Dr Mohammed Mahmoud Youssif

OBJECTIVES: This RCT aimed to evaluate the effect of topical Rebamipide (regular and nanoparticulated) in comparison to topical Clobetasol propionate in the management of methotrexate-induced oral ulcers in rheumatoid arthritis patients.

MATERIALS AND METHODS: Patients were divided randomly into three parallel arms: 1% Rebamipide; 1% nanoparticulated Rebamipide, Clobetasol propionate. The outcome measures included WHO oral mucositis grading, pain (NRS), ulcer size, and healing time. The data was analyzed for any statistical significance.

RESULTS: Intragroup comparisons of mucositis grade improvement and pain reduction revealed significant differences in all the groups. All intergroup comparisons demonstrated non-significant difference, yet nanoparticulated Rebamipide was leading, and all group participants achieved complete healing earlier than the other groups.

CONCLUSION: Rebamipide, regular and nanoparticulated forms, showed comparable results to potent Corticosteroid, Clobetasol propionate in management of the oral ulcers.

CLINICAL RELEVANCE: Rebamipide is an efficient promising alternative modality for management of methotrexate-induced oral ulcers in rheumatoid arthritis patients.

Extrahepatic biliary atresia (EHBA) is a leading cause of neonatal cholestasis, often resulting in end-stage cirrhosis and portal hypertension without early diagnosis and treatment. This report highlights the importance of timely intervention, describing a 6-day-old male newborn diagnosed with EHBA who underwent successful Kasai portoenterostomy at 9 days of age. While the procedure is typically performed within the first 60 days of life, this exceptionally early intervention led to significantly improved outcomes. Postoperative recovery was marked by bilirubin normalization within 2 months and steady improvement in liver function tests, demonstrating the advantages of early surgery. The procedure involved creating a Roux-en-Y hepatic portojejunostomy to restore bile flow, preventing progression to biliary cirrhosis. Early intervention achieved effective bile drainage and substantial clinical improvement. At the 1-year follow-up, the infant displayed normal growth and liver function. This case supports the hypothesis that performing Kasai portoenterostomy earlier than current guidelines recommend may lead to better outcomes. It underscores the need for vigilant neonatal care to recognize early signs of cholestasis and enable prompt surgical intervention. Early diagnosis and intervention can preserve liver function, potentially delaying or preventing the need for liver transplantation.

Extrahepatic biliary atresia (EHBA) is a leading cause of neonatal cholestasis, often resulting in end-stage cirrhosis and portal hypertension without early diagnosis and treatment. This report highlights the importance of timely intervention, describing a 6-day-old male newborn diagnosed with EHBA who underwent successful Kasai portoenterostomy at 9 days of age. While the procedure is typically performed within the first 60 days of life, this exceptionally early intervention led to significantly improved outcomes. Postoperative recovery was marked by bilirubin normalization within 2 months and steady improvement in liver function tests, demonstrating the advantages of early surgery. The procedure involved creating a Roux-en-Y hepatic portojejunostomy to restore bile flow, preventing progression to biliary cirrhosis. Early intervention achieved effective bile drainage and substantial clinical improvement. At the 1-year follow-up, the infant displayed normal growth and liver function. This case supports the hypothesis that performing Kasai portoenterostomy earlier than current guidelines recommend may lead to better outcomes. It underscores the need for vigilant neonatal care to recognize early signs of cholestasis and enable prompt surgical intervention. Early diagnosis and intervention can preserve liver function, potentially delaying or preventing the need for liver transplantation.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) infection is a significant problem in Egypt, as it is associated with various hematological disorders, both benign and malignant. In Egypt, direct-acting antivirals (DAAs) serve as the principal therapy for HCV to achieve a sustained virological response (SVR). This study investigated the effects of sofosbuvir (SOF) and daclatasvir (DCV) on HCV patients with benign blood index abnormalities and examined the correlation between these abnormalities and SVR.

PATIENTS AND METHODS: Data were obtained from 59,069 enrolled patients who were treatment-naïve and met the eligibility criteria for therapy as per the standards of Egypt's National Committee for Control of Viral Hepatitis (NCCVH). The patients adhered to the SOF and DCV therapy protocol.

RESULTS: The predominant hematological abnormality was thrombocytopenia, followed by leukopenia and anemia. Non-SVR was significantly correlated with the existence of one or more baseline cytopenias. The primary predictors of treatment failure were male gender, elevated Fib-4 score, and baseline thrombocytopenia. Despite the low incidence of cytopenia among patients after therapy, non-SVR was seen in instances of anemia.

CONCLUSION: Hematological problems often occur in HCV patients both before and after SOF and DCV treatment. Treatment failure was associated with the presence of one or more baseline cytopenias, as well as the development of anemia during treatment. Nonetheless, SOF and DCV are still safe to be used in the presence of cytopenia.

OBJECTIVE: The purpose of this study was to improve our understanding of severe serine biosynthesis defects through a comprehensive description of prenatal, and postnatal manifestations and the mutational spectrum in a new cohort of 12 unrelated Egyptian Families.

METHODS: Detailed fetal ultrasound examination, postnatal assessment, and whole exome sequencing (WES) were performed in a cohort of 12 fetuses with suspected Neu-Laxova syndrome (NLS), the most severe expression of serine biosynthesis defects. Additionally, a comprehensive review of the literature was conducted by merging the data from all the molecularly-confirmed cases with ours to gain a better understanding of the clinical variability of NLS.

RESULTS: Novel clinical manifestations including intrauterine convulsions, hemivertebrae, natal teeth, holoprosencephaly, and rhombencephalosynapsis were observed. Molecular analysis identified 7 and 2 likely disease-causing variants in the PSAT1 and PHGDH genes, respectively. Four of them were novel, including the c.734G>A missense variant in PSAT1, which has been proposed to be a founder variant among Egyptians.

CONCLUSION: The present cohort expands the spectrum of serine biosynthesis disorders. Moreover, it illuminates the role of prenatal exome sequencing in lethal conditions constituting the most severe end of already-known human diseases.

The current study was deployed to evaluate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-155, along with the inflammatory markers, TNFα and IL-6, and the adhesion molecule, cluster of differentiation 106 (CD106), in Behçet's disease (BD) pathogenesis. The study also assessed MALAT1/miR-155 as promising diagnostic and prognostic biomarkers for BD. The current retrospective case-control study included 74 Egyptian BD patients and 50 age and sex-matched controls. Blood samples were collected, and then, serum samples were separated for further biochemical and molecular investigations. The gene expression of MALAT1 and miR-155 was measured using qRT-PCR, whereas the levels of TNFα, IL-6, and CD106 were estimated using ELISA technique. MALAT1 was significantly downregulated, whereas miR-155 was upregulated among BD patients, compared with control subjects. Levels of TNFα, IL-6, and CD106 were elevated in BD patients. Further downregulation in MALAT1 together with upregulation of miR-155 was observed in active BD patients, relative to the inactive group. Receiver-operating-characteristic analysis revealed that MALAT1 and miR-155 could discriminate BD patients from controls, on the one hand, and active from inactive BD patients, on the other hand. MALAT1 was negatively correlated with TNFα, IL-6, and CD106, while miR-155 was positively correlated with them. Logistic regression analyses demonstrated miR-155 as a significant independent predictor of BD susceptibility, and MALAT1 as an independent negative predictor of BD activity. For the first time, the current research enlightens the role of MALAT1 and miR-155 in BD pathogenesis via impacting IL-6/TNF-α/CD-106 signaling. As well, MALAT1 and miR-155 could be regarded as novel non-invasive biomarkers that may improve BD diagnosis and prognosis. Key Points •MALAT1/miR-155 exerts potential role in Behçet's disease. •MALAT1/miR-155 are promising biomarkers for Behçet's disease. •MALAT1/miR-155 targets IL-6/TNF-α/CD-106 signaling.

The current study was deployed to evaluate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-155, along with the inflammatory markers, TNFα and IL-6, and the adhesion molecule, cluster of differentiation 106 (CD106), in Behçet's disease (BD) pathogenesis. The study also assessed MALAT1/miR-155 as promising diagnostic and prognostic biomarkers for BD. The current retrospective case-control study included 74 Egyptian BD patients and 50 age and sex-matched controls. Blood samples were collected, and then, serum samples were separated for further biochemical and molecular investigations. The gene expression of MALAT1 and miR-155 was measured using qRT-PCR, whereas the levels of TNFα, IL-6, and CD106 were estimated using ELISA technique. MALAT1 was significantly downregulated, whereas miR-155 was upregulated among BD patients, compared with control subjects. Levels of TNFα, IL-6, and CD106 were elevated in BD patients. Further downregulation in MALAT1 together with upregulation of miR-155 was observed in active BD patients, relative to the inactive group. Receiver-operating-characteristic analysis revealed that MALAT1 and miR-155 could discriminate BD patients from controls, on the one hand, and active from inactive BD patients, on the other hand. MALAT1 was negatively correlated with TNFα, IL-6, and CD106, while miR-155 was positively correlated with them. Logistic regression analyses demonstrated miR-155 as a significant independent predictor of BD susceptibility, and MALAT1 as an independent negative predictor of BD activity. For the first time, the current research enlightens the role of MALAT1 and miR-155 in BD pathogenesis via impacting IL-6/TNF-α/CD-106 signaling. As well, MALAT1 and miR-155 could be regarded as novel non-invasive biomarkers that may improve BD diagnosis and prognosis. Key Points •MALAT1/miR-155 exerts potential role in Behçet's disease. •MALAT1/miR-155 are promising biomarkers for Behçet's disease. •MALAT1/miR-155 targets IL-6/TNF-α/CD-106 signaling.

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.

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.

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.

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.

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.

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.

BACKGROUND AND AIM: Alagille syndrome (ALGS) is a rare disorder characterised by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, we evaluated whether SBA predicts liver disease outcomes in ALGS.

METHODS: Patients were ascertained from the Global ALagille Alliance (GALA) cohort. A prognostic threshold of SBA 102 μmol/L was assessed as a time-dependent covariate in Cox regression analyses for native liver survival (NLS) and event-free survival (EFS), while adjusting for total bilirubin (TB) levels.

RESULTS: 570 GALA patients were included (348 [61%] male). There was a moderate positive correlation between SBA and TB (Pearson correlation = 0.47, p < 0.001). SBA below 102 μmol/L was a significant predictor of outcomes (NLS: HR = 3.78, 95% CI 2.39-5.99, p < 0.001; EFS: HR = 3.44, 95% CI 2.35-5.04, p < 0.001). SBA remained a significant predictor for improved EFS after adjusting for TB clearance at 1 year (TB < 2 mg/dL; HR = 2.00, 95% CI 1.10-3.65, p = 0.02). Median SBA in the first year of life above 102 μmol/L, predicted lower NLS (67.2% vs. 83.5% at 7 years p = 0.05) and EFS (63.4% vs. 80.9% at 7 years, p = 0.02).

CONCLUSION: Lower SBA in children with ALGS liver disease predicts improved NLS and EFS. SBA is also associated with NLS in children with ALGS who clear their bilirubin, that is, those with anicteric cholestasis. Although the patients studied here did not receive IBAT inhibition, these data suggest that lowering SBA may improve important clinical outcomes.

BACKGROUND: Fractures related to osteoporosis and low bone mineral density lead to substantial morbidity, mortality, and cost to individuals and health systems. Here we present the most up-to-date global, regional, and national estimates of the contribution of low bone mineral density to the burden of fractures from falls and additional categories of injuries from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021.

METHODS: The burden of low bone mineral density was estimated from 1990 to 2020 in terms of years lived with disability (YLDs), disability-adjusted life years (DALYs), and deaths, for individuals aged 40 years and older, using data from population-based studies from 48 countries or territories (169 unique sources). Mean standardised femoral neck bone mineral density values were estimated by GBD location, age, and sex by meta-regression. Based on a separate meta-analysis of population-based studies from nine countries (12 unique sources), we also estimated the pooled relative risk of fractures per unit decrease in bone mineral density (g/cm). The population-attributable fraction for low bone mineral density was calculated by comparing the observed distributions of standardised femoral neck bone mineral density to an age-specific and sex-specific counterfactual distribution, defined as the 99th percentile of five rounds of the National Health and Nutrition Examination Survey in the USA, by 5-year age group and sex. Hospital and emergency department data were used to derive the incidence of fractures for six categories of injury (road injuries, other transport injuries, falls, non-venomous animal contact, exposure to mechanical forces, and physical interpersonal violence) using ICD codes. Deaths due to fractures were estimated as the proportion of in-hospital deaths due to the specified injury causes for which a fracture (nature of injury code) was more severe than the cause of injury code. YLDs and DALYs attributable to low bone mineral density by cause of injury were also determined according to previous GBD methods.

FINDINGS: In 2020, 8·32 million (95% UI 5·58-10·84) YLDs, 17·2 million (14·1-20·2) DALYs, and 477 000 (411 000-536 000) deaths were attributable to low bone mineral density globally in individuals aged 40 years and older. Between 1990 and 2020, global YLDs, DALYs, and deaths attributable to low bone mineral density increased by 91·8% (88·5-95·1), 89·8% (81·5-99·0), and 127·1% (108·5-144·5), respectively. Over this period, the age-standardised global rates of YLDs, DALYs, and deaths attributable to low bone mineral density showed modest decreases. In 2020, falls accounted for 76·2% (95% UI 74·2-78·3) of YLDs, 65·2% (62·9-67·6) of DALYs, and 71·0% (67·4-72·8) of deaths attributable to low bone mineral density, and road injuries largely accounted for the remaining amount: 12·4% (11·1-13·6) of YLDs, 24·6% (22·5-27·1) of DALYs, and 23·1% (21·6-26·2) of deaths. As a proportion of all fall-related burden, low bone mineral density accounted for 26·6% (23·2-28·7) of YLDs, 25·6% (22·1-27·4) of DALYs, and 40·6% (35·4-44·0) of deaths in 2020. Of all road injury-related burden, 12·6% (10·8-13·5) of YLDs, 6·3% (5·4-6·9) of DALYs, and 8·9% (7·6-9·6) of deaths were attributable to low bone mineral density. In men, road injuries accounted for the largest proportion of DALYs attributable to low bone mineral density in those aged 40-59 years and the largest proportion of deaths in those aged 40-64 years. In women, road injuries were the leading cause of DALYs attributable to low bone mineral density in those aged 40-44 years and the leading cause of deaths attributable to low bone mineral density in those aged 40-54 years. In older age groups among both men and women, falls were the leading cause of the burden attributable to low bone mineral density.

INTERPRETATION: Low bone mineral density is a crucial modifiable risk factor for fractures, which are an important cause of morbidity and mortality particularly in ageing populations. This analysis highlights low bone mineral density as a cause of health loss not just from falls, but also from road injuries.

FUNDING: Gates Foundation.

Acute otitis media (AOM) remains one of the most common middle ear infections, particularly in children, necessitating advanced non-invasive therapeutic strategies. This study introduces Novel Hybrid Tri-Polymer Hyalurosomes, an innovative vesicular system designed to enhance trans-tympanic delivery of ciprofloxacin (CFX). The nanosystems were fabricated using the ethanol injection technique and optimized via a 2 factorial design, evaluating the effects of hyaluronic acid (HA): drug ratio (Factor-A), surfactant: HA ratio (Factor-B), and L121: Brij L4 ratio (Factor-C) on critical quality attributes. The optimized formula, selected using a high desirability index (0.996), exhibited high entrapment efficiency (EE%) of 90.28 %, small particle size (PS) of 218.15 nm, and promising zeta potential (ZP) of -40.4 mV. Transmission electron microscopy (TEM) confirmed the uniform spherical morphology of the optimized formula, which also exhibited a characteristic bi-phasic sustained release profile and pseudoplastic rheological behavior, enhancing ease of application and retention at the administration site. Moreover, the formulation demonstrated excellent storage stability and markedly improved mucoadhesive properties. Ex vivo permeation studies revealed a 2.53-fold enhancement ratio compared to CFX solution. Microbiological assessments showed significantly lower minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against and , along with superior biofilm inhibition activity. Confocal laser scanning microscopy (CLSM) confirmed deeper tissue penetration, consistent with the permeation findings. Additionally, in vivo histopathological evaluation demonstrated the safety of the optimized formula with no observable tissue irritation or damage. Collectively, Novel Hybrid Tri-Polymer Hyalurosomes present a promising non-invasive trans-tympanic delivery platform, holding significant potential for advancing AOM therapy.

Drug-induced liver injury (DILI) represents a critical clinical problem that often necessitates lowering the therapeutic dose or even complete drug withdrawal, ultimately resulting in treatment failure. Curcumin (Cur), a natural polyphenolic compound, demonstrates strong hepatoprotective and antioxidant activity; however, its poor solubility and limited bioavailability hinder its therapeutic use. To overcome these limitations, the present study aimed to develop and optimize curcumin-loaded hyaluronic acid-modified edge-activated spanlastics (Cur-HES) as an efficient delivery system for enhancing the hepatoprotective efficacy of curcumin against carbon tetrachloride (CCl₄)-induced liver damage. Cur-HES were prepared using the ethanol injection method and systematically optimized a 23 full factorial design, where the independent variables included hyaluronic acid-to-surfactant ratio (X1), edge activator-to-drug ratio (X2), and Span 80 % contribution (X3). Formulations were assessed for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimized formulation achieved a desirability value of 0.982, with EE% of 88.4 %, PS of 105.2 nm, PDI of 0.19, and ZP of -20.9 mV. Transmission electron microscopy revealed spherical vesicles. release exhibited biphasic Higuchi diffusion kinetics, while stability testing confirmed preservation of physicochemical properties for three months. evaluation demonstrated that Cur-HES provided significantly greater hepatoprotection than free Cur in the CCl₄-induced hepatotoxicity model, as evidenced by marked reductions in serum ALT and AST levels. Histopathological examination supported these findings, showing preserved liver architecture in treated groups. Overall, Cur-HES represents a promising nanocarrier platform to boost the hepatoprotective activity of Cur, offering a safe and effective therapeutic strategy against DILI.

is a multidrug-resistant gram-negative pathogen associated with high morbidity and mortality, especially in immunocompromised patients. Its resistance mechanisms include aminoglycoside-modifying enzymes, -like quinolone resistance genes, multidrug efflux pumps, and β-lactamases (L1 and L2). With the increasing incidence of infections, effective treatment strategies are urgently needed to combat its growing resistance. We present the case of a preterm male neonate, born at 30 weeks of gestation, who developed respiratory distress requiring mechanical ventilation. Empiric antibiotics were initiated but failed to prevent clinical deterioration. Respiratory cultures confirmed that multidrug-resistant is resistant to standard therapies, necessitating a novel dual regimen of ceftazidime-avibactam and aztreonam. This combination therapy was administered for 14 days, leading to microbiological clearance and clinical improvement, allowing successful extubation. To the best of our knowledge, this is the first documented case of ceftazidime-avibactam and aztreonam successfully treating multidrug-resistant infection in a preterm infant. This case underscores the potential of ceftazidime-avibactam and aztreonam as a viable therapeutic option for multidrug-resistant infections in neonates. Further studies are warranted to validate its safety and efficacy in similar cases.

UNLABELLED: Monogenic liver disorders constitute a major disease burden in pediatric patients presenting with manifestations of liver disease. This is particularly significant in countries with high rates of consanguinity as in Egypt. We recruited 228 infants and children suffering from various forms of liver disease with suspected monogenic background and no conclusive biochemical diagnosis. They presented to the Pediatric Hepatology Unit at Cairo-University-Children’s-Hospital, Egypt, over the period April 2017-June 2023 and were referred for genetic diagnosis by various next-generation-sequencing technologies. One-hundred and eighty-five children (81.1%) had a significant genetic finding. Those included 88 children with a main presentation of organomegaly, 83 with cholestasis, 8 with acute liver failure and 6 with hyperbilirubinemic syndromes. One-hundred seventy-five disease-causing variants (51 pathogenic, 86 likely-pathogenic and 38 of uncertain-significance) in 72 different genes were detected in our cohort, including 85 novel variants in 49 different genes. Variants in (Glycogen storage disease type-III; GSD3), (Progressive familial intrahepatic cholestasis type-III; PFIC3) and (PFIC2) genes were the most common affecting 19, 14 and 13 children, respectively. This study is the first to provide the landscape of pediatric monogenic liver diseases in a homogenous population from the Middle East and Africa, an area notoriously known to be poorly represented in genetic database and literature. Furthermore, our presented data are extremely important for genetic counseling and prenatal diagnosis and will further guide national health care policy makers to prevent or mitigate the effects of such disorders in the future.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-025-02776-4.

Bones are essential components of the human body, providing structural support, enabling mobility, storing minerals, and protecting internal organs. Bone fractures (BFs) are common injuries that result from excessive physical force and can lead to serious complications, including bleeding, infection, impaired oxygenation, and long-term disability. Early and accurate identification of fractures through radiographic imaging is critical for effective treatment and improved patient outcomes. However, manual evaluation of X-rays is often time-consuming and prone to diagnostic errors due to human limitations. To address this, artificial intelligence (AI), particularly deep learning (DL), has emerged as a powerful tool for enhancing diagnostic precision in medical imaging. : This research introduces a novel convolutional neural network (CNN) model, the Multi-Level Feature Fusion Network (MLFNet), designed to capture and integrate both low-level and high-level image features. The model was evaluated using the Bone Fracture Multi-Region X-ray (BFMRX) dataset. Preprocessing steps included image normalization, resizing, and contrast enhancement to ensure stable convergence, reduce sensitivity to lighting variations in radiographic images, and maintain consistency. Ablation studies were conducted to assess architectural variations, confirming the model's robustness and generalizability across data distributions. MLFNet's high accuracy, interpretability, and efficiency make it a promising solution for clinical deployment. : MLFNet achieved an impressive accuracy of 99.60% as a standalone model and 98.81% when integrated into hybrid ensemble architectures with five leading pre-trained DL models. : The proposed approach supports timely and precise fracture detection, optimizing the diagnostic process and reducing healthcare costs. This approach offers significant potential to aid clinicians in fields such as orthopedics and radiology, contributing to more equitable and effective patient care.

The analysis of EEG signals for determining emotion is one of the most important topics in the field of artificial intelligence. It can be applied in a wide variety of areas, such as emotional health care and the man/machine interface. The purpose of the paper is the demonstration that emotions may be identified using EEG recordings in the hybrid approach based on the differentiated support vector machine (SVM) models with various types of kernel functions, as well as fuzzy C-means. The EEG signal of two subjects was recorded with the help of the Muse headband; the signal data was described as positive, neutral, or negative emotions. A Gauss kernel was the second-best outcome (95.78%), and a linear kernel was the best outcome (97.66%). Precision, recall, and F1-scores were used in establishing the performance of the SVM technique in emotion classification in conjunction with the fuzzy C-means classification approach. Besides covering the discussion on the importance of kernel choice in achieving good performance in SVM-based models, the analysis also showed that there was a potential to use EEG-based emotion detection. Moreover, one-way ANOVA statistical analysis has expressed that the linear kernel did perform significantly better as compared to other kernels (p < 0.05). To confirm that the proposed system would be rather robust, other deep learning models (CNN-LSTM hybrids) were designed and tested, the results of which proved that they had similar performance and at the same time less accurate results than the linear SVM. These results indicate the efficacy of SVM and the optimization of kernel parameters along with the integration of fuzzy logic in recognizing emotions based on EEG records.

Meningitis caused by Streptococcus suis serotype 2 (SS2) in humans and pigs is an acute nervous disorder associated with serious sequelae. Bacterial meningitis is tightly associated with immune cell responses and the local immune microenvironment. However, the dynamic changes of the immune system during the disease progression in the brain remains unclear. Here, single-cell mass cytometry analyses are used to comprehensively profile the composition and phenotypes of female mouse brain immune cells at different stages of SS2 meningitis. Ten major immune cell lineages are identified among which T cells and dendritic cells significantly increased during meningitis, with B cells increasing in the late stage. Specifically, SS2PD-L1 neutrophils with strong phagocytosis, bactericidal and apoptotic effects accumulate in the acute phase of SS2 infection. Microglia sequentially display the features of homeostasis, proliferation, and activation (enhanced MHCII and TLR2 signals and TNF-α secretion) during the process of meningitis. Both border-associated and monocyte-derived macrophages contribute to the process of SS2-induced meningitis, exhibiting upregulation of CD38 and MHCII. Interestingly, CD11cCD8T cells are the main contributor of IFN-γ and specifically appeared during SS2 infection. In addition, the appearance of other lymphocytes such as CCR6 B cells, CX3CR1 NK and MHCII ILC3 are related to the progression of meningitis. Moreover, correlation analysis between the composition of immune cell clusters and the SS2 infection process yield a dynamic immune landscape in which key immune clusters, including some previously unidentified, mark different stages of infection. Together, these data reveal the unique infection-stage immune microenvironment during the progression of meningitis caused by SS2 and provide resources for the analysis of immunological pathogenesis, potential diagnostic markers and therapeutic targets for bacterial meningitis.

RATIONALE: This case report highlights the complex clinical course and successful multidisciplinary management of a pediatric patient with multisystem inflammatory syndrome in children (MIS-C), who posed clinical dilemma at presentation. It underscores the ongoing clinical relevance of MIS-C as a post-Coronavirus disease 2019 sequelae and emphasizes the importance of maintaining a high index of suspicion for MIS-C in pediatric differential diagnoses, especially when symptoms overlap with other common conditions.

PATIENT CONCERNS: An 11-year-old previously healthy Saudi girl presented with gastrointestinal symptoms initially suggestive of acute appendicitis. Her condition rapidly deteriorated with signs of cardiovascular compromise.

DIAGNOSES: Surgical exploration confirmed a perforated appendix. Cardiac workup revealed elevated troponin levels, corrected QT interval prolongation (500 ms), ST-segment changes, and echocardiographic evidence of mitral and aortic regurgitation with reduced ejection fraction, leading to a diagnosis of MIS-C fulfilling both Centers for Disease Control and Prevention and World Health Organization criteria. Schwartz et al's criteria are widely accepted for diagnosing long QT syndrome, which guided our interpretation of the corrected QT interval prolongation observed in this case. According to the Centers for Disease Control and Prevention, MIS-C is defined by a constellation of symptoms occurring in individuals under 21 years with recent severe acute respiratory syndrome coronavirus 2 infection or exposure.

INTERVENTIONS: Management included intravenous immunoglobulin, corticosteroids, inotropes, diuretics, aspirin, and broad-spectrum antibiotics, coordinated by a multidisciplinary care team.

OUTCOMES: The patient experienced full cardiac recovery, confirmed through serial electrocardiogram and echocardiography over 1 year.

LESSONS: This case underscores the importance of recognizing MIS-C in children presenting with atypical symptoms such as abdominal pain. Timely diagnosis and early multidisciplinary intervention are essential to prevent serious cardiac complications.

RATIONALE: This case report highlights the complex clinical course and successful multidisciplinary management of a pediatric patient with multisystem inflammatory syndrome in children (MIS-C), who posed clinical dilemma at presentation. It underscores the ongoing clinical relevance of MIS-C as a post-Coronavirus disease 2019 sequelae and emphasizes the importance of maintaining a high index of suspicion for MIS-C in pediatric differential diagnoses, especially when symptoms overlap with other common conditions.

PATIENT CONCERNS: An 11-year-old previously healthy Saudi girl presented with gastrointestinal symptoms initially suggestive of acute appendicitis. Her condition rapidly deteriorated with signs of cardiovascular compromise.

DIAGNOSES: Surgical exploration confirmed a perforated appendix. Cardiac workup revealed elevated troponin levels, corrected QT interval prolongation (500 ms), ST-segment changes, and echocardiographic evidence of mitral and aortic regurgitation with reduced ejection fraction, leading to a diagnosis of MIS-C fulfilling both Centers for Disease Control and Prevention and World Health Organization criteria. Schwartz et al's criteria are widely accepted for diagnosing long QT syndrome, which guided our interpretation of the corrected QT interval prolongation observed in this case. According to the Centers for Disease Control and Prevention, MIS-C is defined by a constellation of symptoms occurring in individuals under 21 years with recent severe acute respiratory syndrome coronavirus 2 infection or exposure.

INTERVENTIONS: Management included intravenous immunoglobulin, corticosteroids, inotropes, diuretics, aspirin, and broad-spectrum antibiotics, coordinated by a multidisciplinary care team.

OUTCOMES: The patient experienced full cardiac recovery, confirmed through serial electrocardiogram and echocardiography over 1 year.

LESSONS: This case underscores the importance of recognizing MIS-C in children presenting with atypical symptoms such as abdominal pain. Timely diagnosis and early multidisciplinary intervention are essential to prevent serious cardiac complications.

Sandestig-Stefanova syndrome (SANDSTEF) (OMIM: 618804) is a recently identified autosomal recessive disorder characterized by a complex phenotype affecting multiple organ systems. To date, only 10 cases have been reported in the literature. Here, we present a newly identified patient exhibiting a distinct clinical presentation, along with a novel homozygous splice variant in NUP188. The proband has multiple system involvement, including ophthalmology, central nervous system, skin, distinct facial features, congenital heart disease, and respiratory system; eventually, he passed away with respiratory failure. A novel splice variant was identified using ES (NM_015354.2c.1962-2A>C p.(?)). The variant was confirmed by Sanger sequencing and was found to segregate from the parents. RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status. The identification of a novel pathogenic variant contributes to a deeper understanding of the molecular mechanisms underlying the disorder and expands its phenotypic spectrum.

INTRODUCTION: This study aimed to compare two different approaches for palatal wound healing following free gingival graft (FGG) harvesting: one involving Nano Bio-Fusion (NBF) gingival gel used in conjunction with a palatal stent, and the other using a palatal stent alone. Outcomes were assessed in terms of wound healing, post-operative pain, and patient satisfaction.

METHODS: This parallel-grouped, two-arm, single-blinded, randomized controlled trial (RCT) included twenty-six patients with mucogingival defects that required harvesting an epithelialized free gingival graft (FGG). Patients were randomly allocated into either test group (NBF gingival gel and palatal stent; n = 13) or control group (palatal stent only; n = 13). Wound healing, the primary outcome, was evaluated over a 30-day period, while secondary outcomes included post-operative pain-measured using the Visual Analog Scale (VAS) and analgesic consumption-and patient satisfaction.

RESULTS: In the test group, wound healing showed statistically significant higher healing index score than control group after 3 days (P = 0.017), then no statistical significance was noted. Regarding post-operative pain, the test group showed statistically significantly lower pain scores (VAS) than control group in the first week, followed by no statistical significance in the second week. In the third day, the test group showed statistically significant lower analgesic consumption dose (P = 0.024) with overall statistically significant higher satisfaction score than control group (P = 0.002).

CONCLUSION: Within the limitations of this study, the results suggest that NBF gingival gel may promote early-stage palatal wound healing, reduce postoperative pain and analgesic consumption during the first week, and enhance overall patient satisfaction.

CLINICAL TRIAL REGISTRATION: (NCT05442359 | | https://www.

CLINICALTRIALS: gov/ 30-June-2022).

AIMS: To explore how nurses working in a high-pressure academic healthcare setting in Saudi Arabia conceptualise, experience and sustain resilience in the face of professional stressors.

DESIGN: A qualitative, descriptive phenomenological study.

METHODS: Semi-structured interviews were conducted with 17 nurses from diverse clinical and academic backgrounds between March and May 2025. Data were analysed using reflexive thematic analysis, incorporating both inductive and interpretive approaches. Researcher reflexivity and methodological rigour were maintained throughout.

RESULTS: Four major themes were identified: (1) Navigating Emotional Demands, which captured nurses' experiences of compassion fatigue and emotional resilience; (2) Support Systems and Collegial Ties, emphasising peer collaboration and mentorship; (3) Organisational Culture and Leadership, which highlighted the role of managerial support, workload policies and institutional climate; and (4) Adaptive Coping Strategies and Personal Development, including mindfulness, spirituality and continuous learning. These themes demonstrate the multilevel nature of resilience, shaped by personal attributes, interpersonal relationships and systemic factors.

CONCLUSION: Nurses develop resilience through an interplay of individual, relational and organisational strategies. Supportive leadership, collegial networks and opportunities for professional growth are critical in mitigating stress and preventing burnout. Findings underscore the need for culturally responsive, system-wide interventions that embed emotional safety, reflective practice and mentorship into healthcare settings. Future research should evaluate the impact of resilience-oriented policies on workforce retention and patient care outcomes.

BACKGROUND: Kidney failure with replacement therapy (KFRT) such as dialysis or transplantation represents a severe stage of chronic kidney disease (CKD) and poses a major global health burden. Although many CKD cases are diagnosed in the earlier stages, the greatest risk occurs when CKD progresses to KFRT. Despite its considerable financial and imposing impact on public health, there is a notable gap in international policies addressing CKD and KFRT. To bridge this gap and help policy makers and health systems effectively tackle the public health challenge of KFRT, a better understanding of the disease burden is essential. Thus, this analysis aims to provide a detailed overview of the global prevalence of KFRT and its associated aetiologies with estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) from 1990 to 2023.

METHODS: This study defined KFRT as individuals on maintenance dialysis for 90 days or more or those who have undergone a kidney transplant, aligning with the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Renal registries served as the primary data sources. Prevalence and underlying aetiology estimates (type 1 diabetes, type 2 diabetes, hypertension, glomerulonephritis, and other causes) were generated with DisMod-MR 2.1, an epidemiological Bayesian mixed-effects meta-regression modelling tool. Both all-age and age-standardised estimates were reported and accompanied with 95% uncertainty intervals (UIs).

FINDINGS: In 2023, the number of global cases of KFRT was 4·59 million (95% UI 4·17-5·08) for both sexes and all ages, with an age-standardised prevalence of 50·7 (46·1-56·0) per 100 000 population. Over the past three decades, there has been a steady increase in KFRT prevalence globally. The highest prevalence was found in the GBD high-income regions, while the lowest was observed in sub-Saharan Africa. KFRT prevalence was generally higher in countries classified within the World Bank's high-income and upper-middle-income groups, while lower prevalence was more common in countries within the World Bank's low-income and lower-middle-income groups. Additionally, a pronounced sex disparity was identified, where male dialysis and transplant prevalence estimates were consistently higher than those for females in most countries. Type 2 diabetes and hypertension were among the leading associated aetiologies of KFRT globally. From 1990 to 2023, the all-age and age-standardised prevalence estimates across the ascribed aetiologies increased for KFRT, with the largest increases associated with type 2 diabetes and hypertension.

INTERPRETATION: KFRT affects approximately 5 million people globally, with high treatment and mortality costs. Our study unveiled considerable geographical variation in KFRT prevalence, which should be seen as indicators of health-care system opportunities. As the prevalence of the leading aetiologies of KFRT-type 2 diabetes and hypertension-continues to rise, there is a crucial need to prioritise the development and implementation of cost-effective strategies aimed at preventing CKD and its progression to KFRT, particularly in low-resource settings. These preventive efforts must happen in tandem with efforts to expand capacity for dialysis and transplant services.

FUNDING: Gates Foundation.