SAID SHEHATA

Previous studies in the horse highlight the potential benefit of prolonged in vitro maturation (IVM) (34 h) compared to short IVM (24 h) with or without prior oocyte holding, but little is known about the optimal IVM duration within this interval. To determine the effect of oocyte holding and duration of IVM ranged between 28 and 34 h on nuclear maturation, cleavage, blastocyst formation, and pregnancy rates, a retrospective study was performed in an equine clinical OPU-ICSI setting. The study included data of 2114 aspirated oocytes from 201 OPU-ICSI sessions. Duration of IVM was divided in three different time windows using quartiles, with 465 oocytes (22.0 %) between 28 and 30 h (first quartile), 1078 oocytes (51.0 %) >30 and 31.7 h (second and third quartiles), and 571 oocytes (27.0 %) >31.7 and 34 h (fourth quartile). Using logistic regression models, the effect of duration of IVM with and without holding was tested on nuclear maturation, cleavage, blastocyst, and pregnancy rates. The three IVM intervals did not show differences in nuclear maturation (respectively 64.5 ± 0.48 %, 65.7 ± 0.47 %, and 67.3 ± 0.47 %), cleavage (respectively 59.7 ± 0.49 %, 58.5 ± 0.49 %, and 64.8 ± 0.48 %), blastocyst (respectively 17.5 ± 0.38 %, 19.0 ± 0.39 %, and 20.8 ± 0.41 %) nor pregnancy rates (respectively 65.4 ± 0.49 %, 70.3 ± 0.46 %, and 74.2 % ± 0.44) (P ≥ 0.38). Oocyte holding prior to IVM did not affect the results either (P ≥ 0.15). In conclusion, oocyte holding and IVM duration between 28 and 34h do not significantly affect outcomes, allowing flexibility in the planning of clinical OPU-ICSI in horses.

PURPOSE: The pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF), might be altered in patients with acute lymphoblastic leukemia (ALL), affecting the optimum dose needed for hepatitis C virus treatment. Limited data are available evaluating the population PK of LDV/SOF and SOF metabolite GS-331007. We aimed to study whether ALL could affect population PK parameters of LDV, SOF, and the SOF major metabolite GS-331007 in hepatitis C virus-infected children, develop and validate a predictive PK model of LDV/SOF disposition in this special population, and identify their explained and unexplained sources of variability.

METHODS: Population PK modeling was performed using MonolixSuite software using the non-linear mixed effect modeling approach. Different compartmental models, absorption models, and lag times for absorption parameters were tested to find out the best-fitting base model. For final model development, data-driven systematic covariate analysis using conditional sampling for the stepwise approach based on the correlation tests method has been performed. The final models were then evaluated using internal validation approaches.

FINDINGS: The PK results of 22 fully compliant patients were included in the population PK analysis. LDV and SOF were best described by a 1-compartment model with zero-order absorption and lag time, while the 2-compartment model with first-order absorption and lag time was the best-fitting model for the SOF metabolite. The internal validation approach confirmed the good predictive power of the selected models. The patients' weight explained the variability in the volume of distribution of LDV and the systemic clearance of SOF and LDV. The final SOF model also included a statistically significant covariate of steatosis stage on its volume of distribution, while the final GS-331007 model included mean corpuscular volume values on GS-331007 central compartment volume, packed cell volume, and direct bilirubin values on metabolite intercompartmental clearance.

IMPLICATIONS: The presence of ALL did not explain any variability in the developed population PK models for SOF, LDV, and GS-331007. Despite weight being a significant covariate in the final models suggesting that weight-based dosing of LDV/SOF is better than fixed dosing, the fixed dosing (45/200 mg LDV/SOF) is more practical in terms of simplicity in dosing children at home besides the proved efficacy and safety through both the clinical outcomes and PK exposure results. Weight-based dosing is still hindered due to the absence of exposure-response analysis, and the unavailability of dose-flexible formulas in the market. Future studies are required to support these findings.

GOV IDENTIFIER: NCT03903185.

Tamoxifen (TAM) is one of the most used drugs in the prevention and treatment of breast cancer. A set of common side effects was recorded associating its prolonged clinical use that ranges 3-10 years. This study aimed to investigate TAM-induced parietal cells (PCs) injury in rats and the possible protective effect of rhubarb (Rh) water extract (WE). Twenty-four adult female rats were distributed as: control group, TAM-group (3 mg/kg/day TAM for 4-weeks) and TAM+Rh-group (combined 3 mg/kg/day TAM and 20 mg/kg Rh-WE for 4-weeks). Blood sample before euthanizing rats was tested for vitamin-B12. PCs in stomach fundus were examined using histological and transmission electron microscopic studies, besides immunohistochemistry for Caspase-3, proliferating cell nuclear antigen (PCNA) and hydrogen potassium (H/K)-ATPase. Gastric homogenates were inspected for malondialdehyde (MDA) by ELISA. TAM intake induced structural and ultrastructural alteration in rat PCs including ballooning degeneration, apoptosis, decreased canaliculi, increased tubulovesicular system and irregular-shaped mitochondria. A significant increase of Caspase-3 immunostaining and MDA expression in gastric tissue was associated with a significant decrease of PCNA and H/K-ATPase-immunostaining and in serum vitamin-B12 as compared to the control group. Combined oral intake of TAM and Rh-WE revealed a significant reversal of the previous findings. Conclusion: Prolonged use of oral TAM substantially affected the structure and function of gastric PCs which can be ameliorated by Rh-WE.

The staging of liver fibrosis is essential in influencing the final clinical management and treatment intervention that depends on proper and prompt diagnosis. The suggested multi-stream deep learning architecture that also involves the combination of EfficientNetB0 and ResNet50 models may be regarded as a feature-level fusion solution that utilizes the most sophisticated normalization/regularization techniques. A full fusion model was also implemented, reaching a classification accuracy of 99.45% and a loss of 0.0295, which was higher than in any of the individual models (EfficientNetB0 with 98.50% and ResNet50 with 99.13%). In order to establish the robustness of the model, ablation analysis was carried out in detail, and it investigated the impact of an architectural element, including batch normalization, dropout layers, and fusion strategies. The results support the advantage of both normalization and dropout in terms of better generalization ability, but the feature fusion dramatically outperforms a simple concatenation in respect to discriminative ability. The findings reveal the strength of the multi-stream approach offered in the problem of homeless liver fibrosis stage classification, which means that it can be used in clinical practice.

This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

OBJECTIVE: To evaluate the augmented effects of trigger point dry needling (TPDN) and instrument-assisted soft tissue mobilization (IASTM) on pain and function in patellofemoral pain syndrome (PFPS).

METHODS: A single-blinded, randomized controlled trial was conducted with 102 participants (15-25 years) diagnosed with PFPS. Participants were randomly assigned to four groups: TPDN ( = 27), IASTM ( = 25), combined TPDN and IASTM ( = 26), and a control group ( = 24). The intervention groups received two treatment sessions per week for four consecutive weeks, in addition to a standardized exercise program for all groups. Primary (pressure pain threshold, PPT) and secondary (Kujala Anterior Knee Pain Scale, AKPS) outcomes were assessed at baseline and post-intervention.

RESULTS: Combined TPDN+IASTM demonstrated superior improvements in both outcomes: PPT increased by 78% and AKPS scores improved by 39% in the combined group. By comparison, the TPDN group showed a 53% increase in PPT and a 24% increase in AKPS, while the IASTM group showed a 54% increase in PPT and a 25% increase in AKPS ( < 0.001).

CONCLUSION: Both TPDN and IASTM are effective in reducing pain and improving function in PFPS. However, their synergistic application offers enhanced clinical benefits over either intervention alone or exercise therapy. These findings support integrating multimodal approaches for managing PFPS.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by motile cilia dysfunction. Identifying pathogenic variants is essential for diagnosis and personalized care, especially in consanguineous populations like Saudi Arabia.

CASE SUMMARY: This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea, chronic productive cough, and recurrent otitis media. Whole-exome sequencing revealed a novel homozygous nonsense variant in the gene (NM_198463.2:c.508C>T), resulting in a truncated, non-functional protein. This mutation likely impairs ciliary motility due to the production of a truncated, non-functional protein. The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms, suggesting a genetic etiology consistent with autosomal recessive inheritance.

CONCLUSION: This case highlights the importance of genetic studies in diagnosing PCD, particularly in communities with a high rate of consanguinity. The identification of a novel homozygous variant in the gene expands the known genetic landscape of the disease. Further research is essential to clarify the functional role of in ciliary biology and its contribution to PCD pathogenesis.

BACKGROUND: Patients are at significant risk of harm from unintended medication errors, which remain prevalent and often preventable in healthcare systems, especially in low- and middle-income countries. Medication reconciliation (MedRec) plays a critical role in minimizing these errors by ensuring an accurate and complete medication list throughout patient transitions in the healthcare system. AIM: This study aimed to assess the current status of the MedRec process in Egypt by exploring the knowledge, attitudes, and practices of physicians and pharmacists as key stakeholders in its implementation. METHODS: This descriptive, cross-sectional study used a structured, validated, self-administered online questionnaire targeting Egyptian physicians and pharmacists. The questionnaire was distributed via snowball sampling through professional networks and social media. Branching logic was used to tailor questions based on respondents’ familiarity with MedRec and hospital-based practices. Descriptive statistics were used to summarize the responses, while Chi-square and Mann–Whitney U tests were used to assess group differences. RESULTS: Among 272 respondents (182 pharmacists, 90 physicians), representing multiple Egyptian governorates and healthcare sectors (public, private, and military). Among them, 66.9% reported familiarity with MedRec, significantly higher among pharmacists (73.1% vs. 54.4%; p = 0.002). Most respondents (70.2%) rated MedRec as “very valuable” for patient safety, and both groups expressed strong responsibility for its core tasks. Among the 136 hospital-based respondents familiar with MedRec, 79.4% reported institutional implementation. Physicians were more likely than pharmacists to ask patients for their current medication lists (93.8% vs. 76.1%; p = 0.021). Sources of medication history included patient lists or physician documents (74.3%), family interviews (74.3%), medication boxes from home (59.56%), discharge orders (52.2%), and transfer orders from other facilities (33.8%). CONCLUSION: Continuous education and training programs are required to close knowledge gaps, strengthen MedRec practices, and promote a culture of patient safety in Egypt.

This paper introduces a novel automated framework aimed at bridging the gap between software design documentation and practical project management schedules. The primary objective is to address the longstanding challenge of manually translating UML sequence diagrams, fundamental design artifacts in software engineering, into executable and accurate project management plans such as Gantt charts and precedence graphs. Current manual approaches to schedule generation are notably error-prone, time-consuming, and inadequately integrated with the dynamic requirements of Agile and iterative project environments. To tackle this critical research gap, the paper proposes an integrated methodological pipeline combining advanced Optical Character Recognition (OCR), dependency graph generation, and machine learning optimization techniques. Specifically, OCR is employed to automatically extract tasks, interactions, and temporal details directly from visual representations of UML sequence diagrams, significantly reducing transcription errors and saving valuable planning time. Following extraction, tasks are structured into a validated Directed Acyclic Graph (DAG), accurately modeling inter-task dependencies and constraints. Further enhancing scheduling accuracy, the study applies gradient descent methods to iteratively predict and optimize task durations, moving beyond static estimates to dynamically refined predictions based on real-world project constraints. A forward pass analysis then calculates the earliest feasible start times, while Critical Path Method (CPM) analysis identifies the tasks crucial for project completion timelines. Comprehensive experimental validation across diverse scenarios clearly demonstrates the effectiveness and reliability of the proposed framework. Results show notable improvements in scheduling precision, visualization clarity through8/ generated Gantt charts and precedence graphs, and offering practical benefits to project managers and software development teams.

BACKGROUND: Lower respiratory infections (LRIs) remain the world's leading infectious cause of death. This analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides global, regional, and national estimates of LRI incidence, mortality, and disability-adjusted life-years (DALYs), with attribution to 26 pathogens, including 11 newly modelled pathogens, across 204 countries and territories from 1990 to 2023. With new data and revised modelling techniques, these estimates serve as an update and expansion to GBD 2021. Through these estimates, we also aimed to assess progress towards the 2025 Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) target for pneumonia mortality in children younger than 5 years.

METHODS: Mortality from LRIs, defined as physician-diagnosed pneumonia or bronchiolitis, was estimated using the Cause of Death Ensemble model with data from vital registration, verbal autopsy, surveillance, and minimally invasive tissue sampling. The Bayesian meta-regression tool DisMod-MR 2.1 was used to model overall morbidity due to LRIs. DALYs were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for all locations, years, age groups, and sexes. We modelled pathogen-specific case-fatality ratios (CFRs) for each age group and location using splined binomial regression to create internally consistent estimates of incidence and mortality proportions attributable to viral, fungal, parasitic, and bacterial pathogens. Progress was assessed towards the GAPPD target of less than three deaths from pneumonia per 1000 livebirths, which is roughly equivalent to a mortality rate of less than 60 deaths per 100 000 children younger than 5 years.

FINDINGS: In 2023, LRIs were responsible for 2·50 million (95% uncertainty interval [UI] 2·24-2·81) deaths and 98·7 million (87·7-112) DALYs, with children younger than 5 years and adults aged 70 years and older carrying the highest burden. LRI mortality in children younger than 5 years fell by 33·4% (10·4-47·4) since 2010, with a global mortality rate of 94·8 (75·6-116·4) per 100 000 person-years in 2023. Among adults aged 70 years and older, the burden remained substantial with only marginal declines since 2010. A mortality rate of less than 60 deaths per 100 000 for children younger than 5 years was met by 129 of the 204 modelled countries in 2023. At a super-regional level, sub-Saharan Africa had an aggregate mortality rate in children younger than 5 years (hereafter referred to as under-5 mortality rate) furthest from the GAPPD target. Streptococcus pneumoniae continued to account for the largest number of LRI deaths globally (634 000 [95% UI 565 000-721 000] deaths or 25·3% [24·5-26·1] of all LRI deaths), followed by Staphylococcus aureus (271 000 [243 000-298 000] deaths or 10·9% [10·3-11·3]), and Klebsiella pneumoniae (228 000 [204 000-261 000] deaths or 9·1% [8·8-9·5]). Among pathogens newly modelled in this study, non-tuberculous mycobacteria (responsible for 177 000 [95% UI 155 000-201 000] deaths) and Aspergillus spp (responsible for 67 800 [59 900-75 900] deaths) emerged as important contributors. Altogether, the 11 newly modelled pathogens accounted for approximately 22% of LRI deaths.

INTERPRETATION: This comprehensive analysis underscores both the gains achieved through vaccination and the challenges that remain in controlling the LRI burden globally. Furthermore, it demonstrates persistent disparities in disease burden, with the highest mortality rates concentrated in countries in sub-Saharan Africa. Globally, as well as in these high-burden locations, the under-5 LRI mortality rate remains well above the GAPPD target. Progress towards this target requires equitable access to vaccines and preventive therapies-including newer interventions such as respiratory syncytial virus monoclonal antibodies-and health systems capable of early diagnosis and treatment. Expanding surveillance of emerging pathogens, strengthening adult immunisation programmes, and combating vaccine hesitancy are also crucial. As the global population ages, the dual challenge of sustaining gains in child survival while addressing the rising vulnerability in older adults will shape future pneumonia control strategies.

FUNDING: Gates Foundation.

There is a recent suggestion by the American Academy of Pediatric Dentistry to seal initial non-cavitated carious lesions in adults. The aim of the present study was to evaluate the sealant retention and inhibition of initial carious lesion progression of the bioactive fissure sealant with SmartCap technology "Biocoat" compared to fluoride releasing fissure sealant "Clinpro sealant" over 24 months in non-cavitated occlusal carious lesions in adults. The present study is a randomized clinical trial, following a parallel group design with superiority framework and 1:1 allocation ratio. Thirty-six participants with 64 non-cavitated occlusal carious lesions were divided into two groups according to random allocation sequence (n = 32); either Biocoat (intervention) or Clinpro (control). Sealants were assessed at baseline, 12 and 24 months for retention and caries progression. Statistical analysis was performed by MedCalc 22 software for Windows. Intergroup comparison between sealants within each follow-up period was done using the Chi-Square test (p ≤ 0.05). Intragroup comparison within each intervention to assess change in clinical performance through time was performed by the Cochran's Q test (p ≤ 0.016). After 24 months, two sealants in Biocoat group and 11 sealants in Clinpro group failed due to loss of retention or caries progression. Biocoat has shown 93.75% success rate, while Clinpro has shown 65.62% success rate after 24 months. The relative risk (RR) was 0.18 (95% CI 0.04374 to 0.7558), showing 82% less risk of failure of Biocoat when compared to Clinpro sealant, and this was statistically significant (p = 0.0190). Biocoat sealant showed better retention rate and inhibition of initial carious lesion progression after 24 months when compared to fluoride releasing sealant in non-cavitated occlusal caries in adults.Clinical relevance: The present study supports the suggestion of AAPD on sealing initial carious lesions. Sealing of initial non-cavitated occlusal carious lesions is a conservative and successful approach and should be implemented in routine dental practice in adults with recent history of dental caries.Trial registration: The present clinical trial was retrospectively registered on clinicaltrials.gov on 22-05-2023 (NCT05891288).

Exposure to nickel (Ni) and chromium (Cr) in environmental and occupational settings appears to be inevitable and significantly affects the liver, the principal organ responsible for their metabolic processes. This research aimed to assess the functional integrity of the liver and the molecular mechanisms underlying hepatic damage in employees exposed to Ni and Cr at work. A cross-sectional investigation was implemented with 86 non-smoking male employees working in a metallurgical factory. Serum Cr, Ni, liver function tests, oxidative and inflammatory indicators, and , , and expression were assessed. In electroplating workers, serum Cr (2.47 ± 2 µg/L), Ni (1.39 ± 0.79 µg/L), liver transaminases, total bilirubin, and NF-κB were all statistically significantly greater than in the referent group. Electroplaters' serum albumin levels were significantly lower than those of controls. Furthermore, oxidative stress was observed in electroplaters, characterized by lower levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and greater levels of malondialdehyde (MDA) with respect to controls ( < 0.05). Additionally, compared to controls, gene expressions in electroplaters showed that was upregulated, while / and were downregulated. In conclusion, occupational exposure to Ni and Cr was associated with hepatic impairment through downregulation of the antioxidant pathway, oxidative stress, and inflammation.

: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. : The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. : Compounds , , , , and showed strong inhibition of both kinases (IC = 0.145-0.970 μM for VEGFR-2 and 0.181-1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound (-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, induced G/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. : Compound was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy.

BACKGROUND: Temporomandibular disorders (TMDs) are a group of musculoskeletal conditions characterized by orofacial pain and functional impairments. The Jaw Functional Limitation Scale (JFLS) is a patient-reported outcome measure recommended by the Diagnostic Criteria for Temporomandibular Disorders. The aim of the study was to translate and cross-culturally adapt the JFLS for the Arabic language and to test its validity and reliability in Egyptian patients with TMDs.

METHODS: The JFLS was translated and cross-culturally adapted into Modern Standard Arabic according to standard guidelines. The construct validity was assessed in 54 patients with TMD who completed the Arabic versions of JFLS (JFLS-Ar), the Arabic version of Oral Health Impact Profile 5 (OHIP5-Ar), and the Numerical Pain Rating Scale (NPRS). Test-retest reliability was estimated in 30 participants who completed the JFLS-Ar again within seven days. Cronbach's alpha coefficient was used to determine the internal consistency of the items in the JFLS-Ar.

RESULTS: The total score (0-200) of the JFLS-Ar showed moderate correlations with both OHIP5-Ar (ρ = 0.58, p < 0.001) and NPRS (ρ = 0.56, p < 0.001). The global score (average of the three domain scores, 0-10) showed moderate correlations with both OHIP5-Ar (ρ = 0.56, p < 0.001) and NPRS (ρ = 0.56, p < 0.001). The short form global score (average of 8 specific items, 0-10) showed moderate correlations with both OHIP5-Ar (ρ = 0.61, p < 0.001) and NPRS (ρ = 0.6, p < 0.001). The total score showed excellent test-retest reliability with an ICC of 0.97 (95% CI: 0.95-0.99), Standard Error of Measurement (SEM) of 6.17, and Minimal Detectable Change (MDC) of 17.1. The global score showed excellent test-retest reliability with an ICC of 0.97 (95% CI: 0.93-0.98), SEM of 0.38, and MDC of 1.06. The short form global score showed excellent test-retest reliability with an ICC of 0.99 (95% CI: 0.98-0.995), SEM of 0.2, and MDC of 0.55. The Cronbach's alpha coefficient of the 20-item JFLS-Ar and the 8-item JFLS-Ar was 0.938 and 0.852, respectively.

CONCLUSIONS: The JFLS-Ar represents a valid and reliable instrument for use in Arabic-speaking patients with TMDs.

Bipolar disorder (BD) is a chronic and prevalent psychiatric disease that has been considered a leading cause of disability among psychiatric conditions. Taking into account that there is yet no satisfactory disease-modifying treatment, we investigated the effect of genistein on ouabain-induced BD in male C57BL/6 mice. Animals were categorized into control, genistein control, ouabain model, lithium (Li)-treated, and genistein-treated groups. BD was induced by bilateral intracerebroventricular injection of 0.625 nmol ouabain. Genistein (10 mg/kg/day) was orally administered for 2 weeks following a single dose of ouabain. Open field test, sucrose preference test, and forced swim test were performed. Na⁺/K⁺-ATPase activity was evaluated through measuring the hippocampal levels of phosphorylated epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase, extracellular signal-regulated kinase, and cAMP response element-binding protein (p-CREB) by western blot analysis. The levels of brain-derived neurotrophic factor (BDNF), serotonin, oxidative stress, and inflammatory markers were quantified by ELISA. The BCL-2-associated X protein (BAX) to B-cell Lymphoma/Leukemia (BCL2) ratio was assessed by qRT-PCR. Genistein reduced manic and anxious behaviors during the manic phase and showed an antidepressant effect during the depression phase, all while maintaining an effective metabolic balance on body weight. Additionally, genistein increased serotonin, p-CREB, and BDNF levels while decreasing inflammation and apoptosis produced by ouabain. Furthermore, genistein restored the normal architecture in both hippocampal and cortical H&E-stained sections. Taken together, genistein was able to activate the Na⁺/K⁺-ATPase signalosome via a multifaceted mode of action, exerting a neuroprotective effect in an animal model of BD, promoting genistein as a therapeutic candidate for BD.

: Accurate segmentation in radiographic imaging remains difficult due to heterogeneous contrast, acquisition artifacts, and fine-scale anatomical boundaries. : This paper presents a Hybrid Attention U-Net, which paired an EfficientNet-B3 encoder with a decoder that is both lightweight, featuring CBAM and SCSE modules, and complementary for channel-wise and spatial-wise recalibration of sharper boundary recovery. : The preprocessing phase uses percentile windowing, N4 bias compensation, per-image normalization, and geometric standardization as well as sparse geometric augmentations to reduce domain shift and make the pipeline viable. : For hand X-ray segmentation, the model achieves results with Dice = 0.8426, IoU around 0.78, pixel accuracy = 0.9058, ROC-AUC = 0.9074, and PR-AUC = 0.8452, and converges quickly at the early stages and remains steady at late epochs. Controlled ablation shows that the main factor of overlap quality of EfficientNet-B3 and that smaller batches (bs = 16) are always better at gradient noise and implicit regularization than larger batches. The qualitative overlays are complementary to quantitative gains that reveal more distinct cortical profiles and lower background leakage. : It is computationally moderate, end-to-end trainable, and can be easily extended to multi-class problems through a softmax head and class-balanced objectives, rendering it a powerful, deployable option for musculoskeletal radiograph segmentation as well as an effective baseline in future clinical translation analyses.

Oral health is a significant contributor to public health and a basic determinant of general health. As Egypt shows high prevalence of oral diseases, the aim of this study is to assess the oral health knowledge, attitudes and behaviors (KAB) among Egyptian adults. The study also correlates the KAB of the participants with their dental habits, caries experience and sociodemographic characteristics. A cross-sectional survey with non-probability convenience sampling was performed in a dental school hospital in Egypt. The Hiroshima University - Dental Behavioral Inventory (HU-DBI) by Kawamura was used to assess the KAB, the survey also included questions about sociodemographic data and dental habits of the participants. In addition, a DMFT index was used to assess the caries experience. Continuous data was explored for normality using Kolmogrov Smirnov test and Shapiro Wilktest. Correlation between age, DMF, KAB and HU-DBI index was performed using spearman's correlation. Association between categorical data and HU-DBI index was performed using the Chi-Square test. Significance level was set at P ≤ 0.05 and all tests were two tailed. The study participants demonstrated fair HU-DBI score. Knowledge (r = 0.70), attitudes (r = 0.59) and behaviors (r = 0.47) had strong positive correlation with the HU-DBI score. The DMFT score showed a moderate negative correlation (r=-0.35) with the overall HU DBI score. In addition, age showed a weak negative correlation (r=-0.29) with HU DBI score. The dental habits and sociodemographic characteristics showed statistically significant effect on the overall HU-DBI score, with the exception for mouth wash use, gender, health status and smoking status which showed no significant effect. Adult patients in Egypt demonstrate fair oral health knowledge and attitude and poor oral health behaviors, in addition to high caries index. We recommend planning and implementing oral health programs to enhance the oral health of adults in Egypt.Clinical trial number: The protocol of the study is registered with ClinicalTrials.gov Identifier: NCT06689202.

Multiple sclerosis (MS) is an enduring autoimmune and neurodegenerative disease affecting the central nervous system with inflammation, demyelination, and axonal degeneration that progresses to neurological impairment. Despite available treatments, their limited efficacy, inability to promote remyelination, and associated adverse reactions highlight the need for unconventional therapies. This study investigated the therapeutic potential of dexmedetomidine (DEX), a selective α2-adrenergic receptor (α2AR) agonist, in a rat model of MS triggered by experimental autoimmune encephalomyelitis (EAE). EAE was induced in male Sprague Dawley rats using guinea pig spinal cord homogenate and complete Freund's adjuvant, replicating MS-like pathology. DEX (10 μg/kg/day, i.p.) was administered for 14 days, significantly improved motor function and muscle coordination, as shown by enhanced performance in the open field, rotarod, and hanging wire tests, along with reduced pain sensitivity in the Randall-Selitto test. Histological analyses (H&E and TEM) confirmed increased axonal remyelination and paralleling improvements in clinical scores. Mechanistically, DEX activated α2AR, stimulating the PI3K/p-Akt pathway and promoting CREB phosphorylation. This cascade upregulated BDNF and TrkB gene expression and enhanced neuronal remyelination and survival. Additionally, DEX exhibited potent anti-inflammatory effects by suppressing HMGB1, thereby downregulating TLR4 expression and inhibiting the pS536-NF-κB p65/TNF-α axis. This shift was evidenced by reduced CD86 immunoreactivity and increased CD163 expression, indicating a transition toward an anti-inflammatory phenotype. In conclusion, DEX exerts neuroprotective effects in EAE-induced MS by simultaneously triggering the PI3K/Akt/CREB/BDNF/TrkB pathway and hindering the HMGB1/TLR4/NF-κB/TNF-α cascade, leading to reduced neuroinflammation and enhanced remyelination. Therefore, DEX represents a promising MS treatment, warranting further clinical exploration.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of mortality and are among the foremost causes of disability globally. CVD burden has continued to increase in most countries since 1990, with trends driven by changing exposures to harmful risk factors, population growth, and population aging.

OBJECTIVES: We report estimates of global, national, and subnational CVD burden, including 18 subdiseases and 12 associated modifiable risk factors. We analyzed change in CVD burden from 1990 to 2023 and identified drivers of change including population growth, population aging, and risk factor exposure.

METHODS: The Global Burden of Disease (GBD) 2023 study, a multinational collaborative research study, quantified burden due to 375 diseases including CVD burden and identified drivers of change from 1990 to 2023 using all available data and statistical models. GBD 2023 estimated the population-level burden of diseases in 204 countries and territories from 1990 to 2023.

RESULTS: CVDs were the leading cause of disability-adjusted life years (DALYs) and deaths estimated in the GBD. As of 2023, there were 437 million (95% UI: 401 to 465 million) CVD DALYs globally, a 1.4-fold increase from the number in 1990 of 320 million (292 to 344 million). Ischemic heart disease, intracerebral hemorrhage, ischemic stroke, and hypertensive heart disease were the leading cardiovascular causes of DALYs in 2023 globally. As of 2023, age-standardized CVD DALY rates were highest in low and low-middle Socio-demographic Index (SDI) settings and lowest in high SDI settings. The number of CVD deaths increased globally from 13.1 million (95% UI: 12.2 to 14.0 million) in 1990 to 19.2 million (95% UI: 17.4 to 20.4 million) in 2023. The number of prevalent cases of CVD more than doubled since 1990, with 311 million (95% UI: 294 to 333 million) prevalent cases of CVD in 1990 and 626 million (95% UI: 591 to 672 million) prevalent cases in 2023 globally. A total of 79.6% (95% UI: 75.7% to 82.5%) of CVD burden is attributable to modifiable risk factors 347 million [95% UI: 318 to 373 million] DALYs in 2023). Globally, high systolic blood pressure, dietary risks, high low-density lipoprotein cholesterol, and air pollution were the modifiable risks responsible for most attributable CVD burden in 2023. Since 1990, changes in exposure to modifiable risk factors have had mixed effects on CVD burden, with increases in high body mass index, high fasting plasma glucose, and low physical activity leading to higher burden, while reductions in tobacco usage have mitigated some of these increases. Population growth and population aging were the main drivers of the increasing burden since 1990, adding 128 million (95% UI: 115 to 139 million) and 139 million (95% UI: 126 to 151 million) CVD DALYs to the increase in CVD burden since 1990.

CONCLUSIONS: CVD remains the leading cause of disease burden and death worldwide with the greatest burden in low, low-middle, and middle SDI regions. Large variation exists in CVD burden even for countries at similar levels of development, a gap explained substantially by known, modifiable risk factors that are inadequately controlled. The decades-long increase in CVD burden was the result of population growth, population aging, and increased exposure to a subset of risk factors led by metabolic risks. Countries will need to adopt effective health system and public health strategies if they are to progress in achieving global goals to reduce the burden of CVD.

For a very long time, herbal treatments have served as remedies for various humans and animals. Natural compounds typically have multiple pharmacological actions because they interact with various biological targets. This characteristic could be exploited to effectively treat disorders with complex physiopathological causes, such as endometriosis. Endometriosis is the proliferation, infiltration, and recurrent bleeding of endometrioid tissue, including stroma and glands, outside the uterine cavity, forming nodules or masses. It affects women of reproductive age and is characterized by persistent inflammation and estrogen dependence, significantly impacting patients' quality of life. Although the precise pathogenic mechanisms remain unclear, current treatments mainly include medication and surgery. Pharmacotherapy typically relies on nonsteroidal anti-inflammatory drugs and hormonal agents, which may cause adverse effects such as gastrointestinal disturbances, hepatic and renal dysfunction, and thrombosis when used as a long-term treatment. Surgical removal of lesions is possible but often followed by recurrence rates of 21.5% after 2 years and up to 50% within 5 years. Therefore, alternative or complementary therapeutic approaches are urgently needed. This review summarizes current evidence on bioactive plant extracts, both crude and refined, and their mechanisms of action against endometriosis, highlighting their multi-target therapeutic potential and underscoring the need for further pre-clinical and clinical studies to develop effective, safer natural treatment strategies.

BACKGROUND AND OBJECTIVE: Perampanel has been approved for the adjunctive treatment of partial-onset seizures and primary generalized tonic-clonic seizures. The oral suspension formulation benefits patients who have difficulty swallowing tablets. The unavailability of an affordable generic perampanel oral suspension formulation increased the need for a cheaper bioequivalent alternative to the marketed reference product. The study aimed to assess the bioequivalence of two formulations of perampanel oral suspension (0.5 mg/mL) administered under fasting conditions focusing on providing a cost-effective and accessible alternative to current formulations.

METHODS: This was an open-label, two-period, two-sequence, crossover, bioequivalence study conducted under fasting conditions. Healthy subjects were randomized to receive single doses of perampanel oral suspension (12 mg), Lepsiramp and Fycompa separated by a 6-week washout period. The maximum concentration and area under the concentration-time curve up to 72 h were the primary pharmacokinetic parameters used to assess bioequivalence.

RESULTS: The geometric mean ratio of test to reference formulations and 90% confidence interval were 109.55 (99.49-120.64) for maximum concentration and 98.15 (90.68-106.23) for the area under the concentration-time curve up to 72 h which were within the 80-125% bioequivalence range. The adverse events were mild headache and dizziness.

CONCLUSIONS: The two oral suspension formulations were bioequivalent, safe, and well tolerated. This provides a beneficial affordable alternative for patients requiring non-tablet oral formulations.

CLINICAL TRIAL REGISTRATION: The ClinicalTrials.gov registration number is NCT06969963, retrospectively registered on 13 May, 2025.

Addressing foodborne illness is a major concern for consumers and food industry regulators; therefore, natural preservatives play a vital role in improving food safety and extending shelf life. Onion (Allium cepa L.) is globally recognized both for its culinary uses and its significant antimicrobial properties. In this study, an integrative approach was employed, combining ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and gas chromatography-mass spectrometry (GC-MS), to profile the metabolome of four Egyptian onion cultivars (cvs.). UPLC-MS analysis annotated 93 metabolites, several previously unreported metabolites such as flavonoids, nitrogenous compounds, and fatty acids. GC-MS analysis identified 24 silylated primary metabolites. Solid-phase microextraction aroma profiling highlighted organosulfur enrichment, particularly dipropyl trisulfide in the Giza 20 cv., contrasted by propenyl propyl disulfide dominance in others. Multivariate data analysis of silylated metabolites demonstrated superior efficacy in capturing metabolome diversity compared to aroma profiles or LC-MS data. Furthermore, vapor-phase antimicrobial assays, using foodborne pathogens, revealed the potential of onion cvs. as a natural food preservative. This study presents the first comparative metabolite profiling and remote antimicrobial assessment of Egyptian onion cvs., offering new insights into their culinary potential, health benefits, and chemical diversity within A. cepa accessions.

Vaginal candidiasis is a medical condition that affects large majority of the women at least once in their lifetime. The condition manifests with itching, irritation, and discharges which is troublesome for women during mundane activities. The purpose of this research was to formulate and evaluate the physicochemical properties and drug permeation of Fenticonazole-loaded cubogel through vaginal mucosa. Concisely, the drug-loaded cubosomes were prepared via hot dispersion emulsification technique. Following, the percent drug entrapment efficiency, particle size, polydispersity index, and zeta potential of the cubosomes were determined. Optimization criteria involved maximizing entrapment efficiency (EE %) and zeta potential (ZP), while maintaining a nanoscale particle size to ensure colloidal stability. The optimized formulation exhibited a high desirability score of 0.933 with EE % of 85.32 2.34 %, PS of 169 0.85 nm, PDI of 0.29 0.02, and ZP of -24.40 1.27 mV. In addition, 86.77 3.79 % of Fenticonazole nitrate was released from the optimum cubosomal formulation after 8 h. Cubical nanovesicles were revealed via transmission electron microscope while infrared spectroscopy revealed the lack of interaction between the used components. Stability was unchanged upon storage for three months. The rheogram of the optimum formulation-loaded cubogel suggested a shear-thinning behavior. Additionally, the optimum cubogel demonstrated higher biofilm inhibitory effect compared to the drug suspension. Similarly, both, ex vivo permeation and confocal laser scanning, suggested the enhanced vaginal epithelium permeability and the deeper vaginal mucosa penetration of the optimum cubogel, compared to the drug suspension and aqueous Rhodamine B carbopol gel, respectively. Histopathological assessment concluded with the safety of the cubogel on the vaginal mucosal epithelium and underlying tissue.

We investigated whether induction of acute pancreatitis (AP) can cause dysregulation in the glycoprotein zymogens, following episodes of nitrosative stress, which may be differentially protected by vitamin E and metformin. AP was induced in rats by L-arginine (2.5 g/kg) injections (two doses given at 1-h interval). The protective groups were pre-treated with either vitamin E (60 mg/kg) or metformin (50 mg/kg) prior to L-arginine injections and continued on these medications until being sacrificed. AP markedly decreased the density of zymogen granules in pancreatic acinar cells (44.5 ± 2.2% in control versus 9.2 ± 1.9% in AP), alongside tissue damage and a significant ( < 0.0001) increase in biomarkers of nitrosative stress (iNOS), inflammation (IL-6 and TNF-α mRNA), and pancreatic injury (amylase, lipase, LDH, and MPO). All these parameters were significantly ( ≤ 0.0005) protected by vitamin E and metformin, with vitamin E providing greater protection for pancreatic glycoprotein zymogens and serum amylase. Thus, AP is associated with the destruction of the glycoprotein zymogens, which is differentially protected by vitamin E and metformin.