Dr Mohammed Mahmoud Youssif

Over the past centuries, Aloe species have been traditionally used in managements of infectious ailments. However, no scientific investigation has been conducted into their mechanistic actions behind their antimicrobial activities. The main purpose of this study is to investigate the anti-virulence activities of Aloe marlothii A. Berger (AM) and Aloe striata Haw (AS) leaves and roots against Pseudomonas aeruginosa based on biofilm, pyocyanin and motility assays. Besides, the metabolic profiling of their different organs was evaluated via HPLC–MS/MS analysis. A molecular docking study of marker compounds into a LasR target was conducted to gain an insight into the bioactive metabolites involved into mechanism of action.

Power networks are being transformed by the incorporation of renewable energy sources (RES), such as photovoltaic systems and wind turbines, which also promote sustainability and lower carbon emissions. However, the widespread use of inverter-based RES threatens power quality and grid stability, with harmonic distortion being a key issue. System performance is compromised by harmonic distortion, elevating the risk of resonance and overheating equipment and increasing power losses. In this study, the Stochastic Fractal Search (SFS) algorithm is used to develop Harmonic Blocking Filters (HBF), an optimized passive power filter for reducing harmonic distortion and minimizing the system active power losses (PLOSS) in electric distribution systems. Two multi-objective optimization algorithms: Multi-Objective Artificial Hummingbird (MOAHA) and Multi-Objective Atomic Orbital Search (MOAOS) efficiently determine the ideal HBF design to maximize the system’s Harmonic-Constrained Hosting Capacity (HCHC) and minimize PLOSS to support RES while minimizing voltage and current total demand distortion (THDV and TDDI). Three test systems (TS) are used to validate the HBF’s superiority in mitigating the harmonics, minimizing PLOSS, and maximizing HCHC. In TS1, the SFS-optimized HBF decreases THDV by 78% and TDDI by 90% while maintaining PLOSS almost the same as compared to the previously obtained results in the literature. In TS2, the SFS-optimized HBF decreases THDV by 16.2%, TDDI by 99.96%, and PLOSS by 27.6% compared to the uncompensated case with no filter connected. In TS3, the SFS-optimized HBF decreases THDV by 45.71%, TDDI by 99.96%, and PLOSS by 33.26% compared to the uncompensated case. For the HCHC enhancement application, MOAOS has proven superior to MOAHA and the MOAOS-optimized HBF increases the system’s HCHC by 4.18% and in TS3, this value is increased by 16.4% compared to the literature.

Phytochemical characterization, and biological assessment of the neuroprotective activities of Achillea santolina L. methanolic extract (AS), its methylene chloride fraction (MF), butanol fraction (BF) and their isolated compounds were investigated. Twenty-two compounds were identified and quantified in AS using HPLC. Luteolin and kaempferol were isolated from MF. Isovitexin and kaempferol 3-O-glucoside were isolated from BF. The anti-inflammatory activity of the isolated compounds was determined by employing cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory assays. Neuroprotective activities of AS, MF and BF were investigated against monosodium glutamate (MSG) induced neurotoxicity in rats. Brain damage amended significantly as indicated by the decreased lactate dehydrogenase and tumor necrosis factor. Brain oxidative status was restored as indicated by increased glutathione and decreased lipid peroxidation. AS, MF and BF markedly attenuated histopathological alterations in cerebral cortex and downregulated expression of COX-2, IL-1B, IL-10 genes. The affinity of the isolated compounds for Human Heme Oxygenase-1, 5-LOX, Kelch-like ECH-associated protein and COX-2 was studied. Molecular dynamics simulation and ADME study proved that isovitexin has stable conformations and binding patterns with the active sites of the studied enzymes. For the first time, the neuroprotective potential of AS, fractions and isolated compounds was determined supported by anti-inflammatory study.

Climate change has a substantial impact on the quality and diversity of insect pests, which may have adverse ecological and economic effects. The family Chrysomelidae represents one of the most economically and ecologically important groups within Coleoptera, with species acting as agricultural pests and contributing substantially to biodiversity in arid regions. Based on bioclimatic, topographic, and vegetation data, the current and future distributions of 4 chrysomelids (Caryedon acaciae (Gyllenhal, 1833), Chaetocnema pulla Chapuis, 1879, Phyllotreta cheiranthi Weise, 1903, and Spermophagus sericeus (Geoffroy, 1785)) in Saudi Arabia were predicted using MaxEnt modeling for 2050 under 2 Shared Socioeconomic Pathways (SSPs), SSP126 (low emission) and SSP585 (high emission) scenarios. The leaf beetle models showed strong performance, with average area under the curve (AUC) values ranging from 0.86 to 0.96 and average TSS values ranging from 0.52 to 0.65. Five predictors were chosen for each species from 21 environmental variables. The results show that the key ecological factors that influence species distributions varied, with vegetation being the most influential. According to habitat suitability maps, in the future, such distribution will be severely altered, mostly by climate change. More precisely, C. acaciae will face minor range shifts, while C. pulla, P. cheiranthi, and S. sericeus will expand their ranges substantially, especially in the Eastern Province. Our results confirm the importance of implementing adaptive pest-management strategies to address the potential range expansions of various agricultural pests, which could intensify local ecological challenges and pose a heightened threat to agricultural systems.

Small bowel obstruction (SBO) is a common surgical emergency associated with substantial morbidity, hospital length of stay (LOS), and healthcare cost. The World Society of Emergency Surgery (WSES) Bologna guidelines provide evidence-informed recommendations for managing adhesive SBO, promoting timely surgical intervention (or non-operative management (NOM) when ischaemia, strangulation, or peritonitis are absent). However, guideline adoption and its impact on outcomes remain under studied. Compliance with the Bologna guidelines was evaluated to determine the impact of compliance on outcomes.SnapSBO, a prospective, multicentre, time-bound, observational cohort study, captured data on patients with adhesive SBO across diverse healthcare settings and patient populations. Patient care was categorized into: successful NOM, surgery after an unsuccessful appropriate trial of NOM (NOM-T), and direct to surgery (DTS). Compliance with diagnostic, therapeutic, and postoperative Bologna guideline recommendations was assessed as either complete or partial. Primary outcomes included adherence to the Bologna guidelines, LOS, complications, and the incidence of the composite metric ‘optimal outcomes’ (LOS ≤5 days, discharge without complications, and no readmission within 30 days).Among 982 patients with adhesive SBO, successful NOM occurred in 561 (57.1%), 224 (22.8%) underwent NOM-T, and 197 (20.1%) proceeded DTS. The mean(s.d.) LOS was 5.3(9.0), 12.9(11.4), and 7.7(8.0) days respectively (P < 0.001). Optimal outcomes were achieved in 61.0%, 16.1%, and 37.6% respectively (P < 0.001) and full guideline compliance was observed in 17.2%, 10.1%, and 0.4% respectively.Patients with adhesive SBO whose care was aligned with the Bologna guidelines had a shorter LOS and a greater incidence of optimal outcomes. Addressing evidence-to-practice gaps through implementation strategies that consider contextual factors will enhance guideline adoption and patient outcomes.Small bowel obstruction happens when the intestine becomes blocked, often due to scar tissue from previous surgery. It is a common reason people are admitted to hospitals for emergency surgery worldwide. Doctors have created clear guidelines (expert advice) on how best to treat this condition to improve patient outcomes. This study looked at whether doctors follow these guidelines and how it affects patient results. Researchers found that hospitals frequently struggle to fully follow the guidelines because they lack necessary resources or due to differences in medical practices. Improving how closely doctors follow these guidelines could help patients recover faster and experience fewer complications.

Elevated pipelines systems are commonly supported by flexible steel frames at regular intervals. During operation, these systems can be subjected to sources of harmonic excitations. In order to control the vibration response for such systems, designers may target a threshold minimum fundamental natural frequency for the system. Within this context, the study first shows that, within the ranges of straight pipelines geometries commonly used in the oil and gas industry, the fluid mass and stiffness of the intermediate flexible supports significantly impact the fundamental natural frequency of the system, while fluid velocity within the practical range of the oil and gas industry, temperature differential between the installation and operating temperatures, and pipe self-weight are less important or negligible. The study further extends the analysis to nonstraight piping systems with L-Shape and S-Shape configurations. In conclusion, design formulas are proposed to estimate the required lateral and transverse stiffnesses for the supporting systems to attain a specified fundamental natural frequency for straight and curved pipelines. Natural frequency comparisons with finite element solutions show the validity of the proposed design formulas.

Rapid digitalization of health care and a dearth of digital health education for medical students and junior physicians worldwide means there is an imperative for more training in this dynamic and evolving field.To develop an evidence-informed, consensus-guided, adaptable digital health competencies framework for the design and development of digital health curricula in medical institutions globally.A core group was assembled to oversee the development of the Digital Health Competencies in Medical Education (DECODE) framework. First, an initial list was created based on findings from a scoping review and expert consultations. A multidisciplinary and geographically diverse panel of 211 experts from 79 countries and territories was convened for a 2-round, modified Delphi survey conducted between December 2022 and July 2023, with an a priori consensus level of 70%. The framework structure, wordings, and learning outcomes with marginal percentage of agreement were discussed and determined in a consensus meeting organized on September 8, 2023, and subsequent postmeeting qualitative feedback. In total, 211 experts participated in round 1, 149 participated in round 2, 12 participated in the consensus meeting, and 58 participated in postmeeting feedback.The DECODE framework uses 3 main terminologies: domain, competency, and learning outcome. Competencies were grouped into 4 domains: professionalism in digital health, patient and population digital health, health information systems, and health data science. Each competency is accompanied by a set of learning outcomes that are either mandatory or discretionary. The final framework comprises 4 domains, 19 competencies, and 33 mandatory and 145 discretionary learning outcomes, with descriptions for each domain and competency. Six highlighted areas of considerations for medical educators are the variations in nomenclature, the distinctiveness of digital health, the concept of digital health literacy, curriculum space and implementation, the inclusion of discretionary learning outcomes, and socioeconomic inequities in digital health education.This evidence-informed and consensus-guided framework will play an important role in enabling medical institutions to better prepare future physicians for the ongoing digital transformation in health care. Medical schools are encouraged to adopt and adapt this framework to align with their needs, resources, and circumstances.

This study comprehensively analyzes the primary metabolites of sweet potato peels and pulps from four cultivars and assesses the impact of four different processing methods on pulp metabolome using a multiplex metabolomics approach of GC–MS and NIR. A total of 69 metabolites were identified. Beauregard cv. showed the highest sugar content (387.85 mg/g), whereas Sahrawy cv. was higher in alcohols (24.63 mg/g) and organic acids (2.98 mg/g). The chemometric analysis identified key markers that distinguished each cv. represented by its pulp, peel, and processed pulp. KEGG enrichment analysis pinpointed key metabolic pathways leading to the metabolic discrepancy of the specimens. Sugars were the most altered class by processing as manifested by a 5 to 11-fold increase, notably in the air-fried pulp. Air-frying also increased alcohol and organic acid contents. NIR analysis revealed that air-frying was the preferred method of processing, preserving the majority of pulp's metabolites, including β-carotene and phenolics.

OBJECTIVES: The aim of this randomized clinical trial was to clinically and radiographically compare the effect of osseodensification (OD) and conventional drilling (CD) on implant stability in the posterior maxilla.

MATERIALS AND METHODS: Twenty patients received 20 implants after being randomly assigned for osteotomy preparation with either OD (test) (n = 10) or CD (control) (n = 10). Implant stability quotient (ISQ) and crestal bone loss were monitored closely from implant insertion through 12 months of loading. Insertion torque and implant survival were also assessed during the study.

RESULTS: In OD group, one patient was lost to follow up and all other implants were in Function after 12 months of loading (9/9), while only 8/10 implants survived in CD group. OD was associated with significantly higher mean ISQ values; post-insertion and during the 1st month of healing, compared to CD. A high relatively unchanged stability was observed throughout osseointegration with OD method, while a stability dip occurred during the 2nd and 3rd weeks of healing in CD group. There was no significant difference in crestal bone loss and insertion torque between groups.

CONCLUSIONS: Within the limitations of this study, OD seems to provide earlier implant stability in terms of ISQ values, and may improve survival rates in the posterior maxilla, compared to CD, with no negative impact on crestal bone after 12 months of implant loading.

CLINICALTRIALS: gov Identifier: NCT04442763 (registration date 15/6/2020).

CLINICAL RELEVANCE: OD may be used as an alternative to CD to achieve earlier implant stability in the posterior maxilla.

The opportunistic pathogen Acinetobacter baumannii is a particularly problematic nosocomial threat worldwide, leading to high morbidity and mortality rates due to its multiple resistance mechanisms, including the production of lipolytic enzymes. Herein, the aerial parts of three coniferous plants, Pinus canariensis C. Sm. (PC), Cupressus lusitanica Mill. (CL), and Cupressus arizonica Greene. (CA), were extracted and fractionated. Among these, the CA extract followed by CL and then PC, exhibited the highest inhibition of bacterial lipase activity, with half-maximal inhibitory concentration (IC) values of 1117 ± 87, 1278 ± 62, and 1926 ± 104 µg/mL, respectively. The methylene chloride fractions of CA and CL extracts exhibited the highest inhibition of bacterial lipase activity, with IC (940 ± 25 µg/mL and 1103 ± 155 µg/mL), respectively. The metabolite profile of the three extracts, along with their most active fractions, were determined using liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS). Interestingly, the metabolite profiles of CL extracts were established here for the first time. A total of 99 secondary metabolites from diverse classes were identified across all samples. Among these, four metabolites were isolated: 3,5-di-p-coumaroylquinic acid, epicatechin, cupressuflavone, and rutin. The biflavonoid cupressuflavone showed the lowest IC value (3812 ± 450 µg/mL). Additionally, partial least squares was applied to assess the key metabolites contributing to the differentiation of the studied bioactivity. Consequently, this study provides novel insights into the bioactivity potential of coniferous plants, demonstrating their value as a natural source of antivirulence agents against the A. baumannii lipase enzyme.

Oxymetholone, a synthetic anabolic steroid, is widely used for medical and performance-enhancing purposes but is associated with significant toxicity. Zinc oxide nanoparticles (ZnO-NPs) have attracted attention for their antioxidant and anti-inflammatory properties, which may counteract such toxic effects. This study investigates the protective role of ZnO-NPs against oxymetholone-induced liver and kidney damage in rats. Twenty-four rats were randomly assigned to four groups and treated orally as follows: control, oxymetholone (10 mg/kg), ZnO-NPs (5 mg/kg), and oxymetholone + ZnO-NPs. Oxymetholone administration significantly increased serum levels of urea, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Furthermore, oxidative stress markers, such as malondialdehyde (MDA), were significantly elevated, whereas reduced glutathione (GSH) levels were decreased in both hepatic and renal tissues. Oxymetholone exposure also upregulated the expression of pro-inflammatory and stress-related genes, including tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and nibrin (NBN). In contrast, it downregulated antioxidant genes such as nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), and superoxide dismutase (SOD). Histopathological examination revealed extensive liver and kidney damage, with immunohistochemistry demonstrating marked NF-κB expression. However, concurrent administration of ZnO-NPs mitigated these toxic effects by restoring antioxidant balance, modulating inflammatory pathways, and preserving tissue integrity. These findings suggest that ZnO-NPs have a protective role against oxymetholone-induced oxidative stress, inflammation, and tissue damage in hepatic and renal tissues.

BACKGROUND: Nonsense-mediated decay (NMD) is a cellular mechanism that degrades mRNAs with premature termination codons (PTCs), preventing the production of truncated, potentially harmful proteins. While its role in viral infections is increasingly recognized, the relationship between NMD-linked mutations in SARS-CoV-2 and COVID-19 severity remains poorly understood. OBJECTIVE: To investigate the presence of SARS-CoV-2 nonsense mutations predicted to trigger NMD and assess their association with clinical disease severity and viral genomic. METHODS: We conducted whole-genome sequencing on samples from 129 hospitalized COVID-19 patients. A panel of 21 nonsense mutations predicted to activate the NMD pathway was identified and analyzed. Statistical correlations with clinical severity were assessed, including multivariate analysis. Receiver Operating Characteristic (ROC) curves and interdependency analysis of mutation combinations were also performed. RESULTS: Five NMD-associated mutations (Variants 5, 6, 7, 9, and 15) showed significant associations with mild disease. These mutations, located in key SARS-CoV-2 genes, include Variant 5 (g.C5575G, T, synonymous substitution in ORF1ab), Variant 6 (g.T5653G, substitution in ORF1ab), Variant 7 (g.G6094GGACAGACTTT/GCCTACACGACGCTAATC, insertion in spike protein), Variant 9 (g.G6446GAATGA, insertion in spike protein), and Variant 15 (g.T10968TATATTGA, insertion in N protein). In the host-adjusted multivariable model, the presence of at least one NMD-inducing mutation was an independent protective factor (OR = 0.34, 95% CI: 0.16–0.72, p = 0.005). However, after adjusting for SARS-CoV-2 lineage, this association was attenuated (OR = 0.67, 95% CI: 0.03–13.84, p = 0.793). In the lineage-only model, Omicron infection showed higher odds of severe disease compared to Delta (OR = 1.91, 95% CI: 0.77–4.77, p = 0.164). ROC analysis indicated limited predictive value for individual variants (AUC = 0.37–0.48), but specific combinations, such as Variants 5 and 7, markedly reduced severe case incidence (92.9–4.8%, p = 0.0001). CONCLUSION: NMD-inducing nonsense mutations were associated with reduced COVID-19 severity in host-adjusted analyses, but this effect diminished after accounting for viral lineage, suggesting that variant distribution, particularly Omicron may influence these associations. Integrating viral genomic background with host and clinical data may enhance risk prediction and inform antiviral strategies.

Polymeric microneedle array patches (MAPs) offer a painless and convenient way for delivering drugs across various biological membranes, including the skin, the cornea and various mucosal surfaces. Conventionally, dissolving MAPs provide rapid drug release but have a limited drug-loading capacity. Hydrogel-forming MAPs can prolong drug release typically for no more than several weeks but often involve harsh manufacturing conditions, such as elevated temperatures above 60 °C for chemical crosslinking. For both types of MAPs, the drug release kinetics depends greatly on the physical properties of the polymers used. However, common polymers used for MAP formulation are very constrained in their ability to balance often conflicting requirements in terms of water solubility, swellability, mechanical strength and manufacturability. To overcome these constraints, this study presents a semi-dissolving, hydrogel-forming MAP formulation approach based on a dual-domain polymeric system, consisting of physically and functionally distinct water-soluble polyvinylpyrrolidone and insoluble chitosan-hydrogel domains. In this unique formulation approach, robust MAPs were produced via micromoulding, using only a hydroalcoholic solvent system and mild temperatures ≤ 37 °C. The drug payload was incorporated into the entire baseplate of the MAPs using one-pot synthesis, which offers not just a high drug-loading capacity but also ease of manufacture. The MAPs extended the in vitro release of dexamethasone sodium phosphate (DSP), a highly hydrophilic drug, to over two months. Kinetic modelling showed that drug release from the MAPs followed non-Fickian transport. The DSP released from the MAPs retained potent anti-inflammatory activity in ex vivo human peripheral blood mononuclear cells. Using microscopy, timelapse imaging and kinetic data, the mechanism of drug release was captured in terms of the structural transformation of the polymeric matrix following hydration. It is proposed that this formulation approach may be extended to other dosage forms, such as implants, to modulate the release of a multitude of drugs, including biologics.

To assess the fracture resistance of prefabricated esthetic crowns for primary molars. Seventy-two human mandibular second primary molars were divided into three groups: preveneered stainless steel crowns (VSS), prefabricated zirconia crowns (PZ) and BioFlx crowns (BF). Crowns were cemented with glass ionomer cement; for each group, 12 samples were tested for fracture resistance and 12 samples underwent 5,000 thermocycles before testing. The fracture mode was assessed for all the samples. Differences in the fracture resistance values between the groups were tested using analysis of variance (ANOVA), followed by Tukey's post hoc test, while the distribution of fracture modes was tested using Fisher's exact test. Statistical significance was set at =0.05 and analyses were conducted using SPSS version 25.0 software. ANOVA tests indicated a significant difference in fracture resistance among the test groups ( <0.001). The groups were ranked as follows: before thermocycling- (1) PZ group (3,327±1497), (2) BF group (1,694±163) and (3) VSS group (536±12); and after thermocycling-(1) PZ group (3,308±162), (2) BF group (1,579±77) and (3) VSS group (413±16). Tukey's post hoc analysis indicated that the PZ group exhibited a significantly higher fracture resistance than the BF and VSS groups ( <0.001). The VSS group showed a predominance of minimal cracks (5.6 percent) and loss of less than half of the crown (11.1 percent). PZ yielded the highest resistance, followed by BF crowns. VSS may require caution in high-stress areas due to their susceptibility to esthetic component failure, although the underlying crown remains functional.

Instigating novel therapeutic strategies to combat breast cancer has become an urgent need. Astaxanthin (ASX), a keto-carotenoid, has been confirmed to possess antitumor activity, yet studies on breast cancer are still limited. The present study was deployed to unveil ASX's antitumor effects, alone or combined with doxorubicin (DOX), on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in Sprague‒Dawley female rats. Five groups of rats were assigned (n = 10), including normal group, which received the vehicle only, whereas other groups received DMBA for tumor induction, after which: group 3 received ASX (25 mg/kg/day; orally), group 4 received DOX (2 mg/kg/week; i.p.), and group 5 received both drugs. This study focused on assessing the role of Notch-1 signaling with some miRNAs orchestrating the pathway. Herein, ASX boosted miR-34a expression, which decreased the level of Notch-1 protein. In addition, miR-34a upregulation halted cell cycle progression by augmenting p21 protein level and triggering apoptosis by decreasing survivin and increasing Bax protein levels. Moreover, the downregulated miR-146a and miR-210 were escorted by decreased NF-κB and VEGF protein levels, respectively, suggesting their potential role in angiogenesis. Remarkably, ASX/DOX combination showed greater effects than either agent alone. Correlation and bioinformatics analyses manifested a significant relationship among all studied parameters. The ASX's restorative effect was further confirmed by histopathological examination. To the best of our knowledge, this study verified ASX's ability to abrogate DMBA-induced mammary tumors by impeding Notch-1 pathway, thus mitigating cell cycle progression and angiogenesis and augmenting apoptosis, exemplifying the interplay between Notch-1 and its downstream targets with different miRNAs.

Multiple sclerosis (MS) is a chronic demyelinating and inflammatory neurodegenerative disease that impacts more than 2.8 million patients worldwide. Hydrogen sulfide (HS) impairment and dysregulation are implicated in the pathogenesis of MS. The current study aims to explore the potential protective effects of HS modulating drugs; diallyl disulfide (DADS) and S-adenosyl-l-Methionine (SAMe) on cuprizone-induced demyelination and to investigate their molecular mechanisms. Male C57BI/6 mice were randomly divided into four groups; control, cuprizone, cuprizone + DADS (100 mg/kg/day, p.o.) and cuprizone + SAMe (20 mg/kg/day, p.o.) groups. Interestingly, treatment with DADS and SAMe successfully enhanced the motor coordination, CBS enzymatic activity and attenuated cuprizone-induced demyelination. They also suppressed neuroinflammation as demonstrated by LFB-stained and H&E-stained corpus callosum. Their neuroprotective effects were further confirmed by the increased levels of the oligodendrocyte markers MBP, Olig2 and CNTF. DADS and SAMe treatments led to restoration of autophagic flux evidenced by the enhanced levels of ULK1, beclin1, ATG5 and LC3-II through upregulation of both AMPK and SIRT1. Additionally, DADS and SAMe suppressed NF-κB and IL-17 levels and increased GSH and TAC, curbing both neuroinflammation and oxidative stress. Furthermore, the levels of fibronectin aggregates were significantly reduced compared to the untreated group. The study also demonstrated that SAMe has superior effects in curbing demyelination, inflammation and oxidative stress and inducing autophagy compared to DADS. The current investigation highlights for the first time that the HS modulating agents (SAMe and DADS) could provide promising treatment options for cuprizone-induced demyelination via regulating HS/AMPK/SIRT1/ULK1/beclin1 pathway.

Serotonin 1 A receptor (5-HT1 AR) signaling is pivotal for stress response, determining vulnerability or resilience to psychopathology. However, the precise pathological mechanisms underlying its role remain inconsistent. Moringa oleifera (MO), a plant with purported medicinal properties, has demonstrated potential efficacy against psychiatric disorders. However, no available information exists regarding its effects on 5-HT1 A signaling under normal and stressed conditions. This study is aimed at elucidating the effects of MO in conjunction with 5-HT1 A signaling. Rats were randomly assigned to four groups: normal (NRML), normal rats receiving MO orally at 200 mg/kg (MO), rats exposed to chronic unpredictable mild stress (CUMS) for 21 days (CUMS), and stressed rats administered MO from day 15 (CUMS + MO). Behavioral analysis was conducted using forced swimming and open field tests. Serotonergic markers, β-catenin, p-Erk, c-myc, and mTOR were assessed via ELISA, while miRNA clusters and individual miRNAs were analyzed using PCR. No significant differences were observed between the NRML and MO groups, both of which exhibited approximately normal biochemical activity, except for a decreased 5-HIAA/5-HT ratio in the MO group, which was reflected behaviorally. Rats subjected to CUMS displayed defective β-catenin signaling, potentially leading to compensatory activation of 5-HT1 A. Consistently, the CUMS + MO group exhibited normalized 5-HT1 A and 5-HT signaling, accompanied by reduced pThr183-Erk and its downstream targets, c-myc and miR- 203, to mitigate pathological anxiety. Additionally, mTOR and its downstream target, miR- 217, were reduced compared to stressed rats. MO exhibited a promising anxiolytic effect by modulating 5-HT1 A signaling, as evidenced by improved neurobehavioral outcomes and restoring biochemical balance in stressed rats. These findings highlight its potential therapeutic role in anxiety management.

Binge drinking (BD) is heavy episodic alcohol drinking that is progressively practiced. Vast evidence verified that BD elicits neuronal and cognitive impairments. Debilitated autophagic machinery is a key culprit in BD-induced neurotoxicity. Palonosetron is a potent selective serotonin 5-HT3 receptor antagonist whose impact on BD has not yet been scrutinized. Thus, the present study aimed at exposing the potentiality of palonosetron and its link with AKT/mTOR/AMPK/ULK1 pathway in the BD-rat model. Rats were divided into 4 groups; group 1 received saline and Vanilla Ensure® Plus, whereas groups 2, 3 and 4 received 20 % w/v ethanol in Vanilla Ensure® Plus (intragastric gavage) every 8 h for 4 days, concomitantly with palonosetron (0.1 mg/kg, twice daily; i.p.) in groups 3 and 4, and chloroquine (50 mg/kg/day; i.p.) in group 4. BD impaired memory, locomotor, and cognitive functions, with concomitant TNF-α and IL-1β elevation implicating neuroinflammation-driven cognitive decline. The former effect was, mechanistically, triggered by halting autophagy via augmenting hippocampal pAKT/tAKT, pmTOR/tmTOR and pULK1/tULK1 ratios, while reducing pAMPK/tAMPK, with resultant imbalance of the autophagic markers; Beclin-1, LC3-II/LC3-I, p62 and caspase-3. Aberrant upregulation of miRNA-155 was also detected and was markedly correlated to AKT/mTOR/AMPK and autophagy trajectories. Palonosetron treatment significantly alleviated all the aforementioned deviations. Histopathological analysis further corroborated palonosetron neuroprotective effect. Chloroquine, a classical autophagy inhibitor, blunted palonosetron-induced improvement. The identified parameters were validated using the ShinyGO-0.81 database for functional enrichment analysis and KEGG pathway mapping. For the first time, palonosetron is likely to offer a reliable neuroprotective effect in BD via orchestrating the crosstalk between miRNA-155 and AKT/mTOR/AMPK signaling cascade.

AIM: To explore the ethical considerations and challenges faced by nursing professionals in integrating artificial intelligence (AI) into patient care.

BACKGROUND: AI's integration into nursing practice enhances clinical decision-making and operational efficiency but raises ethical concerns regarding privacy, accountability, informed consent, and the preservation of human-centered care.

METHODS: A systematic review was conducted, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Thirteen studies were selected from databases including PubMed, Embase, IEEE Xplore, PsycINFO, and CINAHL. Thematic analysis identified key ethical themes related to AI use in nursing.

RESULTS: The review highlighted critical ethical challenges, such as data privacy and security, accountability for AI-driven decisions, transparency in AI decision-making, and maintaining the human touch in care. The findings underscore the importance of stakeholder engagement, continuous education for nurses, and robust governance frameworks to guide ethical AI implementation in nursing.

DISCUSSION: The results align with existing literature on AI's ethical complexities in healthcare. Addressing these challenges requires strengthening nursing competencies in AI, advocating for patient-centered AI design, and ensuring that AI integration upholds ethical standards.

CONCLUSION: Although AI offers significant benefits for nursing practice, it also introduces ethical challenges that must be carefully managed. Enhancing nursing education, promoting stakeholder engagement, and developing comprehensive policies are essential for ethically integrating AI into nursing.

IMPLICATIONS FOR NURSING: AI can improve clinical decision-making and efficiency, but nurses must actively preserve humanistic care aspects through ongoing education and involvement in AI governance.

IMPLICATIONS FOR HEALTH POLICY: Establish ethical frameworks and data protection policies tailored to AI in nursing. Support continuous professional development and allocate resources for the ethical integration of AI in healthcare.

AIM: This study aimed to explore the perceptions, experiences, and ethical considerations of nursing academic reviewers regarding the integration of artificial intelligence (AI) into the peer review process, with a focus on acceptance dynamics and implications for nursing journal policy.

DESIGN: A qualitative descriptive design was employed, guided by an interpretivist approach and reported according to the COREQ checklist.

METHODS: Fifteen nursing academic reviewers from four countries (Saudi Arabia, Egypt, Australia, and the United States) were recruited via snowball sampling. Semi-structured interviews were conducted between January and March 2025 using Zoom video conferencing. Interviews were held in Arabic or English, transcribed verbatim, translated as needed, and thematically analyzed using reflexive thematic analysis per Braun and Clarke's six-phase framework.

RESULTS: Five themes were generated: perceived benefits of AI (efficiency, fairness, and workload reduction), ethical concerns (transparency, bias, and data privacy), risks to reviewer autonomy and judgment, divergent attitudes toward AI adoption, and the need for clear guidelines and training. Participants expressed cautious optimism, emphasizing that while AI tools may enhance consistency and reduce administrative burden, they raise complex ethical questions and must not replace human judgment.

CONCLUSION: The integration of AI into peer review processes presents both opportunities and ethical challenges. The nursing academic reviewers in this study recognize the utility of AI for supporting routine tasks but remain concerned about algorithmic bias, transparency, and its impact on scholarly independence. Ethical AI adoption requires structured policies and capacity-building initiatives.

IMPLICATIONS FOR NURSING PRACTICE AND POLICY: To uphold scholarly integrity, nursing journals and academic institutions should develop transparent AI governance frameworks, invest in reviewer education on responsible AI use, and preserve the central role of human judgment in peer review. These steps are vital to ensuring AI complements rather than compromises research quality and ethics in global nursing scholarship.

Bacterial quorum sensing is often mediated by multiple signaling systems that interact with each other. The quorum-sensing systems of Pseudomonas aeruginosa, for example, are considered hierarchical, with the las system acting as a master regulator. By experimentally controlling the concentration of auto-inducer signals in a signal deficient strain (PAO1ΔlasIΔrhlI), we show that the two primary quorum-sensing systems-las and rhl-act reciprocally rather than hierarchically. Just as the las system's 3‑oxo‑C12‑HSL can induce increased expression of rhlI, the rhl system's C4‑HSL increases the expression level of lasI. We develop a mathematical model to quantify relationships both within and between the las and rhl quorum-sensing systems and the downstream genes they influence. The results show that not only do the systems interact in a reciprocal manner, but they do so asymmetrically, cooperatively, and nonlinearly, with the combination of C4‑HSL and 3‑oxo‑C12‑HSL increasing expression level far more than the sum of their individual effects. We next extend our parameterized mathematical model to generate quantitative predictions on how a QS-controlled effector gene (lasB) responds to changes in wildtype bacterial stationary phase density and find close quantitative agreement with an independent dataset. Finally, we use our parameterized model to assess how changes in multi-signal interactions modulate functional responses to variation in social (population density) and physical (mass transfer) environment and demonstrate that a reciprocal architecture is more responsive to density and more robust to mass transfer than a strict hierarchy.

BACKGROUND: In 2022, a repeatable protocol for in vitro fertilization (IVF) using fresh semen was established in horses. This facilitated successful capacitation of equine semen allowing to explore novel applications.

OBJECTIVES: We aimed to extend this technique to IVF with frozen-thawed semen and intracytoplasmic sperm injection (ICSI), and determine the outcome parameters such as blastocyst production and euploidy rates.

MATERIALS AND METHODS: A total of 221 oocytes were subjected to either IVF with frozen-thawed semen, ICSI with frozen-thawed semen incubated under capacitating conditions (ICSI cap) or control ICSI with washed frozen-thawed semen. Cleavage and blastocyst rates were assessed and compared across the three groups using one-way ANOVA. Shallow whole genome sequencing was performed on embryos obtained from IVF and ICSI cap.

RESULTS: We established a repeatable protocol for IVF with frozen-thawed semen resulting in higher blastocyst rates per collected oocyte (22.4%) when compared to control ICSI (16.4%) (p = 0.048). Furthermore, the use of semen incubated under capacitating conditions for ICSI resulted in higher blastocyst rates than washed sperm, with 69.0% versus 50.0% blastocysts per cleaved embryo (p = 0.03) and 27.8% versus 16.4% blastocysts per collected oocyte (p = 0.04), respectively. It also yielded higher blastocyst rates per cleaved embryo than IVF, with 69.0% versus 45.9% (p = 0.04). The average day of blastocyst formation was not different between the three groups (p = 0.73). Shallow whole genome sequencing revealed no differences in aneuploidy rates between IVF (1/17) and ICSI cap (0/18) (p = 0.49).

CONCLUSION: The incubation of sperm under capacitating conditions for use in ICSI or IVF with frozen-thawed semen may represent a novel method to improve the clinical efficiency of equine IVP embryos, without affecting aneuploidy rates.

One of the biggest obstacles to treating breast cancer effectively is chemotherapy resistance, which emphasizes the need for innovative therapeutic approaches. An important factor in tumor progression is the mitochondrial enzyme monoamine oxidase-A (MAO-A). In the development of anticancer drugs, isatin (1-indole-2,3-dione), a MAO inhibitor obtained from , has shown great promise. This study assessed isatin's ability to fight resistance in tamoxifen-resistant LCC2 breast cancer cells, both by itself and in combination with tamoxifen. Chromatographic techniques were used to extract and purify isatin, which was subsequently examined for cytotoxicity, cell cycle arrest, colony formation, and migratory inhibition. Isatin and tamoxifen together dramatically decreased cell viability, prevented migration, stopped the advancement of the cell cycle, and repressed proliferation. Using qRT-PCR, gene expression analysis showed that important indicators for treatment resistance and metastasis, including MAO-A, HIF-1α, TWIST, MMP2, MMP9, and ABCB1, were downregulated. ELISA-based protein expression analyses further validated the modification of proteins linked to migration and apoptosis, including BAX, BCL2, and caspases 3, 8, and 9. The ATP-binding cassette transporter ABCB1, which is intimately linked to multidrug resistance, was similarly impacted by the isatin-tamoxifen combination. In conclusion, our findings demonstrate that isatin, alone or in combination with tamoxifen, exerts significant anticancer effects in tamoxifen-resistant breast cancer cells by promoting apoptosis, cell cycle arrest, and suppression of resistance-associated pathways. These effects may involve modulation of MAO-A and HIF-1α signaling, highlighting MAO-A as a lesser-studied but promising target in breast cancer.

BACKGROUND: Myocardial infarction (MI) is a significant global cause of chronic heart failure. In post-ischemic cardiac hypertrophy, multiple molecular targets and signals within the cardiac tissue are evident. Mesenchymal stem cell-derived exosomes (MSC-EXO) and exercise (EXE) showed promise in enhancing post-ischemic cardiac repair.

AIM: To investigate how the exosomes released by stem cells and/or EXE can promote cardiac repair and improve isoproterenol (ISO)-induced post-ischemic hypertrophy.

METHODS: The enrolled animals were divided into 8 control rats and 32 experimental rats. Induction of MI was performed using ISO. Then, the experimental rats were divided into 4 groups: Rats subjected to 4 weeks of swimming EXE, rats treated with exosomes, and the combined treatment. Additionally, functional and interactional exploration of targeted proteins was conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and STRING database, along with histological examination.

RESULTS: Both MSC-EXO or EXE significantly improved ISO induced elevation of cardiac enzymes, oxidative stress, and inflammatory markers, as well as the degenerative changes of the cardiac muscles, fibrosis, and apoptosis. Meanwhile, the combined treatment of EXE and MSC-EXO resulted in a significant improvement in cardiac function and structure as compared to all groups that synchronized with dual inhibition of extracellular signal-regulated kinase and protein kinase B/mammalian target of rapamycin ( < 0.01) signaling and modulation of matrix metalloproteinase 9 and sarcoplasmic endoplasmic reticulum calcium ATPase type 2a, with significant improved angiogenesis.

CONCLUSION: Functional and structural cardiac improvements are accompanied by reduced inflammation, oxidative stress, and apoptosis. Both MSC-EXO and EXE exert cardio-protection by upregulating sarcoplasmic endoplasmic reticulum calcium ATPase, the critical pump for normal calcium handling.

Agomelatine (AGO) is a dual action drug. Being serotonin receptor antagonist, AGO is orally administered for depression treatment. Here in, AGO was used for intraocular pressure management due to its agonistic activity on the melatonin receptors in the eyes. AGO is a BCS II drug, with low oral bioavailability and massive first-pass metabolism. Oleic acid enriched leciplexes were investigated as novel mucoadhesive cationic nanocarriers to improve AGO's ocular bioavailability and prolong its pharmacological effect. Twenty-four AGO loaded leciplexes were fabricated by single-step procedure. AGO: lipid ratio, surfactant: phosphatidyl choline ratio, cationic surfactant type, permeation enhancer type were investigated. For optimization; in-vitro assessment of size, homogeneity, surface charge, drug entrapment and in-vitro release was conducted. The optimum system was further examined for crystallinity, compatibility, morphology, pH, refractive index, surface tension and stability. L20 developed at a drug: lipid ratio of 1: 20, cetyltrimethylammonium bromide and phosphatidyl choline at a ratio of 1:5 respectively and 0.25% w/v oleic acid was the optimum system with respect to shape and PS (spherical, 491 nm), PDI (0.29), ZP (31.1 mV), EE (81.8%), in-vitro release (Q; 34.9%, Q; 91.2%), crystallinity, pH (6.3), refractive index (1.24), surface tension (46.2 mN/m) and stability. AGO pharmacodynamic and histopathological studies were conducted in rabbits. Compared to AGO dispersion, elevated maximum IOP reduction (74.2%), prolonged mean residence time (12.88 h), enhanced bioavailability (3 folds) and normal histopathological micrographs proved the potential of L20 leciplex in improving and sustaining the ocular bioavailability of AGO and maintaining its safety.

Exploration of new niches for microorganisms capable of degrading recalcitrant molecules is still required. We hypothesized that the gut microbiota associated with the field population carries pesticide-degrading bacteria that would enhance the host's ability to metabolize pesticides. Three strategies were implemented to address this principle: (i) isolation and identification of chlorpyrifos-degrading gut bacteria from field-collected larvae; (ii) evaluation of chlorpyrifos biodegradation capacity through in vitro assays; and (iii) assessment of the impact of specific bacterial taxa capable of degrading chlorpyrifos directly within the gut. In this study, we successfully isolated four chlorpyrifos-degrading gut bacterial isolates from a field-collected population of . These isolates were identified using 16S rDNA sequencing as strain 60D (PP504878), strain 64D (PP504879), strain 66D (PP504880), and strain 71D (PP504881). In vitro chlorpyrifos degradation assays revealed that all isolates exhibited strong degradative capacities, with strain 64D achieving the highest degradation rate, 80.38%, after one day of inoculation. In contrast, in vivo chlorpyrifos biodegradation assessment demonstrated a clear protective effect of gut bacteria on host survival. Among the mono-associated groups, larvae colonized with strain 66D exhibited the most pronounced reduction in mortality by 19.16-fold compared to antibiotic-treated larvae following exposure to chlorpyrifos suspension.

BACKGROUND: Pseudomonas aeruginosa infections are often challenging to treat due to multiple drug resistance, besides the development of biofilms and a plethora of virulence factors regulated by quorum sensing. Quorum-quenching enzymes, such as N-acyl homoserine lactonases, represent a promising anti-virulence strategy by disrupting this signaling mechanism without exerting selective pressure, leading to resistance. This study aimed to screen endophyte and epiphyte isolates for lactonase activity and evaluate their potential to inhibit virulence in Pseudomonas aeruginosa.

RESULTS: Fifty-two bacterial isolates (42 endophyte and 10 epiphyte) were isolated from ten plants. The aiiA gene encoding lactonase enzyme was detected in 11 endophytes and one epiphyte isolate, among which nine showed complete degradation (100%) of the quorum sensing signal molecule N-hexanoyl-L-homoserine lactone. The partially purified lactonase enzyme from the endophyte Bacillus cereus AL1 isolate exhibited significant anti-virulence activity, reducing biofilm formation, swarming motility, and pyocyanin production against Pseudomonas aeruginosa PAO1 and clinical Pseudomonas aeruginosa isolates. Sequence alignment of the Bacillus cereus AL1 lactonase protein revealed close similarity to the homologous lactonase from Bacillus cereus. The quorum quenching activity of the partially purified lactonase AL1 provided protection in a Galleria mellonella infection model.

CONCLUSION: The study highlights the potential of Bacillus cereus AL1 lactonase as an effective anti-virulence agent against Pseudomonas aeruginosa without the pressure for resistance development.

OBJECTIVE: Oncogenic viruses have been implicated in thyroid carcinogenesis, yet their prevalence and clinicopathological associations remain incompletely understood. Thus, it is crucial to investigate the prevalence of human papillomavirus (HPV), Epstein-Barr virus (EBV), and polyomaviruses (JCV and BKV) in thyroid tumors and assess their association with clinic-pathological characteristics.

METHODS: This study included 70 fresh biopsy samples collected from 45 TC patients and 25 patients with benign thyroid tumors, along with 10 normal thyroid tissues. Viral DNA was extracted and screened for HPV, EBV, and polyomaviruses using SYBR Green-based real-time PCR.

RESULTS: HPV, EBV, and polyomaviruses, particularly JCV, were detected at significantly lower frequencies in the normal group when compared to malignant and benign groups (p-value = 0.030, p-value = 0.030, and p-value = 0.001, respectively). In TC patients, HPV common, HPV-16, HPV-6, and HPV-11 positivity was correlated with obesity (p-value < 0.05), polyomaviruses, particularly JCV, with older age (p-value = 0.041 and p-value = 0.011), BKV with larger tumor size (p-value = 0.030), and EBV with family cancer history (p-value = 0.020). In benign tumors, polyomavirus was absent in Hashimoto thyroiditis (p-value = 0.020), BKV was linked to older age (p-value = 0.030), and absence of BKV was associated with COVID-19 vaccination (p-value = 0.046).

CONCLUSION: The current study is the first of its kind in Egypt to investigate the prevalence of HPV, EBV, and polyomaviruses in thyroid tumors and to examine their associations with certain clinicopathological characteristics. The findings underline the importance of viral profiling in understanding thyroid tumor behavior and influencing cancer risk as well.

BACKGROUND: Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study-part of the latest GBD release, GBD 2023-aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time.

METHODS: We used 24 025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950-2023. For the first time, we used complete birth history data for ages 5-14 years, age-specific sibling history data for ages 15-49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution.

FINDINGS: In 2023, 60·1 million (95% UI 59·0-61·1) deaths occurred globally, of which 4·67 million (4·59-4·75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35·2% (32·2-38·4) over the 1950-2023 study period, during which the global age-standardised all-cause mortality rate declined by 66·6% (65·8-67·3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67·7% decrease); the largest increases in mortality for those aged 5-14 years, 25-29 years, and 30-39 years occurring in high-income North America (11·5%, 31·7%, and 49·9%, respectively); and the largest increases in mortality for those aged 15-19 years and 20-24 years occurring in Eastern Europe (53·9% and 40·1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5-14 years (87·3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950-2021 period) and for females aged 15-29 years (61·2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13·2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51·2 (50·6-51·7) years for females and 47·9 (47·4-48·4) years for males in 1950 to 76·3 (76·2-76·4) years for females and 71·4 (71·3-71·5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74·7 (74·6-74·8) years for females and 69·3 (69·2-69·4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76·3 [76·0-76·6] years for females and 71·5 [71·2-71·8] years for males). 194 (95·1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61·8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally.

INTERPRETATION: This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020-23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950-2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world.

FUNDING: Gates Foundation.

BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations.

METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds.

FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value.

INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales.

FUNDING: Gates Foundation.

In this case‒control study conducted at Cairo's National Cancer Institute, the associations between bisphenol A (BPA), an endocrine-disrupting chemical (EDC), and ovarian cancer were investigated. BPA levels in the urine, oxidative stress markers (reactive oxygen species (ROS) and superoxide dismutase (SOD) activity), and KRT4 gene expression were analyzed in 30 patients and 30 controls. Significant risk factors for BPA exposure included consuming microwave meals, consuming canned beverages, using PVC food storage, eating fast food, handling thermal paper, exposure to dust, and recurrent hospitalizations (all p < 0.001). Compared with normal controls, ovarian cancer patients presented increased BPA levels, ROS, and KRT4 expression, along with reduced SOD activity (p < 0.001). A strong positive correlation was found between BPA and KRT4, suggesting that KRT4 is a potential biomarker. The cutoff values for urinary BPA and KRT4 achieved 100% sensitivity and specificity in distinguishing patients from controls. These findings suggest that BPA plays a role in ovarian cancer pathogenesis, likely through oxidative stress and gene dysregulation. This study emphasizes the importance of minimizing BPA exposure (e.g., by reducing the use of canned or packaged foods) and calls for larger studies to further investigate the role of EDCs in hormone-dependent cancers.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent worldwide. Performance of non-invasive tests (NITs) in patients with MASLD recruited from different regions of the world was evaluated.

METHODS: MASLD patients with liver biopsies and NIT data [fibrosis-4 index (FIB-4), enhanced liver fibrosis (ELF), and liver stiffness measurement (LSM)] were enrolled through the Global NASH Council collaboration (G-MASLD). FibroScan-AST (FAST) and Agile-3+/Agile-4 were calculated. NITs' performance for predicting ≥F2 (significant fibrosis), ≥F3 (advanced fibrosis), or cirrhosis (F4) was determined in patients from different regions.

RESULTS: A total of 17,792 MASLD patients from 41 countries were included: 14% had F0, 32% F1, 18% F2, 22% F3, 13% F4 (cirrhosis); 48% NAS ≥5. Advanced fibrosis prediction by NITs was variable across regions for FIB-4 [pooled AUC (95% CI)=0.80 (0.79-0.81)], the lowest in Latin America [0.75 (0.71-0.79)], the highest in MENA [0.84 (0.82-0.87)], and ELF [pooled AUC=0.77 (0.76-0.79)], the lowest in Europe [0.72 (0.69-0.76)], the highest in North America [0.80 (0.78-0.82)]. Prediction of advanced fibrosis by LSM [pooled AUC=0.84 (0.83-0.85)] was similar across regions except North America [0.78 (0.76-0.81)]. In addition, FAST [AUC=0.75 (0.74-0.76)] and Agile-3+ [AUC=0.87 (0.86-0.88)] performed similarly across regions. Similar trends were observed for the NITs predicting significant fibrosis. Finally, the accuracy of Agile-4 for predicting cirrhosis [AUC=0.90 (0.89-0.91)] was the lowest in North America [0.85 (0.83-0.87)], the highest in MENA [0.96 (0.94-0.98)].

CONCLUSIONS: The diagnostic performance of common NITs for fibrosis in MASLD varies across the world. In the large multinational G-MASLD sample, the most accurate NITs were Agile-3+ and Agile-4 composite scores.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent worldwide. Performance of non-invasive tests (NITs) in patients with MASLD recruited from different regions of the world was evaluated.

METHODS: MASLD patients with liver biopsies and NIT data [fibrosis-4 index (FIB-4), enhanced liver fibrosis (ELF), and liver stiffness measurement (LSM)] were enrolled through the Global NASH Council collaboration (G-MASLD). FibroScan-AST (FAST) and Agile-3+/Agile-4 were calculated. NITs' performance for predicting ≥F2 (significant fibrosis), ≥F3 (advanced fibrosis), or cirrhosis (F4) was determined in patients from different regions.

RESULTS: A total of 17,792 MASLD patients from 41 countries were included: 14% had F0, 32% F1, 18% F2, 22% F3, 13% F4 (cirrhosis); 48% NAS ≥5. Advanced fibrosis prediction by NITs was variable across regions for FIB-4 [pooled AUC (95% CI)=0.80 (0.79-0.81)], the lowest in Latin America [0.75 (0.71-0.79)], the highest in MENA [0.84 (0.82-0.87)], and ELF [pooled AUC=0.77 (0.76-0.79)], the lowest in Europe [0.72 (0.69-0.76)], the highest in North America [0.80 (0.78-0.82)]. Prediction of advanced fibrosis by LSM [pooled AUC=0.84 (0.83-0.85)] was similar across regions except North America [0.78 (0.76-0.81)]. In addition, FAST [AUC=0.75 (0.74-0.76)] and Agile-3+ [AUC=0.87 (0.86-0.88)] performed similarly across regions. Similar trends were observed for the NITs predicting significant fibrosis. Finally, the accuracy of Agile-4 for predicting cirrhosis [AUC=0.90 (0.89-0.91)] was the lowest in North America [0.85 (0.83-0.87)], the highest in MENA [0.96 (0.94-0.98)].

CONCLUSIONS: The diagnostic performance of common NITs for fibrosis in MASLD varies across the world. In the large multinational G-MASLD sample, the most accurate NITs were Agile-3+ and Agile-4 composite scores.

IL-21/IL-21R signaling is crucial in various immune diseases and cellular development, however, its role in bacterial pneumonia remains unclear. Here, IL-21R knockout (IL-21R) mice were more susceptible to Actinobacillus pleuropneumoniae (APP) than wild-type (WT) mice. High-dimensional mass cytometry analysis revealed that IL-21R deficiency inhibited neutrophil activation, decreased the numbers of monocytes and proinflammatory macrophages, and augmented the defective CD3 T cells in the lungs. Intracellular cytokine staining showed decreased IFN-γ/TNF-α/IL-6 production in IL-21R mice, particularly in CD8⁺ T cells. Furthermore, a previously unrecognized Ly6CLy6GCD4 T cell subset emerged only in the lungs of WT mice post-APP infection, which was in an activated status with stronger secretion capacities of IL-10, IL-21, granzyme B, and perforin by flow cytometry. These cells polarized macrophages into M2- or M1- phenotype without/with infection, respectively, and enhanced proliferation, phagocytosis, and macrophage extracellular traps/ROS-mediated bactericidal activity of macrophages against-APP, Klebsiella pneumoniae, or Escherichia coli infection. Thus, our study demonstrated that IL-21 drives the differentiation of neutrophils, monocytes, and macrophages into pro-inflammatory subsets. IL-21-induced Ly6CLy6GCD4 T cells cooperate with macrophages to enhance bacterial clearance, providing a promising target for preventing bacterial pneumonia.