SAID SHEHATA

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

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

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

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

FUNDING: Gates Foundation.

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

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

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

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

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

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

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

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

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

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

Bladder cancer (BLCA) is a malignant growth that originates from the urothelial lining of the urinary bladder. Diagnosing BLCA is complex due to the variety of tumor features and its heterogeneous nature, which leads to significant morbidity and mortality. Understanding tumor histopathology is crucial for developing tailored therapies and improving patient outcomes. Early diagnosis and treatment are essential to lower the mortality rate associated with bladder cancer. Manual classification of muscular tissues by pathologists is labor-intensive and relies heavily on experience, which can result in interobserver variability due to the similarities in cancerous cell morphology. Traditional methods for analyzing endoscopic images are often time-consuming and resource-intensive, making it difficult to efficiently identify tissue types. Therefore, there is a strong demand for a fully automated and reliable system for classifying smooth muscle images. This paper proposes a deep learning (DL) technique utilizing the EfficientNet-B3 model and a five-fold cross-validation method to assist in the early detection of BLCA. This model enables timely intervention and improved patient outcomes while streamlining the diagnostic process, ultimately reducing both time and costs for patients. We conducted experiments using the Endoscopic Bladder Tissue Classification (EBTC) dataset for multiclass classification tasks. The dataset was preprocessed using resizing and normalization methods to ensure consistent input. In-depth experiments were carried out utilizing the EBTC dataset, along with ablation studies to evaluate the best hyperparameters. A thorough statistical analysis and comparisons with five leading DL models-ConvNeXtBase, DenseNet-169, MobileNet, ResNet-101, and VGG-16-showed that the proposed model outperformed the others. The EfficientNet-B3 model achieved impressive results: accuracy of 99.03%, specificity of 99.30%, precision of 97.95%, recall of 96.85%, and an F1-score of 97.36%. These findings indicate that the EfficientNet-B3 model demonstrates significant potential in accurately and efficiently diagnosing BLCA. Its high performance and ability to reduce diagnostic time and cost make it a valuable tool for clinicians in the field of oncology and urology.

BACKGROUND: Feline parvovirus (FPV) causes feline panleukopenia (FPL) and cerebellar ataxia (CA) in cats. to date, only two complete Egyptian VP2 sequences have been available in GenBank. To investigate FPV diversity And evolution in Egypt, we generated 24 complete VP2 sequences from diseased cats during two FPV activity peaks in 2023 (January-February and November-December). Egyptian sequences were Analyzed with 967 global references to assess selection pressure and phylogenetic relationships. In silico predictions of VP2 Antigenic sites, 3D structure, and phosphorylation potential were performed to evaluate the impact of identified mutations.

RESULTS: Egyptian sequences showed 99.3-100% nt And 99.8-100% aa identity among themselves, And 98.6-100% nt And 98.4-100% aa identity with global references. The overall dN/dS ratio was 0.121, with codon 101 under positive selection. Compared to the prototype FPV-b strain (M38246), Egyptian strains had 32 mutations (3 nonsynonymous: Ala5Thr, Ile101Thr, and Thr390Ala; 29 synonymous), forming 19 nt And 3 aa sequence types. Notably, Thr390Ala was unique to Egyptian sequences and absent from all global references. Phylogenetically, Egyptian strains formed two subclades: one composed solely of sequences carrying Thr390Ala (n = 13), And Another including the remaining 11 sequences clustering with 19 global strains sharing the synonymous mutation C135T in addition to A927G and/or A1236G. The Thr390Ala variant predominated in the first peak (11/17, 64.7%) but declined in the second (2/7, 28.6%). Residue 390 lies within an epitope-rich region (aa 350-450) and was predicted to be a phosphorylation site. Thr390Ala caused a modest drop in epitope score, disrupted local hydrogen bonding, and abolished predicted phosphorylation.

CONCLUSIONS: Beyond expanding the global dataset with the largest number of Egyptian full-length VP2 sequences to date, this study highlights the Thr390Ala mutant as a classic example of evolutionary trade-off: it emerged and predominate during the first peak, potentially as an immune escape variant, but declined in the second peak, likely due to structural constraints and competition with fitter variants. Despite strong purifying selection, this case illustrates that FPV evolution is not entirely static. This underscores the need for continuous genetic monitoring to capture viral evolution in real time and inform effective control strategies.

BACKGROUND: Gastric ulcer is one of the most common gastrointestinal tract diseases with a higher extent in male patients. Selenium nanoparticles (SeNPs) possess therapeutic benefits, including antimicrobial, antioxidant, anti-inflammatory, and anti-ulcerative agents. The study aimed to investigate the modulatory effect of yeast-mediated SeNPs on gastric ulcers and microbiota dysbiosis in a rat model.

METHOD: Twenty-four rats were randomly divided into four groups. Both the control and SeNPs-only groups received distilled water orally, and after 1 h, they received 2 % carboxymethyl cellulose (CMC). The ulcer model and SeNPs-treated groups received 99 % ethanol (5 ml/kg orally) for ulcer induction, followed by 2 % CMC after one hour. The SeNPs-treated group got SeNPs (60 mg/kg) suspended in 2 % CMC. We measured ulcer markers (ulcer index and gastric juice pH and volume and stomach tissue oxidative stress markers (malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), and catalase (CAT)), in addition to histopathological examination of gastric tissues stained with three different satins: hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), and Masson's trichrome stains (many-color dye), and microbiological analysis of freshly collected fecal sample.

RESULTS: SeNPs treatment significantly decreased gastric volume, ulcer index, malondialdehyde, and increased glutathione levels. A macroscopic examination of the treated stomach revealed decreased ulcer lesion numbers. Furthermore, histopathological examination showed that SeNPs treatment repaired ulcerative gastric tissue through the regeneration of epithelial cells and reduction in damaged areas and collagen fibers. In the treated group, microbiological analysis of rat feces showed a significant increase in Leuconostoc pseudomesenteroides, Escherichia coli, and Enterococcus faecium counts.

CONCLUSION: This research suggests that SeNPs exhibit anti-ulcer activity and can accelerate ulcer healing via their antioxidant action. They also have a modulatory effect on gut microbiota dysbiosis associated with gastric ulcers. This is the first research studying the impact of safe yeast-mediated SeNPs on rat's gastric ulcer and gut microbiota.

The neuroprotective potential of tyrosine kinase inhibitors (TKIs), potent anticancer drugs, was verified against various neurodegenerative insults, but not Huntington's disease (HD). These promising outcomes were due to their ability to modulate various intracellular signalling pathways. Hence, the current study aimed to evaluate the neuroprotective effects of lapatinib and pazopanib in the 3-nitropropionic (3-NP)-induced HD model in rats. After 14 days of 3-NP administration, rats received saline, lapatinib, or pazopanib for 21 days. Treatment with lapatinib or pazopanib improved the striatal microscopic architecture, neuronal survival, and neuroinflammatory responses, with a pronounced effect observed for pazopanib. At the molecular level, lapatinib and pazopanib reduced the striatal gene expression of NF-κB and TNF-α receptors, curbed the glutamate/calpain-2 axis, and modified the striatal content of inflammatory molecules as well as neurotransmitters. In addition, they activated the neuroprotective trajectory viz., m-Tor/ULK-1/Beclin-1/LC3-II, an effect dependent on tyrosine kinase inhibition. Moreover, treated groups showed normalised tyrosine hydroxylase and glial fibrillary acidic protein in the striatum. In conclusion, this study provides strong evidence that lapatinib or pazopanib significantly improved motor function, alleviated cognitive decline, and attenuated neurodegeneration in HD rats via modulating key signalling pathways implicated in HD pathogenesis. These results underscore the promising therapeutic potential of TKIs in managing HD and warrant further investigation into their clinical application.

Inorganic arsenical compounds, such as arsenic trioxide (ATO), are toxic environmental contaminants that occur widely in soil, water, and biological systems. Besides, zinc oxide nanoparticles (ZNPs) have been recently incorporated in various industrial and medicinal applications. Thus, their co-existence in the environment could widely occur. This study examined the potential protective activity of gallic acid (GA, 20 mg/kg b. wt) against the harmful impacts of 60-day co-exposure to ATO (8 mg ATO/kg b. wt) and ZNPs (100 mg ZNPs/kg b. wt) on the kidneys of rats. The results indicated that ZNPs and/or ATO exposure resulted in increased serum levels of markers associated with renal damage, an imbalance in electrolytes (sodium, potassium, and calcium), diminished levels of antioxidant enzymes in the kidneys, and an increased malondialdehyde (MDA) concentration. Furthermore, ZNPs and/or ATO co-exposed rats demonstrated markedly increased levels of renal zinc (Zn) and arsenic (As), accompanied by pronounced histopathological alterations, including interstitial nephritis, renal tubular necrosis, and vascular wall thickening. Immunohistochemical analysis revealed that exposure to ZNPs and/or ATO reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while increasing that of heat shock protein 90 (HSP90) in kidney tissues. Co-exposure to ZNPs and ATO produced more pronounced alterations, including increased serum uric acid and creatinine, decreased sodium levels, reduced renal GPx activity, increased MDA content, greater renal accumulation of As and Zn, and diminished Nrf2 expression, compared with individual exposures, suggesting additive toxic effects. However, GA notably reduced renal tissue damage, oxidative stress, and disturbances in renal function and electrolyte balance in rats co-exposed to ZNPs and ATO. Conclusively, the study found that exposure to ZNPs and ATO, especially when combined, was toxic to the kidneys, leading to impaired renal function through increased oxidative stress and disrupted electrolyte balance. However, GA effectively protected kidney health at the administered doses by counteracting these effects through its antioxidant properties and by modulating cellular defense mechanisms involving Nrf2 and HSP90.

BACKGROUND: Epidermolysis bullosa dystrophica (EBD) is characterized by mucocutaneous fragility with blistering, scarring and severe growth retardation attributed to many factors.

METHODS: This cross-sectional study included 51 patients aged 1-12 years with recessive dystrophic EB (RDEB). Weight and height were measured, with the calculation of weight standard deviation (SD), height SD, and body mass index (BMI), followed by plotting them on Egyptian growth curves. Serum levels of basal growth hormone (GH), insulin-like growth factor 1 (IGF-1), hemoglobin (Hb) level, erythrocyte sedimentation rate (ESR), and thyroid functions (TSH and free T4) were measured. Growth hormone stimulation test was performed in 11 patients.

RESULTS: Weight SD and height SD were lower than normal measurements (p < 0.05*). Growth hormone, growth hormone stimulation, and IGF-1 were lower than the normal range (p < 0.05*). Hb levels were lower than normal, whereas ESR levels were elevated (p < 0.001*). A negative correlation was found between ESR and basal GH, and a positive correlation between ESR and IGF-1.

CONCLUSION: Children with generalized RDEB have poor growth and low circulating GH and IGF-1 levels, likely due not only to malnutrition and anemia, but possibly also as a consequence of inflammation that suppresses the GH/IGF-1 axis. Future treatments targeting the correction of GH and IGF-1 levels as well as the chronic inflammatory state should be considered.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05390073.

BACKGROUND: Chronic kidney disease (CKD) is common and ranks among the leading causes of mortality and morbidity. This analysis aimed to present global CKD estimates using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to inform evidence-based policies for CKD identification and treatment.

METHODS: This analysis focused on adults aged 20 years and older over the period 1990 to 2023, from 204 countries and territories. Data sources used were published literature, vital registration systems, kidney failure treatment registries, and household surveys. Estimates of CKD burden, including deaths, incidence, prevalence, and disability-adjusted life-years (DALYs), were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool. A comparative risk assessment approach estimated the proportion of cardiovascular deaths attributable to impaired kidney function and estimated risk factors for CKD.

FINDINGS: Globally, in 2023, 788 million (95% uncertainty interval 743-843) people aged 20 years and older were estimated to have CKD, up from 378 million (354-407) in 1990. The global age-standardised prevalence of CKD in adults was 14·2% (13·4-15·2), a relative rise of 3·5% (2·7-4·1) from 1990. The region with the highest age-standardised prevalence was north Africa and the Middle East (18·0%; 16·9-19·4). Most people had stage 1-3 CKD, with a combined prevalence of 13·9% (13·1-15·0). In 2023, CKD was the ninth leading cause of death globally, accounting for 1·48 million (1·30-1·65) deaths, and the 12th leading cause of DALYs, with an age-standardised DALY rate of 769·2 (691·8-857·4) per 100 000. Impaired kidney function as a risk factor accounted for 11·5% (8·4-14·5) of cardiovascular deaths. High fasting plasma glucose, body-mass index, and systolic blood pressure were all leading risk factors for CKD DALYs.

INTERPRETATION: CKD is a major global health issue, with rising prevalence and increasing importance as a cause of death and as a risk factor for cardiovascular death. A better understating of aetiology, appropriate screening, and implementation programmes are needed to translate advances in CKD treatment into improved patient outcomes.

FUNDING: Gates Foundation, Wellcome, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-]pyridines (-, -, and ) as potential anticancer agents and Topoisomerase II inhibitors. The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase IIα (TOPIIα) inhibition. Initial single-dose screening identified several active compounds, notably , , , , , , , and . Among these, compound exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI MG-MID value of 1.33 µM (range: 0.54-2.08 µM). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound significantly inhibited the DNA relaxation activity of TOPIIα in a dose-dependent manner, comparable to etoposide. The study highlights compound as a promising pyrazolo[3,4-]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase IIα. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development..

BACKGROUND: This study compared ultrasound-guided supraclavicular subclavian vein (SCV) cannulation and internal jugular vein (IJV) cannulation in neonates and infants weighing less than 5 kg.

METHODS: A total of 108 neonates and infants were randomly assigned to either the SCV group (n = 54) or the IJV group (n = 54). The primary outcome was the success rate on the first insertion attempt. Secondary outcomes included procedure times, adverse events, and other characteristics of venous cannulation.

RESULTS: In neonates and infants weighing less than 5 kg, the SCV group demonstrated a significantly higher first-attempt success rate compared to the control group [43 (79.6%) vs. 30 (55.6%), relative risk (95% CI): 0.7 (0.53-0.92), p =  0.007]. Additionally, the SCV group experienced fewer adverse events (5.6 % vs. 29.6%, p =  0.002).

CONCLUSION: Ultrasound-guided SCV cannulation resulted in a significantly higher first-attempt success rate and a lower incidence of adverse events compared to IJV cannulation in neonates and infants weighing under 5 kg. These findings indicate that SCV cannulation may offer a preferable approach for improving success rates.

REGISTRATION: ClinicalTrial.gov(NCT05956028).

Otitis media (OM) is a frequent infectious condition that affects the middle ear especially in children. The purpose of this project was to create fenchone-augmented novasomes to enhance the trans-tympanic penetration of levofloxacin (LFX) and improve its antibacterial efficacy. Novasomes were formulated using the ethanol injection technique and optimized using a 2 factorial design. The factors analyzed included the stearic acid to drug ratio (A), cholesterol to fenchone ratio (B), and surfactant concentration (%) (C). The optimization feature of Design-Expert® software was utilized to identify the optimal formulation by minimizing particle size (PS) and poly-dispersity index (PDI) while maximizing entrapment efficiency (EE%) and the absolute value of the zeta potential (ZP). The best formulation achieved a desirability of 0.964, with an EE% of 73.39%, a PS of 179.25 nm, and a ZP of - 31.95 mV. The formulation will be subjected to additional evaluations, including in vitro, ex vivo, microbiological, and in vivo testing. A thorough in vitro analysis revealed a biphasic release profile, significant stability, and a spherical morphology. Novasomes exhibited greater ex vivo permeation and superior flux values compared to the LFX solution. The optimum formula demonstrated high otic tolerance. The optimized formula demonstrated markedly enhanced antibacterial activity, with significantly lower minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against Staphylococcus aureus and Pseudomonas aeruginosa compared to the drug solution. Moreover, it exhibited superior biofilm inhibition, even at sub-MIC concentrations, underscoring its efficacy. These findings highlight the potential of LFX-loaded novasomes as an efficient non-invasive method for managing middle ear infections.

: Lower-grade gliomas (LGGs) are a biologically and clinically heterogeneous group of brain tumors, for which molecular stratification plays essential role in diagnosis, prognosis, and therapeutic decision-making. Conventional unimodal classifiers do not necessarily describe cross-layer regulatory dynamics which entail the heterogeneity of glioma. : This paper presents a protein-protein interaction (PPI)-informed hybrid model that combines multi-omics profiles, including RNA expression, DNA methylation, and microRNA expression, with a Graph Attention Network (GAT), Random Forest (RF), and logistic stacking ensemble learning. The proposed model utilizes ElasticNet-based feature selection to obtain the most informative biomarkers across omics layers, and the GAT module learns the biologically significant topological representations in the PPI network. The Synthetic Minority Over-Sampling Technique (SMOTE) was used to mitigate the class imbalance, and the model performance was assessed using a repeated five-fold stratified cross-validation approach using the following performance metrics: accuracy, precision, recall, F1-score, ROC-AUC, and AUPRC. : The findings illustrate that a combination of multi-omics data increases subtype classification rates (up to 0.984 ± 0.012) more than single-omics methods, and DNA methylation proves to be the most discriminative modality. In addition, analysis of interpretability using attention revealed the major subtype-specific biomarkers, including UBA2, LRRC41, ANKRD53, and WDR77, that show great biological relevance and could be used as diagnostic and therapeutic tools. : The proposed multi-omics based on a biological and explainable framework provides a solid computational approach to molecular stratification and biomarker identification in lower-grade glioma, bridging between predictive power, biological clarification, and clinical benefits.

BACKGROUND/OBJECTIVES: Diabetic nephropathy (DN) is a prevalent microvascular diabetic complication that is not totally unveiled. In this study, we considered GAS6, AXL, GAS6-AS1, and GAS6-DT as possible early diagnostic biomarkers of DN.

SUBJECTS/METHODS: The study included 70 patients with normoalbuminuria type 2 diabetes (DM), 70 patients with microalbuminuria type 2 diabetes (DN), and 60 apparently healthy controls. Fasting plasma glucose, glycosylated hemoglobin, and plasma creatinine were enzymatically assayed. Albuminuria, plasma GAS6, and AXL levels were determined using ELISA. Long non-coding RNAs GAS6-AS1 and GAS6-DT levels were determined in blood using qRT-PCR. Several bioinformatics databases were employed to suggest interactions with the studied biomolecules.

RESULTS: GAS6 and AXL were downregulated in DM + DN compared to controls, being the lowest in DN (p < 0.0001). GAS6-DT was upregulated in DM + DN compared to controls, being the highest in DN (p < 0.0001). GAS6-AS1 was higher in DN than in controls (p = 0.013). GAS6, AXL, and GAS6-DT showed fair-to-moderate significant correlations with HbA1c, fasting glucose, creatinine, and albuminuria. ROC curves showed remarkable diagnostic power of GAS6, AXL, and GAS6-DT (AUC = 0.72-1.0), but not GAS6-AS1, in DN and DM, with moderate-to-excellent agreement with conventional diagnostics.

CONCLUSIONS: The current findings emphasize the significance of the GAS6/AXL pathway in DM and DN progression, where GAS6, AXL, and GAS6-DT showed significantly altered values in DM, and further in DN, with notable diagnostic power for both diseases. To date, this is the first study confirming the diagnostic power of AXL and GAS6-DT in DN and DM. Future studies are warranted to evaluate therapeutically targeting this pathway to manage DN.

Schizophrenia is a severe psychiatric disorder marked by significant cognitive, perceptual, and social deficits, the neurobiological basis of which remains incompletely elucidated. Increasing evidence implicates disruptions in protein homeostasis, including misfolding and aggregation of key neuronal proteins, as contributing factors to its pathogenesis. While proteinopathies have been extensively studied in neurodegenerative diseases, their role in schizophrenia has only recently gained attention. Central to these processes is endoplasmic reticulum (ER) stress and the activation of the unfolded protein response, which regulate protein folding and cellular quality control. Dysregulation of ER stress pathways, alongside impaired chaperone protein function and mitochondrial dysfunction, can lead to accumulation of misfolded proteins and neuronal dysfunction. Proteins such as DISC1, CRMP1, NOS1AP, and others have been identified with altered expression and aggregation patterns in schizophrenia, linking protein abnormalities to disease pathology. Additionally, mounting evidence suggests that chronic ER stress can activate microglia, the brain's immune cells, triggering the release of proinflammatory cytokines and promoting neuroinflammation. Sigma-1 receptor, a unique ER chaperone protein involved in modulating ER stress and calcium signaling, has emerged as a critical regulator of neuronal proteostasis and survival. Agonists of the sigma-1 receptor show promising therapeutic potential by alleviating ER stress, enhancing neuroprotection, halting inflammation, and restoring cellular homeostasis in preclinical models of schizophrenia and other brain disorders. In this review, we will discuss these interconnected molecular mechanisms, highlighting novel therapeutic pathways focused on proteostasis restoration and sigma-1 receptor modulation, which offer a promising avenue for future interventions in schizophrenia.

Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.

IMPORTANCE: Different degrees of growth delay have been reported in children with Alagille syndrome (ALGS), yet these patients are routinely evaluated using standard growth charts.

OBJECTIVE: To develop condition-specific growth charts for ALGS using modern statistical approaches.

DESIGN, SETTING, AND PARTICIPANTS: This case series used data from the international, multicenter Global Alagille Alliance (GALA) study accrued between May 14, 2018, and March 20, 2023. Children born at full term between January 1, 1997, and August 31, 2019, with a clinically and/or genetically confirmed ALGS diagnosis and their native liver were included. Data from children with a known history of prematurity were excluded for the development of the growth charts. Data were analyzed from March 25, 2023, to December 30, 2024.

EXPOSURE: Growth of children with Alagille syndrome.

MAIN OUTCOMES AND MEASURES: Generalized additive models for location scale and shape were fitted to generate percentile plots for weight and height relative to age and superimposed on US Centers for Disease Control and Prevention (CDC) growth charts to illustrate differences in growth patterns compared with children with typical development.

RESULTS: Data from 1204 children with ALGS in overlapping cohorts (median [IQR] gestational age, 38 [37-39] weeks) were analyzed (1204 in the weight cohort; 695 boys [57.7%]; 9855 weight observations; 995 with neonatal cholestasis [82.6%]; 306 receiving a liver transplant [25.4%]; 98 deaths [8.1%] and 1106 in the height cohort, 635 boys [57.4%]; 8464 height observations; 906 with neonatal cholestasis [81.9%]; 287 receiving a liver transplant [25.9%]; 86 deaths [7.8%]) were included for the modeling of the weight-for-age and height-for-age charts, respectively. The median birth weight was 2.8 kg (IQR, 2.5-3.0 kg) for boys and 2.6 kg (IQR, 2.4-2.9 kg) for girls. The median birth length was 48.0 cm (IQR, 46.0-50.0 cm) for boys and 47.0 cm (IQR, 45.0-49.0 cm) for girls. The weight-for-age and height-for-age growth charts for boys and girls with AGLS differed significantly from CDC growth charts. The estimated height at age 18 years corresponded to the 50th percentile was 171.5 cm for boys and 156.5 cm for girls on the condition-specific charts vs 176 cm and 163 cm, respectively, on the CDC growth charts.

CONCLUSIONS AND RELEVANCE: These findings suggest that condition-specific growth charts for ALGS may provide a crucial tool for clinicians to evaluate growth and aid in decision-making around listing children for liver transplant.

Diabetes mellitus is a metabolic disorder with escalating prevalence. It's a chief cause of microvascular complications, notably diabetic retinopathy (DR), which can predispose to permanent vision loss. Inflammation and oxidative stress are pivotal contributors to the progression of DR. Luteolin (LUT), a naturally occurring flavonoid, possesses strong anti-inflammatory and antioxidant properties, offering therapeutic potential against DR. However, its clinical use is impeded by its restricted intestinal permeability and poor water solubility. In this study, twelve lipid-polymer hybrid nanoparticles (LPNPs) were developed using a 12 complete factorial design to explore the impact of three formulation variables: poly(ε-caprolactone) (PCL): d-alpha-Tocopheryl polyethylene glycol 1,000 succinate (TPGS) ratio (A), preparation technique (B) and phospholipid (PL) content (C). The optimized formulation (LP8), composed of 50 mg of phospholipid, PC: TPGS (2:1) and prepared via the emulsion solvent evaporation method, demonstrated a high zeta potential (-34.9 ± 5.2  mV), a small particle size (215.3 ± 10.3  nm), and a high entrapment efficiency (93.1 ± 2.4 %). Compared to LUT suspension, LP8 demonstrated prolonged in vitro drug release and markedly enhanced ex vivo intestinal permeability. In streptozotocin (STZ)-induced diabetes, LP8 resulted in significant reduction in hyperglycemia, retinal inflammation, oxidative stress and angiogenesis while preserving retinal structure. Moreover, LP8 significantly downregulated the expression of MDA, IL-1β, NLRP3, ASC, and VEGF while upregulated GSH and Nrf2 levels in the retina. Additionally, pharmacokinetic study confirmed a substantial improvement in oral bioavailability of LUT-loaded LP8 compared to LUT-suspension. These findings proposed that the optimized LUT-loaded LPNPs represent a potential oral nanoplatform for the effective management of DR.

Primary ciliary dyskinesia is a rare autosomal recessive disorder that impairs mucociliary clearance and predisposes children to chronic respiratory infections. Invasive fungal infections caused by are typically confined to profoundly immunocompromised hosts and are exceptionally uncommon in patients without systemic immunosuppression. We report the case of a 6-year-old boy with genetically confirmed primary ciliary dyskinesia (C3orf67 mutation) and right-middle-lobe bronchiectasis who developed persistent cough and increased sputum production. High-resolution chest computed tomography demonstrated right-lower-lobe consolidation and segmental atelectasis. Bronchoalveolar lavage microscopy revealed broad, aseptate/pauci-septate hyphae, and the culture yielded , establishing the diagnosis of pulmonary mucormycosis. The child received intravenous liposomal amphotericin B for 18 days, followed by oral azole step-down therapy, resulting in complete clinical and radiological recovery. This case expands the spectrum of invasive mucormycosis to include pediatric patients with primary ciliary dyskinesia in the absence of classical immunosuppressive risk factors. Early bronchoscopy, mold-directed culture, and prompt antifungal therapy, supported by multidisciplinary care, are critical for favorable outcomes.

Primary ciliary dyskinesia is a rare autosomal recessive disorder that impairs mucociliary clearance and predisposes children to chronic respiratory infections. Invasive fungal infections caused by are typically confined to profoundly immunocompromised hosts and are exceptionally uncommon in patients without systemic immunosuppression. We report the case of a 6-year-old boy with genetically confirmed primary ciliary dyskinesia (C3orf67 mutation) and right-middle-lobe bronchiectasis who developed persistent cough and increased sputum production. High-resolution chest computed tomography demonstrated right-lower-lobe consolidation and segmental atelectasis. Bronchoalveolar lavage microscopy revealed broad, aseptate/pauci-septate hyphae, and the culture yielded , establishing the diagnosis of pulmonary mucormycosis. The child received intravenous liposomal amphotericin B for 18 days, followed by oral azole step-down therapy, resulting in complete clinical and radiological recovery. This case expands the spectrum of invasive mucormycosis to include pediatric patients with primary ciliary dyskinesia in the absence of classical immunosuppressive risk factors. Early bronchoscopy, mold-directed culture, and prompt antifungal therapy, supported by multidisciplinary care, are critical for favorable outcomes.

Parkinson's disease (PD) is the fastest growing neurodegenerative disorder worldwide. Available treatments are only symptomatic, urging the demand for new therapies. Ferroptosis is increasingly reported as a critical player in neurodegeneration. Meanwhile, ferroptosis is activated by impaired mitophagy under rigorous milieu of oxidative stress that disrupts mitochondrial homeostasis. However, the interplay between ferroptosis and mitophagy is not fully elucidated in PD. Carvedilol is a cardiovascular antioxidant, antiferroptotic drug with lipophilic nature that allows its passage via blood brain barrier. Moreover, its effect on modulating mitochondrial balance is emerging in multiple disorders. Therefore, This study aimed to explore the possible neuroprotective mechanistic effects of carvedilol on rotenone-induced PD rat model in context of ferroptosis-mitophagy interaction. Rotenone-induced toxicities were detected by Immunohistochemistry, ELISA, qPCR and western blot analysis techniques. Rotenone disrupted key players of ferroptosis-mitophagy axes. Nrf2, Glutathione peroxidase (GPX4), Catalase, PINK 1/PARKIN levels were drastically decreased. Acyl coA synthetase long chain (ACSL4), MDA and NF-κB levels were significantly increased. Contrarily, carvedilol preserved adequate Nrf2, GPX4, PINK1 and PARKIN levels and increased catalase. Furthermore, it downregulated ACSL4, reduced NF-κB and MDA levels to maintain normal mitophagy and inhibit ferroptosis. Carvedilol's protective effects extended to alleviate α-synuclein and upregulate tyrosine hydroxylase in the striata and substantia nigra leading to distinguished improvements of motor functions. To the best of our knowledge, this is the first study to highlight carvedilol's neuroprotective capacity against PD pathologies in terms of ferroptosis - mitophagy interaction as a novel therapeutic approach to tackle PD at earlier stages.

Brucellosis is a zoonotic disease with significant global health implications, particularly in endemic regions such as Saudi Arabia. It is characterized by clinical manifestations that mimic both infectious and noninfectious diseases, making diagnosis challenging. Congenital brucellosis, a rare entity, can be transmitted transplacentally from a bacteremic mother or through exposure to maternal secretions during delivery. This report describes the case of a neonate with extremely low birth weight and severe respiratory distress syndrome, who was ultimately diagnosed with congenital brucellosis caused by . Despite treatment with trimethoprim-sulfamethoxazole (TMP/SMX) and rifampin, the infant developed abdominal distension and hypotension, showed a clinical picture consistent with sepsis, and succumbed on day 28 of life. This report underscores the importance of early recognition and management of congenital brucellosis to improve outcomes and highlights gaps in antenatal screening and preventive strategies. Diagnosis was confirmed by isolating from blood culture using standard microbiological methods. The patient was treated with trimethoprim-sulfamethoxazole (8 mg/kg/day) and rifampin (10 mg/kg/day). Clinical signs such as persistent hypoxemia and abdominal distension developed before death on day 28. Antenatal screening gaps in endemic regions such as Saudi Arabia contributed to delayed diagnosis.