ABSTRACT Introduction Selenium supplementation has been suggested as a therapeutic option for Hashimoto's thyroiditis, but its effects on thyroid function and other patient‐related outcomes remain unclear. Methods This retrospective cohort study utilised a global federated health research network to compare patients with Hashimoto's thyroiditis who received selenium supplementation after diagnosis to those who did not. Propensity score matching was performed to balance baseline characteristics. Primary outcomes included longitudinal thyroid function measures, while secondary outcomes included development of autoimmune diseases, thyroid cancer, need for thyroidectomy and all‐cause mortality. All outcomes were followed for 5 years. Results After matching, 2347 patients were included in each cohort. Selenium supplementation was associated with persistently higher mean TSH, free T4 and TPOAb levels, as well as greater proportions of elevated TPOAb (> 35 IU/mL) at 3 years (6.9% vs. 5.0%, p = 0.01) and 5 years (7.9% vs. 5.3%, p < 0.01). The incidence of autoimmune disorders was higher in the selenium group (RR 1.33, 95% CI 1.14–1.56), particularly Sjögren's syndrome (RR 1.61, 95% CI 1.03–2.52) and psoriasis (RR 2.69, 95% CI 1.52–4.76). The rates of thyroid cancer and need for thyroidectomy were similar between groups. However, selenium use was associated with increased all‐cause mortality (RR 1.38, 95% CI 1.09–2.03). Conclusion Selenium supplementation in Hashimoto's thyroiditis was associated with worsened biochemical autoimmunity, increased autoimmune comorbidity and higher mortality. These findings should be interpreted cautiously given the absence of baseline selenium measurements, which limits assessment of deficiency status. Nevertheless, they highlight the need for further research to confirm these results.

Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the LPCAT1*rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. Methods: The LPCAT1 (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the LPCAT1 gene was elucidated using bioinformatic approaches. Results: The LPCAT1*rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, p = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, p = 0.416). Apgar score and Silverman-Andersen respiratory severity score (RSS) were statistically significant with prematurity classes (p < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. Conclusions: This research exhibited a significant difference between the LPCAT1 (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates.

Background Radiofrequency ablation (RFA) is an emerging treatment option for small, low-risk papillary thyroid carcinoma (PTC). This systematic review and meta-analysis aimed to evaluate and compare the efficacy and safety profiles of RFA for primary T1a vs. T1b PTC. Methods PubMed, Web of Science, Embase, Google Scholar, and ScienceDirect databases were searched from inception to February 14, 2024 for studies reporting outcomes of RFA for T1a vs. T1b PTC with no known nodal or distant metastasis. The primary outcomes assessed were pooled proportions of tumor disappearance, volume reduction, complications, and recurrence. Results Twenty studies with 6,613 RFA-treated PTC nodules were included. The median age was 44 years, and the average follow-up was 36.4 months. The mean tumor volume and diameter were 168.9 mm3 and 0.69 cm, respectively. The pooled tumor disappearance rate was 94.3 % for all tumors, with rates of 96.1 % for T1a and 76.7 % for T1b lesions (p = 0.05). The disappearance rate increased from 61.8 % at 12 months to 91.5 % at 48 months post-RFA. The overall volume reduction rate (VRR) was 99.4 % for both T1a and T1b tumors, increasing from 36.8 % at 1 month to 99.6 % at 48 months. Tumor progression occurred in only 1.33 % of the cases overall, with low recurrence rates in both T1a (1.11 %) and T1b (4.21 %) lesions. New cancer foci and lymph node metastases were rare, observed in 0.81 % and 0.20 % of cases, respectively. The overall complication rate was 1.71 %, with transient voice change (0.44 %) and neck pain (0.30 %) being the most common. Conclusions RFA is a safe and effective minimally invasive treatment option for both T1a and T1b PTC, with high tumor disappearance and volume reduction rates and low complication and recurrence rates. The low progression rates in both tumor sizes suggest that RFA is a promising alternative to surgery for selected low-risk PTC patients. Prospective studies with standardized protocols are warranted to validate these findings.

BACKGROUND/OBJECTIVES:Sleep disorders represent a significant health burden among children and adolescents with autism spectrum disorder (ASD), affecting their core symptoms, behavior, and quality of life. While physical activity has shown promise in managing sleep disorders in the general pediatric population, its effectiveness for children and adolescents with ASD remains understudied. METHODS:This retrospective cohort study analyzed electronic health records from 132 healthcare organizations, examining 155,860,529 individuals to determine sleep disorder prevalence in ASD populations and evaluate the impact of physical activity interventions. We identified 248,940 children and adolescents with ASD aged 5-18 years, of whom 38,976 had documented sleep disorders. Propensity score matching was performed to compare patients with ASD and sleep disorders who received physical activity interventions with matched controls. Primary outcomes included sleep disorder resolution and medication utilization changes at 1- and 5-year follow-up. Bonferroni correction was applied to secondary analyses to account for multiple comparisons. RESULTS:The prevalence of sleep disorders was markedly higher in children and adolescents with ASD (19.25%) compared to non-ASD peers (3.37%), with risk ratios escalating from childhood (RR = 5.34, 95% CI: 5.28-5.40) to adolescence (RR = 6.12, 95% CI: 6.05-6.19). After matching, 3709 patients were included in each group. Physical activity interventions were associated with significantly higher sleep disorder resolution at 1 year (-59.9% vs. -5.05%, p = 0.001) and sustained benefit at 5 years (-49.83% vs. +7.26%, p = 0.001). After Bonferroni correction, improvement in sleep apnea at 1 year remained statistically significant (-62.26% vs. +9.39%, Bonferroni-adjusted p = 0.040). Improvements in parasomnia and insomnia did not survive correction and were considered exploratory. Age emerged as a key effect modifier: adolescents (12-18 years) demonstrated sustained improvements in overall sleep outcomes at both 1- and 5-year follow-up that met Bonferroni-corrected thresholds, whereas younger children (5-11 years) showed limited and inconsistent responses. Among comorbidity groups, anxiety-comorbid patients exhibited the strongest overall improvement (-58.7% vs. -12.4%, p < 0.01), while reductions in amphetamine use and changes in melatonin prescribing patterns should be interpreted as exploratory findings requiring prospective confirmation. CONCLUSIONS:This large-scale observational study suggests structured physical activity interventions are associated with sustained improvements in overall sleep disorders among children and adolescents with ASD. While subtype- and subgroup-specific associations were observed, many attenuate after multiple comparison adjustments, highlighting the need for cautious interpretation. Findings support exploring physical activity in comprehensive care plans, with prospective randomized trials needed to confirm causality, optimize protocols, and address multiplicity.

BACKGROUND:The contribution of MTHFR and TP53 genetic variants to breast carcinoma (BC) susceptibility has been examined, but their findings have been inconclusive. This work is designed to explore the potential roles of the MTHFR (rs1801131, rs1801133) and TP53 (rs1042522) variants with increased risk of BC using genetic and bioinformatic approaches. METHODS:This work included a total of 242 female participants [142 BCE patients and 100 healthy controls]. We genotyped the allelic discrimination analysis for these genetic variants using the T-ARMS-PCR technique. Logistic regression, haplotype analysis, genetic association models, and multivariate clustering were executed. RESULTS:The rs1801131*C allele revealed a significant association with elevated risk of breast carcinoma compared to healthy controls under allelic (OR = 2.02, p-value < 0.001) and recessive (OR = 3.26, p-value < 0.001) models. Moreover, the rs1801133*T allele was correlated to cancer susceptibility under allelic (OR = 1.81, p-value = 0.002) and dominant (OR = 3.33, p-value < 0.001) models, while the rs1042522*G allele was associated with increased risk of BC under allelic (OR = 2.98, p-value < 0.001) and recessive (OR = 3.21, p-value < 0.001) models. BC women carrying the rs1801131*C/C genotype were associated with histological grade III, while those with the rs1801133*T/T and rs1042522*G/G genotypes were correlated with a moderate/poor NPI score (p-value < 0.05). CONCLUSIONS:The rs1801131*C, rs1801133*T, and rs1042522*G alleles are associated with an increased risk of BC. The rs1801133*T and rs1042522*G alleles correlated with moderate/poor NPI score. These findings pave the way for the diagnostic functions of these genetic variants as potential prognostic biomarkers.

BACKGROUND:The relationship between thyroid disorders and neurodegenerative diseases remains poorly understood. This large-scale retrospective cohort study aimed to investigate the association between thyroid disorders and various neurodegenerative diseases, as well as the potential impact of thyroidectomy. METHODS:We analyzed data from 3,719,666 patients with thyroid disorders and 2,945,438 controls from 120 healthcare organizations (TriNetX database). After propensity score matching, each group included 2,033,096 patients. We compared the risk of neurodegenerative diseases between these groups and examined the effect of thyroidectomy in a subgroup analysis of 31,753 matched pairs. RESULTS:Patients with thyroid disorders showed significantly higher risks of Alzheimer's disease (RR = 1.15, 95% CI: 1.110-1.195), Parkinson's disease (RR = 1.25, 95% CI: 1.187-1.318), amyotrophic lateral sclerosis (RR = 1.35, 95% CI: 1.131-1.622), frontotemporal dementia (RR = 1.44, 95% CI: 1.219-1.702), Lewy body dementia (RR = 1.15, 95% CI: 1.107-1.186), progressive supranuclear palsy (RR = 1.41, 95% CI: 1.095-1.819), vascular dementia (RR = 1.32, 95% CI: 1.266-1.369), Niemann-Pick disease type C (RR = 1.34, 95% CI: 1.092-1.638), and Wilson's disease (RR = 1.26, 95% CI: 1.056-1.507). Interestingly, the risk of multiple sclerosis was lower (RR = 0.80, 95% CI: 0.738-0.862). Thyroidectomy was associated with a 44.2% lower risk of Lewy body dementia (RR = 0.558, 95% CI: 0.339-0.919, p = 0.020). CONCLUSIONS:Thyroid disorders are significantly associated with an increased risk of several neurodegenerative diseases. Thyroidectomy may have a protective effect against Lewy body dementia. These findings suggest a complex relationship between thyroid function and neurodegeneration, emphasizing the need for neurological monitoring in patients with thyroid disorders and further research into thyroid-brain interactions.

Background/objectives: Cystic fibrosis (CF) is a life-limiting genetic disorder affecting multiple organ systems. This study compared clinical outcomes, hospitalization rates, and survival between children and adolescents with CF who received CFTR modulator therapies (ivacaftor, lumacaftor, tezacaftor, and elexacaftor). Methods: A retrospective cohort study was conducted using data from the TriNetX global collaborative network. Patients with CF aged 2–12 years (children) and 13–18 years (adolescents) who received CFTR modulator therapies were included. The propensity score matching balanced baseline characteristics between the two age groups. Results: After propensity score matching, 946 patients per group were analyzed. The incidence of respiratory failure (3.81% vs. 1.06%, p < 0.001) and respiratory infections (62.7% vs. 57.5%, p = 0.021) were significantly higher in adolescents compared to children. Adolescents had a higher risk of respiratory failure (HR = 3.6, 95% CI = 1.79–7.21, p < 0.001) and respiratory infections (HR = 1.09, 95% CI = 1.01–1.17, p < 0.001). Adolescents also had a higher hospitalization rate (29.6% vs. 20.3%, p < 0.001), with a 47% higher risk (HR = 1.47, 95% CI = 1.22–1.77, p = 0.001), more hospital visits per person (8.8 vs. 3.7, p = 0.004), and longer hospital stays (32.7 vs. 20.4 days, p = 0.006). Mortality rates were similar between the groups (1.58% vs. 1.26%, p = 0.56). Conclusions: CF patients who initiated CFTR modulator therapies during adolescence had a higher incidence of respiratory failure, respiratory infections, hospitalization rates, and healthcare resource utilization compared to those who started therapy in childhood, despite similar mortality rates. These findings highlight the importance of the early initiation of CFTR modulator therapies.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated significant efficacy in obesity treatment beyond their original development for type-2 diabetes management. This comprehensive study investigated the relationship between GLP-1RA use and cancer incidence in individuals with obesity across a 5-year follow-up period. Methods: We conducted a large-scale cohort study using the TriNetX US Collaborative Network database (2013-2023) examining adult patients with obesity. The study utilized propensity score matching to pair GLP-1RA-treated patients with controls (1:1) using the nearest neighbor method. Cancer incidence served as the primary outcome measure over the 5-year follow-up, with subgroup analyses considering individual GLP-1RA agents, patient sex, and BMI categories. Results: Analysis revealed significant cancer-risk reductions associated with GLP-1RA use across multiple cancer types compared to matched controls. Notable risk reductions were observed in gastrointestinal (HR 0.67, 95% CI 0.59-0.75), skin (HR 0.62, 95% CI 0.55-0.70), breast (HR 0.72, 95% CI 0.64-0.82), female genital (HR 0.61, 95% CI 0.53-0.71), prostate (HR 0.68, 95% CI 0.58-0.80), and lymphoid/hematopoietic cancers (HR 0.69, 95% CI 0.60-0.80). Semaglutide demonstrated superior protective effects, particularly in gastrointestinal cancers (HR 0.45, 95% CI 0.37-0.53). Conversely, liraglutide showed increased risks for thyroid (HR 1.70, 95% CI 1.03-2.82) and respiratory cancers (HR 1.62, 95% CI 1.13-2.32). Conclusions: This research provides compelling evidence for GLP-1RA's potential role in cancer-risk reduction, with semaglutide showing particularly promising results. The differential effects observed among GLP-1RA agents emphasize the importance of personalized medicine approaches. These findings suggest significant implications for clinical practice and future research in both obesity management and cancer prevention.

Editorial: The role of regulatory networks in virulence and antimicrobial resistance of microbial pathogens

Ginger (Gin) has numerous therapeutic properties. One of Gin’s most potent components is 6-gingerol, a naturally occurring phenol. This study aimed to investigate the therapeutic impact of gingerol and/or sorafenib on the ATG4/CASP3 and COIIV/COX-2/NF-B Expression as a potential therapy for DAB-induced HCC. Gin was administered to HCC mice induced by p-Dimethylaminoazobenzene (DAB) alone or combined with sorafenib (Sor). Superoxide dismutase (SOD), catalase (CAT), and oxidative stress malondialdehyde (MDA), as well as biochemical markers including AST, ALT, ALP, Albumin, and Bilirubin, were examined. The expression of oncogenes (COIIV, COX-2, NF-κB, and survivin) and tumor suppressor genes (ATG4 and CASP3) was evaluated using qPCR. According to the results, the levels of MDA have been markedly decreased, while SOD and CAT have been increased. Further, the expression levels of tumor suppressor genes were upregulated, whereas the expression levels of oncogene genes were downregulated. Furthermore, in a dose-dependent manner, gingerol has shown the potential to alleviate hepatic portal vein (PV) dilatation and could offer a reliable therapy for HCC. This suggests combining the two compounds may be more effective than alone and that Gin could be a promising therapeutic option for HCC. The binding of Gin and Sor to the active sites of the target genes prevents them from functioning normally, which in turn stops the pathways from carrying out their oncogenic functions. Additionally, COX-2 inhibition reduces the production of certain pro-inflammatory compounds, which further averts oncogenesis. Conclusively, this study indicated that Gin has cytoprotective properties and anti-cancer activity that may be related to controlling oxidative stress. This effect may be achieved by suppressing the COIIV/COX-2/NF-κB pathway and upregulating the ATG4 /CASP3 pathways.

The renin–angiotensin–aldosterone system has an indispensable function in the uteroplacental circulation, placental growth, and blood pressure optimization. The angiotensin I converting enzyme (ACE) gene is a critical integrator for electrolyte balance, and water retention, along with inhibiting preeclampsia. The main goal of this pertaining study is to assess the contribution of ACE*(Ins/Del) variant with the susceptibility for preeclampsia with focus on the severity of the disease among gestational hypertensive women. This retrospective study included 225 participants [125 PE gestational women, and 100 normotensive healthy controls] matching with age, and geographical region. PE women classified into 82 early-onset PE women, accompanied with 43 late-onset PE women. Additionally, PE women categorized into 59 mild PE women, together with 66 severe PE women. The genotyping and characterization of ACE*(Ins/Del) variant were applied using the PCR technique. Our findings indicated higher frequency of the ACE*(Del/Del) genotype and ACE*(D allele) with elevated risk of preeclampsia compared to normotensive controls under recessive (OR = 2.09, and p-value = 0.007), and allelic (OR = 1.75, and p-value = 0.012) models. In addition, testing logistic regression revealed that the levels of endothelin-1 and malondialdehyde exposed significant difference for the ACE*(Del/Del) genotype among early-onset and late-onset PE women ( p-value = 0.024, and 0.23, respectively). Furthermore, carriers of the ACE*(Del/Del) genotype observed statistically significant with lower sodium concentrations among severe PE women ( p-value = 0.034). The ACE*(Del/Del) genotype and ACE*(D allele) were associated with increased risk preeclampsia among gestational women. Furthermore, early-onset PE and late-onset PE were correlated with endothelin-1 and malondialdehyde concentrations among Egyptian women.

Background Thermal and chemical ablation techniques may consolidate recurrent metastatic cervical lymph nodes as alternatives to repeat neck dissection in thyroid cancer patients. This meta-analysis aims to compare the efficacy and safety across modalities. Methods Four databases were searched for studies on radiofrequency (RFA), microwave (MWA), laser (LA), and ethanol ablation (EA) treating metastatic cervical nodes from thyroid cancer. The outcomes analyzed included treatment response, oncologic control, and complications. Random effects meta-analytical pooling was conducted. Results There were 25 studies (n=1061 nodes) examining the four ablation methods. Patients showed comparable baseline characteristics and initial lymph node sizes ranging from 0.96 to 1.28 cm. All modalities achieved substantial node volume reduction (88.4%) and disappearance (62.8%), with significant biochemical decline (from 6.01 to 1.13 ng/ml, p=0.18 between groups). MWA showed the highest volume reduction (99.4%) and disappearance rate (87.6%) versus slower efficacy of RFA (93.0%, 72.1%), LA (77.9%, 62.5%), and EA (81.8%, 58.4%). New malignancy/metastases risks ranged from 0.03% to 1.3% without between-group differences (p=0.52). Major complications were absent; transient voice changes (0.05%-10.6%) and neck pain (0.0%-5.9%) were the main overall complaints. However, overall complication rates significantly varied by modality (1.1%-10.6%; p=0.003). Conclusions Thermal and chemical ablation is effective in controlling the metastatic disease burden in patients with thyroid cancer, offering a potentially less morbid and non-surgical alternative to re-operation. Additional prospective data could confirm the long-term equivalent of revision neck dissection and stratify patients based on concomitant Hashimoto's and genomic mutations. Clarifying optimal patient selection and standardizing prognostic indexing could further enhance utilization.

Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form “platforms” that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = − 12.58 kcal/mol), emetine (S = − 11.65 kcal/mol), pimozide (S = − 11.29 kcal/mol), carvedilol (S = − 11.28 kcal/mol), mebeverine (S = − 11.14 kcal/mol), cepharanthine (S = − 11.06 kcal/mol), hydroxyzin (S = − 10.96 kcal/mol), astemizole (S = − 10.81 kcal/mol), sertindole (S = − 10.55 kcal/mol), and bepridil (S = − 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = − 10.43 kcal/mol), making them better options for inhibition.

Background Pediatric epilepsy is a complicated neuropsychiatric disorder that is characterized by recurrent seizures and unusual synchronized electrical activities within brain tissues. It has a substantial effect on the quality of life of children, thus understanding of the hereditary considerations influencing epilepsy susceptibility and the response to antiepileptic medications is crucial. This study focuses on assessing the correlation of the ABCB1, ABCC2, CYP1A2, and CYP2B6 genetic polymorphisms with the susceptibility to epileptic seizures and their contributions to antiepileptic medication throughout the course of the disease. Methods This study included 134 Egyptian epileptic children, comprising 67 drug-responsive and 67 drug-resistant patients, along with 124 healthy controls matching for age, gender, and geographical district. Genotyping of the rs2032582, rs717620, rs2273697, rs762551, and rs3745274 variants was performed using the PCR technique. Statistical analyses, including haplotype, multivariate, logistic regression, and bioinformatics approaches, were conducted to evaluate the associations within the disease. Results The ABCC2*rs717620 (T allele) revealed an increased risk of epilepsy compared to healthy controls (OR = 2.12, p-value < 0.001), with the rs717620 (C/T + T/T genotypes) showing significant differences between drug-responsive and drug-resistant patients (p-value < 0.05). Moreover, the ABCC2*rs2273697 (A allele) indicated a decreased risk of epileptic seizures compared to healthy controls (OR = 0.51, p-value = 0.033), with the rs2273697 (G/A + A/A genotypes) indicating a significant association with drug-resistant patients (OR = 0.21, p-value = 0.002). The rs717620*T/rs2273697*G haplotype was significantly correlated with an elevated risk of epileptic seizures within drug-responsive patients (OR = 2.26, p-value = 0.019). Additionally, the CYP1A2*rs762551 (A allele) represented a protective effect against epilepsy susceptibility (OR = 0.50, p-value < 0.001), with the rs762551 (G/A + A/A genotypes) disclosing a substantial association with a decreased risk of epileptic seizures among drug-resistant patients compared to drug-responsive patients (OR = 0.07, p-value < 0.001). Conversely, the ABCB1*rs2032582 (G allele) and the CYP2B6*rs3745274 (T allele) did not attain a significant difference with the epilepsy risk compared to healthy controls (p-value > 0.05). Conclusions The findings of our study emphasize the importance of pharmacogenetic screening in epilepsy research, particularly regarding to drug-resistant patients. The ABCC2*rs717620 variant conferred a significant correlation with elevated risk of epileptic seizures, while the ABCC2*rs2273697 and CYP1A2*rs762551 variants confirmed their contributions as protective markers against epilepsy development. Conversely, the ABCB1*rs2032582 and CYP2B6*rs3745274 alleles were not considered as independent risk factors with the course of epilepsy disease.

BACKGROUND:GLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. OBJECTIVE:To evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. METHODS:This comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. RESULTS:Obese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer's disease (RR = 0.627, 95 %CI = 0.481-0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462-0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327-0.588). The risk reduction for Parkinson's disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580-1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369-0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493-0.558). CONCLUSION:This study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment.

BackgroundThe relationship between GEMIN4 genetic variants and cancer, especially bladder carcinoma (BLCA), has been explored without conclusive results. This study aims to elucidate the link between GEMIN4 polymorphisms and BLCA susceptibility through genetic analyses, bioinformatics, and molecular dynamics (MD) simulations.MethodsA cohort of 249 participants (121 BLCA patients and 128 unrelated controls) was enrolled. PCR was employed for allelic discrimination of GEMIN4 variants, followed by subgroup stratification, haplotype analyses, structural prediction using the AlphaFold2 prediction tool, subsequent MD simulations, structural analysis, and residue interaction mapping using Desmond, UCSF ChimeraX, and Cytoscape softwares.ResultsThe rs.2740348*G variant demonstrated a protective role against BLCA in allelic (OR = 0.55, p = 0.002) and recessive (OR = 0.54, p = 0.017) models, whereas the rs.7813*T variant increased BLCA risk under the recessive model (OR = 1.90, p = 0.019). Haplotype analysis revealed a significant association between GEMIN4 haplotype (rs.2740348*C/rs.7813*T) with increased BLCA risk (OR = 2.01, p = 0.004). Univariate analysis revealed associations of the variants with albumin levels and absolute neutrophil count in BLCA patients. Pathogenicity evaluation categorized p.Gln450Glu as neutral and p.Arg1033Cys as deleterious. MD simulations revealed structural alterations and conformational shifts in the GEMIN4 protein induced by the Glu450 and Cys1033 mutations.ConclusionsThe study highlights the dual role of GEMIN4 variants in BLCA susceptibility, with rs.2740348 conferring protection and rs.7813 increasing risk. The Glu450 residue positively impacted protein stability, while Cys1033 had a detrimental effect on protein function. These findings underscore the significance of GEMIN4 variants in BLCA susceptibility and pave the way for future diagnostic and therapeutic initiatives.

Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein–protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis. Graphical Abstract

Oxidative stress is a sophisticated situation that orignates from the accumulation of reactive free radicals within cellular compartments. The antioxidant mechanism of the MnSOD enzyme facilitates the removal of these lethal oxygen species from cellular components. The main goal of this pertained work is to study the contribution of the SOD2 (rs4880; p.Val16Ala) variant to the development of bronchial asthma among children. The study’s design was carried out based on a total of 254 participants including 127 asthmatic children (91 atopic and 36 non-atopic) along with 127 unrelated healthy controls. Allelic discrimination analysis was executed using the T-ARMS-PCR protocol. This potential variant conferred a significant association with decreased risk of bronchial asthmatic children under allelic (OR = 0.56, P-value = 0.002), recessive (OR = 0.32, P-value = 0.011), and dominant (OR = 0.51, P-value = 0.040) models. Additionally, atopic and non-atopic asthmatic children indicated a protection against bronchial asthma development under allelic, and dominant models (p-value < 0.05). Our findings suggested that the SOD2*rs4880 variant was correlated with decreased risk of childhood bronchial asthma.

The microRNA (miRNA) biogenesis mechanism remains elusive, yet various genetic variants may play a role in predicting the biological function of this machinery system and its association with the advancement of specific tumors. This study aimed to investigate the relationship between AGO1 and AGO2 gene variants with the elevated risk of bladder carcinoma (BLCA) using genetic, biochemical, and bioinformatic approaches. This retrospective study comprised of 252 participants [122 BLCA patients and 130 cancer-free controls], matched for age and gender. The AGO1*rs595961 and AGO2*rs4961280 genetic variants were characterized using TaqMan genotyping assay. A bioinformatics framework, stratification analysis, and multivariate regression were employed. The genetic distribution of AGO1 * rs595961 was associated with an increased risk of bladder carcinoma under allelic (OR = 1.50, p = 0.026) and recessive (OR = 2.01, p = 0.010) models. In contrast, the AGO2*rs4961280 variant demonstrated no considerable association with bladder carcinoma progression under various genetic models ( p > 0.05). An in-depth examination of AGO1 and AGO2 protein revealed their involvement in gene silencing by miRNA, post-transcriptional gene silencing, regulatory RNA binding, and positive regulation of mRNA catabolic processes. The AGO1 * rs595961 genetic variant was correlated with an elevated risk of bladder carcinoma, whereas the AGO2*rs4961280 variant was not. Further research is warranted to understand the underlying molecular mechanisms and potential clinical implications.