Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers.

Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 µM HePG-2, 8.04 µM PC-3 and 12.90 µM MCF-7) and 17 (IC50 = 9.98 µM HePG-2, 33.66 µM PC-3 and 14.62 µM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 µM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 µM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 µM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.

The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality.

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo C. elegans oogenesis model to determine the intrinsic properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and the Lsm protein, CAR-1. We demonstrate that MEX-3 undergoes liquid-liquid phase separation and appears to have intrinsic gel-like properties in vitro . We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. CCT and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins that are associated with de-repression of maternal mRNA. This regulatory network is essential to preserve oocyte quality, prevent infertility, and may have implications for understanding the role of hMex3 phase transitions in cancer. Significance statement: The molecular mechanisms that regulate phase transitions of oogenic RNA-binding proteins are critical to elucidate but are not fully understood.We identify novel regulators of RNA-binding protein phase transitions in maturing oocytes that are required to maintain translational repression of maternal mRNAs and oocyte quality.This study is the first to elucidate a regulatory network involving the CCT chaperonin, actin, and the ER for phase transitions of RNA-binding proteins during oogenesis. Our findings for the conserved MEX-3 protein may also be applicable to better understanding the role of hMex3 phase transitions in cancer.

Incorporation of compost and biochar enhances yield and medicinal compounds in seeds of water-stressed Trigonella foenum-graecum L. plants cultivated in saline calcareous soils.

BACKGROUND: The combination of compost and biochar (CB) plays an important role in soil restoration and mitigation strategies against drought stress in plants. In the current study, the impact of CB was determined on the characteristics of saline calcareous soil and the productivity of fenugreek (Trigonella foenum-graecum L.) plants. The field trials examined CB rates (CB0, CB10 and CB20 corresponding to 0, 10, and 20 t ha‒1, respectively) under deficit irrigation [DI0%, DI20%, and DI40% receiving 100, 80, and 60% crop evapotranspiration (ETc), respectively] conditions on growth, seed yield (SY), quality, and water productivity (WP) of fenugreek grown in saline calcareous soils. RESULTS: In general, DI negatively affected the morpho-physio-biochemical responses in plants cultivated in saline calcareous soils. However, amendments of CB10 or CB20 improved soil structure under DI conditions. This was evidenced by the decreased pH, electrical conductivity of soil extract (ECe), and bulk density but increased organic matter, macronutrient (N, P, and K) availability, water retention, and total porosity; thus, maintaining better water and nutritional status. These soil modifications improved chlorophyll, tissue water contents, cell membrane stability, photosystem II photochemical efficiency, photosynthetic performance, and nutritional homeostasis of drought-stressed plants. This was also supported by increased osmolytes, non-enzymatic, and enzymatic activities under DI conditions. Regardless of DI regimes, SY was significantly (P ≤ 0.05) improved by 40.0 and 102.5% when plants were treated with CB10 and CB20, respectively, as similarly observed for seed alkaloids (87.0, and 39.1%), trigonelline content (43.8, and 16.7%) and WP (40.9, and 104.5%) over unamended control plants. CONCLUSIONS: Overall, the application of organic amendments of CB can be a promising sustainable solution for improving saline calcareous soil properties, mitigating the negative effects of DI stress, and enhancing crop productivity in arid and semi-arid agro-climates.

Evaluation of the diagnostic utility of NCOA3, Maspin and VHL protein expression in pancreatic ductal adenocarcinoma: An immunohistochemical study.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal tumor with a high mortality rate. The distinction between PDAC and chronic pancreatitis is sometimes challenging on routine histopathological examination, highlighting the need to identify biomarkers that can facilitate this distinction. This retrospective study was conducted to evaluate the diagnostic utility of nuclear receptor co-activator 3 (NCOA3), Maspin and Von Hippel-Lindau protein (VHL) immunostaining in PDAC. Eighty cases of PDAC, 46 cases of chronic pancreatitis and 53 normal pancreatic tissue were immunohistochemically assessed using NCOA3, Maspin and VHL antibodies on sections from a tissue microarray. NCOA3, Maspin and VHL were positive in 90 %, 100 % and 35 %, of PDAC cases respectively, whereas NCOA3, Maspin and VHL expressions were positive in 3.8 %, 0 and 100 % of normal pancreatic tissue and in 15.2 %, 21.7 % and 97.8 % of chronic pancreatitis cases respectively. Significant differences were observed between PDAC and other groups regarding NCOA3, Maspin and VHL expression (p < 0.001). The H scores of NCOA3, Maspin and VHL could significantly distinguish between PDAC and normal cases with high sensitivity (90 %, 100 % and 98.75 % respectively) and specificity (100 %, 100 % and 96.23 % respectively). Similar findings were found in the distinction between PDAC and chronic pancreatitis (Sensitivity: 90 %, 95.25 % and 98.75 %; specificity: 100 %, 100 % and 93.48 % for NCOA3, Maspin and VHL respectively). In conclusion, NCOA3 and Maspin were found to be significantly expressed in PDAC compared to non-tumorous tissue while VHL was significantly expressed in non-tumorous tissue. A panel of NCOA3, Maspin and VHL could potentially distinguish PDAC from non-tumorous pancreatic tissue.

Garlic bioactive substances and their therapeutic applications for improving human health: a comprehensive review.

Garlic (Allium sativum L.) is a widely abundant spice, known for its aroma and pungent flavor. It contains several bioactive compounds and offers a wide range of health benefits to humans, including those pertaining to nutrition, physiology, and medicine. Therefore, garlic is considered as one of the most effective disease-preventive diets. Many in vitro and in vivo studies have reported the sulfur-containing compounds, allicin and ajoene, for their effective anticancer, anti-diabetic, anti-inflammatory, antioxidant, antimicrobial, immune-boosting, and cardioprotective properties. As a rich natural source of bioactive compounds, including polysaccharides, saponins, tannins, linalool, geraniol, phellandrene, ß-phellandrene, ajoene, alliin, S-allyl-mercapto cysteine, and ß-phellandrene, garlic has many therapeutic applications and may play a role in drug development against various human diseases. In the current review, garlic and its major bioactive components along with their biological function and mechanisms of action for their role in disease prevention and therapy are discussed.

24 Factorial Design Formulation Optimization and In vitro Characterization of Desloratadine Nanosuspension Prepared Using Antisolvent Precipitation.

INTRODUCTION: Desloratadine, a second-generation antihistaminic drug, is poorly watersoluble and requires amelioration of the dissolution rate to improve its pharmacokinetics properties. METHOD: This study investigated the impact of polymer, surfactant types, and concentration on the particle size, zeta potential, and dissolution efficiency of nanosuspensions formulated through the solvent antisolvent precipitation method. To optimize the delivery of Desloratadine nanosuspension, we used Minitab software and a 4-factor, 2-level full factorial design. Physicochemical properties and drug release studies were conducted to evaluate the suggested nanosuspension formulations. The optimization goals included minimizing particle size and zeta potential while maximizing dissolution efficiencies. RESULT: The selected optimal nanosuspension demonstrated favourable values, including a particle size of 478.63 ± 15.67 nm, a zeta potential of -36.24 ± 3.21 mV, and dissolution efficiencies in double distilled water and buffer of 90.29 ± 3.75 % and 93.70 ± 3.67 %, respectively. The optimized formulation was subjected to additional analysis using X-ray powder diffraction (XPRD), scanning and transmission electron microscopy (SEM and TEM), and Fourier-transform infrared spectroscopy (FTIR). CONCLUSION: The optimized nanosuspension formulation also underwent further studies under optimal lyophilization conditions, revealing the effectiveness of mannitol as a cryoprotectant at a concentration of 8%.

Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory.

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.

The clinical significance of neopterin and NT-pro BNP in chronic heart failure: a systematic review.

BACKGROUND: Biomarkers emerged as powerful adjuncts to conventional clinical care in heart failure (HF). The aim of this study is to evaluate neopterin and NT-pro BNP as diagnostic and prognostic biomarkers in HF. METHODS: A systematic search was conducted in six electronic databases from inception to July 24th, 2022. Independent reviewers screened the title, abstract and full text then data extraction and critical appraisal of included studies were performed. RESULTS: A total of eleven studies were included. Neopterin and NT-pro BNP levels were elevated in HF patients as compared to control. Moreover, within HF patients, levels of biomarkers were significantly higher in patients with advanced HF and more severe disease state. Patients who suffered cardiovascular adverse events had high levels of biomarkers. Two studies assessed the effect of treatment on biomarkers levels, showed that levels of neopterin and/or NT-pro BNP decreased with treatment. Studies confirmed the potential of relying on neopterin and NT-pro BNP as diagnostic and prognostic biomarkers in HF in addition to assessing disease severity. CONCLUSION: Biomarkers levels correlate with disease severity and could be used as diagnostic and prognostic biomarkers in HF. Further research is needed for a definitive conclusion about using these biomarkers to determine the efficacy of therapy.

Design, synthesis, antineoplastic activity of new pyrazolo[3,4-d]pyrimidine derivatives as dual CDK2/GSK3ß kinase inhibitors; molecular docking study, and ADME prediction.

In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a-h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3ß inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3ß inhibitory activity with IC50 of 0.244 and 0.128 µM, respectively, against CDK2, and IC50 of 0.317 and 0.160 µM, respectively, against GSK-3ß. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3ß downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and ß-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3ß in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells' progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in Healthy Male Volunteers.

BACKGROUND AND OBJECTIVE: Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. METHODS: A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞],  half-life (T½) and time to reach Cmax (Tmax) were calculated. RESULTS: The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. CONCLUSION: Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Robust detection and refinement of saliency identification.

Salient object detection is an increasingly popular topic in the computer vision field, particularly for images with complex backgrounds and diverse object parts. Background information is an essential factor in detecting salient objects. This paper suggests a robust and effective methodology for salient object detection. This method involves two main stages. The first stage is to produce a saliency detection map based on the dense and sparse reconstruction of image regions using a refined background dictionary. The refined background dictionary uses a boundary conductivity measurement to exclude salient object regions near the image's boundary from a background dictionary. In the second stage, the CascadePSP network is integrated to refine and correct the local boundaries of the saliency mask to highlight saliency objects more uniformly. Using six evaluation indexes, experimental outcomes conducted on three datasets show that the proposed approach performs effectively compared to the state-of-the-art methods in salient object detection, particularly in identifying the challenging salient objects located near the image's boundary. These results demonstrate the potential of the proposed framework for various computer vision applications.

Lipid Nanoparticles as a Platform for miRNA and siRNA Delivery in Hepatocellular Carcinoma.

Liver cancer is the sixth most common cancer and the fourth leading cause of death worldwide. Hepatocellular carcinoma (HCC) comprises 75-80% of liver cancer cases. Therapeutic strategies for HCC are available and have been shown to prolong survival but not treat HCC. Gene expression and regulation are responsible for the pathogenesis and progression of HCC. Altering these genetic networks can impact cellular behaviors and in turn cure HCC. Single-stranded and double-stranded non-coding ribonucleic acid known as microRNA and small interfering RNA, respectively have been investigated as possible therapeutic options. Currently, efficient delivery systems that ensure cell-specific targeting and efficient transfection into tumor cells are still under investigation. Viral vectors have been studied extensively, but immunogenicity hinders their use as delivery systems. Non-viral vectors which include inorganic, lipid, or polymeric nanoparticles are promising delivery systems. However, there are a lot of challenges during the formulation of such systems to ensure efficient and specific delivery. In vitro and in vivo studies have investigated different LNPs to deliver miRNA or siRNA. In this review, we highlight the role of LNPs as a delivery system for miRNA and siRNA in HCC in addition to the latest results achieved using this approach.

Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).

Finite element analysis of the effect of framework material and thickness on the biomechanical performance of 'All­on­Four' full-arch prosthesis.

The aim of this research was to evaluate the stress distribution in the 'All-on-Four' prosthesis and the surrounding bone, with different framework materials and thicknesses. Five frameworks (alumina, zirconia, titanium, fiberglass reinforced resin (FRR), and polyether ether ketone (PEEK)) with two thicknesses (3.5 &5.5 mm) were stimulated in this research. A vertical force of 200 N was applied on a 1 mm circular area, at the cantilever, and at the region of the incisors, simulating different mastication mechanisms. The results illustrated that the 5.5 mm framework reduced the stresses on most parts, mucosa, and bone tissues, compared to 3.5 mm.

Microbiological and molecular studies on a multidrug-resistant Pseudomonas aeruginosa from a liver transplant patient with urinary tract infection in Egypt.

BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen responsible for complicated UTIs and exhibits high antibiotic resistance, leading to increased mortality rates, especially in cases of multidrug-resistant strains. This study aimed to investigate the antibiotic susceptibility patterns and genomic characterization of XDR strains identified in end-stage liver disease patients who underwent liver transplants. METHODS: In this study, a number of 30 individuals who underwent liver transplants were registered. Ninety urine and 60 wound site swab samples were collected and processed for culturing, identification, and antimicrobial sensitivity. Extensively drug-resistant strain EMARA01 was confirmed through Sanger sequencing and was then processed for whole genome sequencing to characterize the genomic pattern. Sequencing data were processed for de novo assembly using various tools and databases, including genome annotation, serotype identification, virulence factor genes, and antimicrobial resistance gene. Pangenome analysis of randomly selected 147 reference strains and EMAR01 sequenced strain was performed using the Bacterial Pan Genome Analysis (BPGA) software. RESULTS: Of these total examined samples, nosocomial infection due to P. aeruginosa was detected in twelve patients' samples. AST analysis showed that P. aeruginosa strains exhibit resistance to tobramycin, erythromycin, and gentamicin, followed by piperacillin and ofloxacin, and no strains exhibit resistance to meropenem and imipenem. The CARD database identified 59 AMR genes similar to the EMAR01 strain genome and mostly belong to the family involved in the resistance-nodulation-cell division (RND) antibiotic efflux pump. Five genes; nalC, nalD, MexR, MexA, and MexB, exhibit resistance to 14 classes of antibiotics, while two AMR; CpxR, and OprM, exhibit resistance to 15 classes of drugs. Pangenome analysis revealed that the pan-genome remained open, suggesting the potential for acquiring accessory and unique genes. Notably, the genes predominantly involved in amino acid transport metabolism were identified using the KEGG database. CONCLUSIONS: This study provides valuable insights into the antimicrobial resistance profile, genetic features, and genomic evolution of P. aeruginosa strains causing UTIs in liver transplant patients. The findings emphasize the significance of comprehending AMR mechanisms and genetic diversity in P. aeruginosa for developing effective treatment strategies and infection control measures.

Clinical decision support systems to optimize adherence to anticoagulant guidelines in patients with atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Clinical decision support systems (CDSS) have been utilized as a low-cost intervention to improve healthcare process measures. Thus, we aim to estimate CDSS efficacy to optimize adherence to oral anticoagulant guidelines in eligible patients with atrial fibrillation (AF). METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) retrieved from PubMed, WOS, SCOPUS, EMBASE, and CENTRAL through August 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). PROSPERO ID: CRD42023471806. RESULTS: We included nine RCTs with a total of 25,573 patients. There was no significant difference, with the use of CDSS compared to routine care, in the number of patients prescribed anticoagulants (RR: 1.06, 95% CI [0.98, 1.14], P = 0.16), the number of patients prescribed antiplatelets (RR: 1.01 with 95% CI [0.97, 1.06], P = 0.59), all-cause mortality (RR: 1.19, 95% CI [0.31, 4.50], P = 0.80), major bleeding (RR: 0.84, 95% CI [0.21, 3.45], P = 0.81), and clinically relevant non-major bleeding (RR: 1.05, 95% CI [0.52, 2.16], P = 0.88). However, CDSS was significantly associated with reduced incidence of myocardial infarction (RR: 0.18, 95% CI [0.06, 0.54], P = 0.002) and cerebral or systemic embolic event (RR: 0.11, 95% CI [0.01, 0.83], P = 0.03). CONCLUSION: We report no significant difference with the use of CDSS compared to routine care in anticoagulant or antiplatelet prescription in eligible patients with AF. CDSS was associated with a reduced incidence of myocardial infarction and cerebral or systemic embolic events.

Analysis of the Marginal Continuity in Different Designs of Monolithic Zirconia Inlay-Retained Fixed Dental Prostheses: An In Vitro Study.

PURPOSE: To evaluate the marginal integrity of three inlay-retained fixed dental prosthesis (IRFDP) designs fabricated using monolithic zirconia. MATERIALS AND METHODS: In total, 30 IRFDPs were fabricated using 4-YTZP monolithic zirconia and randomly divided into three groups according to the cavity design. Groups ID2 and ID1.5 received an inlay cavity preparation, which includes a proximal box and an occlusal extension with a depth of 2 mm or 1.5 mm, respectively. Group PB received a proximal box cavity preparation without an occlusal extension. The restorations were fabricated and cemented using a dual-cure resin cement (Panavia V5) and subjected to an equivalent of 5 years of aging. The specimens were evaluated under an SEM to measure marginal continuity before and after the aging process. RESULTS: During the whole 5-year aging process, no specimens showed signs of cracking, fracture, or loss of retention in any restorations. In the SEM analysis, most marginal defects observed in the restorations were areas of microgaps at the tooth/cement interface (TC) or zirconia/cement interface (ZC), resulting in loss of adaptation. There was a significant difference between the groups after the aging process at both the TC (F = 4.762, P < .05) and ZC (F = 6.975, P < .05), with Group ID2 presenting the best performance. There was a significant difference between TC and ZC in all groups (P < .05), with ZC presenting more gaps in all groups. CONCLUSIONS: Inlay cavity designs including a proximal box and an occlusal extension exhibited better marginal stability than a proximal box without occlusal extension.

Etrolizumab as an induction and maintenance therapy for ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials.

Background and Aim: Etrolizumab is a gut-targeted anti-ß7 integrin monoclonal antibody. However, the evidence of etrolizumab efficacy and safety in ulcerative colitis remains inconclusive. Therefore, we aim to evaluate the safety and efficacy of etrolizumab as an induction and maintenance therapy for active moderate to severe ulcerative colitis. Methods: We synthesized randomized controlled studies (RCTs) from MEDLINE, Scopus, EMBASE, PubMed, Web of Science, and Cochrane Library until April 2023. The risk ratio (RR) for dichotomous outcomes with the corresponding 95% confidence interval (CI) was used. The study protocol was registered in PROSPERO with ID: CRD42023437040. Results: Five RCTs with 1849 participants were included. The etrolizumab group had a significant clinical response (RR: 1.28 with 95% CI [1.08, 1.51], P = 0.005), clinical remission rates during the induction phase (RR: 2.47 with 95% CI [1.48, 4.11], P = 0.0005), compared with the placebo group in ulcerative colitis; however, there was no statistically significant difference between the two groups, regarding the corticosteroids-free remission rate (RR: 1.92 with 95% CI [0.94, 3.92], P = 0.07). Moreover, endoscopic improvement, endoscopic remission, and histologic remission rates were observed more in the etrolizumab group during both the induction and maintenance phases. For safety outcomes, etrolizumab was significantly safer, but any adverse event was higher in the etrolizumab group than in the placebo. Conclusion: Etrolizumab shows its effectiveness as both an induction and maintenance therapy for moderate or severe UC. The findings demonstrate its positive impact on clinical, endoscopic, and histologic remission rates. Regarding safety, other than any side effects, etrolizumab showed a good safety than a placebo.

Gut dysbiosis is linked to metabolic syndrome in obese Egyptian women: potential treatment by probiotics and high fiber diets regimen.

Metabolic syndrome (MetS) is defined as a cluster of glucose intolerance, hypertension, dyslipidemia, and central obesity with insulin resistance. The role of gut microbiota in metabolic disorders is increasingly considered. To investigate the effects of probiotic supplements and hypocaloric high fiber regimen on MetS in obese Egyptian women. A longitudinal follow-up intervention study included 58 obese Egyptian women, with a mean age of 41.62 ± 10.70 years. They were grouped according to the criteria of MetS into 2 groups; 23 obese women with MetS and 35 ones without MetS. They followed a hypocaloric high fiber regimen weight loss program, light physical exercise, and received a probiotic supplement daily for 3 months. For each participating woman, blood pressure, anthropometric measurements, basal metabolic rate (BMR), dietary recalls, laboratory investigations, and microbiota analysis were acquired before and after 3 months of follow-up. After intervention by the probiotic and hypocaloric high fiber regimen and light exercise, reduction ranged from numerical to significant difference in the anthropometric parameters, blood pressure, and BMR was reported. All the biochemical parameters characterized by MetS decreased significantly at p ≤ 0.05-0.01. Before the intervention, results revealed abundant of Bacteroidetes bacteria over Firmicutes with a low Firmicutes/Bacteroidetes ratio. After the intervention, Log Lactobacillus, Log Bifidobacteria, and Log Bacteroidetes increased significantly in both groups, while Log Firmicutes and the Firmicutes/Bacteroidetes Ratio revealed a significant decrease. In conclusion, this study's results highlight a positive trend of probiotics supplementation with hypocaloric high-fiber diets in amelioration of the criteria of the Mets in obese Egyptian women.