SAID SHEHATA

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.

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.

BACKGROUND: Diabetes mellitus type 2 (DMT2) is a chronic metabolic disorder caused by a disruption or resistance in insulin secretion. AKT /PI3K, GSK-3β and CREB signaling pathways influence insulin sensitivity and glucose metabolism.

PURPOSE: This study aimed to compare the therapeutic impact of pectin extracted from different sources (lemon, orange and grapefruit peels) against diabetic rats.

METHODS: Fourier transform infrared spectroscopy (FT-RI) and Proton Nuclear Magnetic Resonance (H-NMR) analysis of pectin were done. Treatments were administered daily for one month (500 mg/kg) post diabetes induction a single dose of streptozotocin (STZ) (40 mg/kg) considering Metformin as a reference drug (250 mg/kg). Biochemical, mutagenicity and genotoxicity analyses were assessed.

RESULTS: The FT-IR andH-NMR revealed that lemon pectin had a strong peak at ≈3.7 ppm. Orange pectin showed a moderate peak at ≈3.7 ppm, and grapefruit pectin showed a weak peak at ≈3.7 ppm. Diabetic rats showed alterations in glucose, insulin, liver function enzymes, urea, oxidative stress indices, IL-6, TNF-α, AKT, PI3K levels and GSK-3β and cAMP responsive element binding protein 1(CREB) genes expression. Changes in micronuclei of polychromatic erythrocytes, chromosomal aberrations, sperm abnormalities and the histopathology of liver and pancreas were also observed. Pectin treatments declared a notable amelioration in glucose and insulin levels as well as the other selected parameters.

CONCLUSION: Pectin extracted from lemon, orange and grapefruit peels showed a promising therapeutic impact against DMT2. High degree of esterification in lemon pectin may explore its potent effect regulating glucose, α-amylase and the metabolic genes expression pathways. Orange pectin exhibits the strongest anti-mutagenic properties. Together, citrus pectin may be considered as a nutraceutical agent against diabetes.

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.