (T6). RESULTS: A total of 14 patients (8 males and 6 females) with age range from 20 to 43 years old with a mean of 42.1 years were involved in our study. Radiographically, there was a significant statistical difference in comparing between two groups for the creation of a horizontal alveolar bone at T0. In the inlay group, the mean preoperative bone width was 3.9 ± 0.3 mm at T0 and 5.7 ± 0.5 mm at T6. While in the onlay group, the mean preoperative bone width was 3.7 ± 0.7 mm at T0 while at T6 the mean bone width was 6.1 ± 0.8 mm. This was statistically significant. CONCLUSION: Inlay block graft appears to be a successful treatment option for horizontal ridge augmentation in the maxillary arch. CLINICAL SIGNIFICANCE: both techniques are viable techniques for augmentation of atrophic alveolar ridge with uneventful healing. How to cite this article: Elsayed AO, Abdel-Rahman FH, Ahmed WMAS, et al. Clinical and Radiographic Outcomes of Autogenous Inlay Graft vs Autogenous Onlay Graft for Anterior Maxillary Horizontal Ridge Augmentation: A Randomized Control Clinical Study. J Contemp Dent Pract 2024;25(2):107-113.

The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.

BACKGROUND: Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates. METHODS: Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA. RESULTS: The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model. CONCLUSIONS: These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA.