In the present research work, graph theory has been used to represent the molecular structures of antiviral drugs corresponding to the influenza strain treatment using degree-based topological descriptors and Laplacian energy to understand their structural and physicochemical behavior. The graph theory-based descriptors are used to construct the quantitative structure property relationship and provide input to an ANN model used to predict various physicochemical properties among the selected antiviral drugs. The comparison shows that the ANN model outperforms the Linear Regression model by demonstrating higher R2 and lower RMSE. The suggested ANN-QSPR model was verified through the 5-fold cross-validation process, showing high prediction efficiency and better robustness regarding various physicochemical properties of antiviral compounds. Moreover, an MCDM approach using the TOPSIS method has been employed to assess and rank the antiviral drugs using both structural and physicochemical aspects. The integrated framework in the present research work offers a comprehensive mathematical and computational platform to perform drug analysis and decision-making in antiviral drug design tasks.
Hospitalization provides an opportunity to improve the Hepatitis C Virus (HCV) cascade of care among people who inject drugs. Little is known about whether this potential opportunity is utilized. We conducted a retrospective chart review at four U.S. academic medical centers among patients hospitalized between 1/1/2018-3/31/2022 with ICD-10 diagnosis codes for both opioid use disorder and acute bacterial or fungal infection. Electronic medical records were reviewed manually to confirm injection drug use-related infection for inclusion in the study. Data abstracted from medical records included baseline HCV status at the time of admission; whether HCV antibody screening and confirmatory viral load testing were performed during hospitalization, and their results; follow up for HCV treatment within the same medical system after discharge; and response to treatment. A total of 1651 patients were included. Seventy-five percent of patients with unknown HCV status at the time of admission were screened for HCV during hospitalization, of whom 66% screened positive. Of those with a confirmatory ribonucleic acid (RNA) test, 62% had a detectable viral load (VL). Seventeen percent of those with detectable VL attended a follow up appointment within 12 months. Fifty-five percent of patients with known prior HCV infection were RNA tested, and 65% of those tested had detectable virus. Results revealed sizeable attrition along the entire HCV cascade of care and missed opportunities to engage people who inject drugs in follow up during hospitalization for other infections. Hospitalized individuals who inject drugs need targeted interventions to improve HCV screening, diagnosis, and care linkage.
This study aimed to establish a novel in vitro model by combining jejunal stem cells from commercially available cryopreserved human intestinal mucosal epithelium (CHIM), which can be used without ethical concerns, with 96-well Vitrigel inserts for high-throughput screening. Jejunal stem cells were successfully isolated from CHIM, and stable long-term expansion in spheroid culture was achieved. The differentiated cells exhibited mRNA expression and function of major pharmacokinetic-related genes. Comparable metabolic and transport activities were maintained even with 96-well Vitrigel inserts instead of the conventional 24-well culture inserts. In a 96-well transcellular transport assay, a significant correlation was observed between the in vitro Papp values and the reported FaFg values (the fraction of orally administered drugs reaching the portal vein) in humans for 10 compounds known to be primarily absorbed via passive diffusion, allowing us to construct a fitting curve. Applying this curve, the FaFg values of transporter substrates could also be estimated with reasonably high accuracy. Furthermore, to estimate human Fg values (the fraction of orally administered drugs escaping from intestinal metabolism), we assessed 5 compounds known to be metabolized by intestinal enzymes. Their predicted Fg values closely matched the reported Fg ones, indicating that our cell model enables their accurate prediction. These findings suggest that a combination of CHIM-derived jejunal stem cells and 96-well Vitrigel inserts provides a practical in vitro model for the quantitative prediction of human intestinal absorption of orally administered drugs. SIGNIFICANCE STATEMENT: In this study, we demonstrated that a combination of commercially available cryopreserved human intestinal mucosal epithelium-derived intestinal stem cells, whose use is free from ethical concerns and restricted tissue availability, and 96-well Vitrigel inserts enables a high-throughput assay that quantitatively predicts human intestinal absorption with high accuracy.
Acute bipolar depression poses a significant burden and socioeconomic costs. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar depression, considering dose effects across different age groups. We conducted a network meta-analysis (NMA), searching for randomized controlled trials (RCTs) comparing pharmacological interventions against each other/or placebo in patients with acute bipolar depression (Type-I/Type-II/other), indexed in PubMed/MEDLINE, Embase, Web-of-Science/and Scopus (database inception up to 2025.11.25). Co-primary outcomes were change in depressive symptoms/response/and acceptability. Tolerability/remission/change in anxious symptoms/and risk-of-manic/hypomanic switches were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. 103 RCTs, encompassing 71 distinct treatment combinations, included 20,941 participants. Sensitivity analysis including low-risk-of-bias studies only and excluding outliers for possible effect modifiers indicated that lamotrigine 50 mg/day or 200 mg/day, quetiapine extended-release 150 mg/day and 300 mg/day, and lumateperone 42 mg/day outperformed placebo for depressive symptoms, with estimates ranging from -1.53(95%C.I. = -2.13;-0.93) for lamotrigine 50 mg/day, to -0.36(95%C.I. = -0.68;-0.04) for lumateperone 42 mg/day. Several additional drugs might be efficacious, although they emerged as outliers for either mean age of participants/proportion of females/BD-II participants/psychotic features/rapid cycling/baseline severity of depression/and trial duration. No treatment outperformed placebo for response/remission/acceptability/tolerability/and manic/hypomanic switches. Our findings are consistent with previous NMAs and current guidelines, thereby expanding knowledge by concurrently appraising different drugs, doses, and age groups.
The risk of drug overdose and disease acquisition is highly elevated for those recently initiated into injecting drug use. Despite this, there are few harm reduction interventions developed specifically for new initiates. Further, international technical documents have historically provided little guidance on how to appropriately meet the needs of what is an inexperienced and difficult to engage sub-population. However, the recently updated operational guide for Needle and Syringe Programmes for People Who Inject Drugs from the World Health Organization (WHO), stresses that reaching new initiates requires "tailored, inclusive approaches". In this commentary, we leverage the updated WHO guide to call for renewed focus on new initiates and the development of tailored harm reduction interventions. We describe our recent experiences co-designing interventions for new initiates in Kachin, Myanmar as a case study for how such work may proceed. Finally, we make two key recommendations; 1) that an accepted international definition of new initiates be developed that accounts for risk and opportunity to engage, and 2) that more explicit highlighting and technical guidance on targeting new initiates is made in international documentation. Engaging people who inject drugs as soon as possible after initiation, when vulnerability to blood-borne infections and overdose is greatest, will likely maximise the preventive impact of tailored interventions, thereby providing enduring harm reduction outcomes across injecting careers. The updated WHO guide is the perfect time to re-frame this conversation and re-focus these efforts.
Neuroinflammation plays a key role in epileptogénesis, with interleukin 6 (IL-6) implicated in drug-resistant epilepsy (DRE). The objective was to compare serum IL-6 levels between patients with DRE and non-drug-resistant epilepsy (n-DRE) and to evaluate their relationship with the use of anti-seizure drugs (ASDs). Retrospective multicentre study (March 2019 to April 2022) in two hospitals in Buenos Aires. Patients >18 years of age with epilepsy, at least 2 years of follow-up and no seizures in the last 2 weeks were included. Serum IL-6 was measured by ELISA. Demographic, clinical and treatment data were collected. Comparisons were made using the t-test, Mann-Whitney test, chi-square test, or Fisher's exact test. 121 patients were included (43 with DRE and 78 with n-DRE). The median IL-6 levels did not differ significantly between the two groups. Focal epilepsy and focal seizures with altered consciousness were more frequent in patients with DRE (p = 0.039). In monotherapy, higher IL-6 levels were observed in patients receiving valproic acid (p = 0.027), especially in women (p < 0.05). In this cohort, IL-6 levels were not associated with drug resistance. However, IL-6 concentrations varied according to ASD and sex. Future studies are needed to clarify the role of cytokines in epileptogénesis and their possible value as prognostic biomarkers. Introducción: La neuroinflamación desempeña un papel clave en la epileptogénesis, estando la interleucina 6 (IL-6) implicada en la epilepsia farmacorresistente (EFR). El objetivo fue comparar los niveles séricos de IL-6 entre pacientes con EFR y epilepsia no resistente a los fármacos (n-EFR), y evaluar su relación con el uso de drogas anticrisis (DAC). Materiales y métodos: Estudio multicéntrico retrospectivo (marzo de 2019 a abril de 2022) en dos hospitales de Buenos Aires. Se incluyeron pacientes mayores de 18 años con epilepsia, al menos con 2 años de seguimiento y sin convulsiones en las últimas 2 semanas. La IL-6 sérica se midió mediante ELISA. Se recopilaron datos demográficos, clínicos y de tratamiento. Las comparaciones se realizaron mediante la prueba t, Mann-Whitney, chi-cuadrado o la prueba exacta de Fisher. Resultados: Se incluyeron 121 pacientes (43 con EFR y 78 con n-EFR). La mediana de los niveles de IL-6 no difirió significativamente entre ambos grupos. La epilepsia focal y las crisis focales con alteración del estado de conciencia fueron más frecuentes en los pacientes con EFR (p = 0.039). En monoterapia, se observaron niveles mayores de IL-6 en pacientes que recibían ácido valproico (p = 0.027), especialmente en mujeres (p < 0.05). Conclusión: En esta cohorte, los niveles de IL-6 no se asociaron con la resistencia a los fármacos. Sin embargo, las concentraciones de IL-6 variaron según las DAC y el sexo. Futuros estudios son necesarios para esclarecer el papel de las citocinas en la epileptogénesis y su posible valor como biomarcadores pronósticos.
Cancer remains a leading cause of mortality globally, with the incidence projected to reach 28.4 million new cases annually by 2040. Traditional drug discovery is notoriously inefficient: 10-17 years and up to $2.8 billion per approved drug, with fewer than 10% of clinical candidates succeeding. This review critically examines how the integration of experimental methods with computational biology and artificial intelligence (AI) can accelerate anticancer drug development. We argue that an iterative feedback loop in which sophisticated in vitro and in vivo models provide biological context for validation while AI accelerates target identification, de novo molecular design, and ADMET prediction offers a path forward. FDA-approved drugs, including imatinib, crizotinib, and larotrectinib, have emerged from such integrated pipelines. A persistent translational gap still limits progress owing to three major barriers: poor data fidelity and lack of standardization, limited interpretability of AI models (the black box problem), and regulatory complexity. Addressing these challenges requires physiologically relevant organ-on-a-chip systems, explainable and physics-informed AI, federated learning ecosystems, and adaptive regulatory frameworks. Overall, the continuous integration of computational prediction with experimental validation in a rigorous, data-driven pipeline is critical for accelerating the development of next-generation anticancer therapies.
Stereotaxic surgery is a powerful technique used to deliver drugs, viral vectors, and/or probes into discrete regions of the brain. Over the past decade, the emphasis on performing complex surgeries for neural circuit manipulations or studying multiple brain regions in the same animal has increased. While analog stereotaxic instruments are generally suitable for these types of experiments, the surgeon must accurately read vernier scales for each brain region of interest, which is both time consuming and prone to user error. Although vendors now offer digital stereotaxic instruments that overcome the limitations of analog instruments, digital units are cost-prohibitive and often come in limited configurations that lack clear paths to customize or upgrade as experimental needs change. To overcome these issues, we've created StereoPylot, an open-source Raspberry Pi-based stereotaxic controller with 3D printed components. StereoPylot features motorized control of X, Y, and Z axes, variable motor speed, programmable buttons, and a digital display for stereotaxic coordinates. We also created a custom graphical user interface which allows surgeons to move the manipulators to an area of interest by manually entering stereotaxic coordinates on screen or by loading a preset file that contains a list of user-defined stereotaxic coordinates. We demonstrate practical application of StereoPylot by quantifying viral expression in 3 male and 3 female Long Evans rats and provide instrument accuracy and precision measurements. StereoPylot is therefore feature rich and highly customizable, while being relatively inexpensive to implement onto existing analog instruments commonly found in neuroscience laboratories.Significance Statement We developed a fully motorized digital stereotaxic apparatus using a mixture of commercially available and 3D printed components. StereoPylot is controlled by a Raspberry Pi device and features a 3D printed controller box with customizable buttons and a large digital display. We designed StereoPylot so that it can be retrofitted onto a variety of 0.1mm commercially available stereotaxic manipulators. StereoPylot provides repeatable accuracy and push button control of automated features designed to relieve the surgeon from having to perform repetitive motions and calculations which contribute to potential errors during stereotaxic surgery. The open-source nature of our design encourages users to further customize StereoPylot to accommodate their specific experimental needs.
Objective: To construct a reverse genetic system for the genotype ON1 of human respiratory syncytial virus subtype A (HRSV-A) expressing fluorescent reporter genes. Methods: Recombinant plasmids encoding EGFP or mCherry were constructed based on the 2019 Beijing HRSV-A ON1 dominant strain (6914). Recombinant viruses, rescued by co-transfecting BSR/T7-9 cells with helper plasmids, were identified via indirect immunofluorescence, whole-genome sequencing, and Western blot. Biological properties were characterized through fluorescent quantitative RT-PCR (qRT-PCR), immunostaining plaque assay and fluorescent focus assays (FFA). Results: Two recombinant viruses expressing EGFP or mCherry (rRSVA6914-EGFP and rRSVA6914-mCherry) were successfully rescued. Western blot analysis confirmed that the expression levels of key structural proteins (G, F, and N) in the recombinant strains were consistent with the parental virus. Multistep growth curve analysis revealed that the replication kinetics of the two recombinant viruses in HEp-2 cells did not differ significantly from those of the parental strain. Two recombinant viruses exhibited substantial neutralizing activity against both palivizumab and nirsevimab used in clinical settings. Furthermore, the viral titer of rRSVA6914-mCherry in A549 cells [(1.19±0.05)×105 PFU/ml] was significantly higher than in HEp-2 cells [(7.60±0.79)×104 PFU/ml] (P<0.001). For rRSVA6914-EGFP, the viral titers determined by immunostaining plaque assay and FFA methods were (1.15±0.17)×105 PFU/ml and (1.36±0.19)×105 FFU/ml. For rRSVA6914-mCherry, the corresponding titers were (3.50±0.23)×104 PFU/ml and (3.37±0.07)×104 FFU/ml. There was no statistically significant difference between the immunostaining plaque assay and FFA methods (both P>0.05). Conclusion: The HRSV-A genotype ON1 reverse genetic system expressing fluorescent reporter genes has been successfully constructed and systematically verified, providing a scientific tool for investigating the pathogenic mechanism of genotype ON1 and for screening antiviral drugs. 目的： 构建携带荧光报告基因的人呼吸道合胞病毒A亚型（HRSV-A）ON1基因型反向遗传学系统。 方法： 利用2019年北京地区分离的HRSV-A优势流行株ON1基因型6914株，构建携带增强型绿色荧光蛋白（EGFP）或红色荧光蛋白（mCherry）报告基因的重组质粒。通过与辅助质粒共转染至BSR/T7-9细胞拯救重组病毒；利用间接免疫荧光、全基因组测序、Western blot等方法鉴定病毒；基于荧光定量RT-PCR、免疫染色空斑试验及荧光灶形成试验（FFA）评价其生物学特性。 结果： 成功拯救出携带EGFP或mCherry报告基因的两株重组病毒（rRSVA6914-EGFP与rRSVA6914-mCherry）。Western blot证实重组病毒关键结构蛋白（G、F、N）表达水平与亲本株一致。多步生长曲线分析显示，两株重组病毒在HEp-2细胞中的复制动力学与亲本株基本一致。重组病毒对临床使用的帕丽珠单抗和尼塞韦单抗均表现出显著的中和活性。rRSVA6914-mCherry在A549细胞［（1.19±0.05）×105 PFU/ml］中的病毒滴度高于HEp-2细胞［（7.60±0.79）×104 PFU/ml］（P<0.001）。rRSVA6914-EGFP采用免疫染色空斑试验法和FFA法测得的病毒滴度为（1.15±0.17）×105 PFU/ml和（1.36±0.19）×105 FFU/ml，rRSVA6914-mCherry为（3.50±0.23）×104 PFU/ml和（3.37±0.07）×104 FFU/ml，两种方法测得的病毒滴度差异均无统计学意义（均P>0.05）。 结论： 成功构建并系统验证了携带荧光报告基因的HRSV-A ON1基因型反向遗传系统，可为ON1基因型致病机制研究及抗病毒药物筛选提供科学工具。.
Over 30 million individuals globally are afflicted with heart failure with preserved ejection fraction (HFpEF). Despite this substantial figure, treatment options for HFpEF remain limited. This is largely attributed to the variability in disease features and comorbidities with which patients present in the clinic. A common feature among HFpEF patients is reduced nitric oxide (NO) bioavailability-a finding which prompted the use of therapeutics targeting the NO signaling pathway in HFpEF preclinical and clinical trials. While many of these therapeutics were successful in animal models, clinical trials have yielded neutral, negative, or contradictory results. In this review, we will summarize the outcomes of HFpEF clinical trials investigating drugs that target the NO signaling pathway (nitrates, nitrites, soluble guanylyl cyclase [sGC] stimulators, and phosphodiesterase 5 [PDE5] inhibitors) and discuss potential pitfalls underlying the neutral or negative results, as well as considerations for the design of future studies.
Treatment of mental disorders is carried out through of drugs that are associated with hyposalivation. The study assessed the oral and salivary profiles of mental disorder patients undergoing drug treatment. A cross-sectional study, it involved participants over 18 years with mental disorders. Data collection included demographic, clinical, and oral health assessments, such as salivary flow, pH, and buffering capacity analyses. Of the 50 participants, 68% exhibited salivary alterations, with predominance of women. Schizophrenia was prevalent, with most patients taking three or more medications daily. Comorbidities were more common in the salivary alterations group. Salivary flow at rest was significantly lower in the group with alterations. While plaque index and tongue coating were similar in both groups, stimulated sialometry was lower in the alteration group. Xerostomia complaints were prevalent, indicating salivary dysfunction in psychiatric drug users, impacting oral health parameters like plaque index, tongue coating, pH, and buffering capacity.
Current treatments for Parkinson's disease (PD) fail to halt dopaminergic neurodegeneration and remain largely ineffective against cognitive impairment. Here, we developed IP@ALipo, a nanoplatform that co-delivers the clinical drug pramipexole (PPX) and PEGylated iron oxide nanozyme particles (PEG-IO) via Angiopep-2-modified liposomes capable of crossing the blood-brain barrier (BBB). In the PD mouse model, in vivo photometry showed that a single dose of IP@ALipo significantly enhanced dopaminergic signaling from the substantia nigra pars compacta (SNc) to the striatum (STr) via its PPX component. Facilitated by PEG-IO in IP@ALipo, repeated administration further suppressed cerebral ROS and promoted sustained dopaminergic recovery, resulting in improved motor function. Importantly, the PEG-IO component also preserved hippocampal neurons and restored synaptic architecture, yielding pronounced cognitive benefits. This study demonstrates a nanozyme-augmented strategy for clinical drugs that not only sustains nigrostriatal dopaminergic recovery but also provides cognitive improvements beyond conventional Parkinson's treatments, offering a comprehensive therapeutic approach.
Challenges in the precise diagnosis and treatment of nasopharyngeal carcinoma (NPC) remain, mainly due to the absence of a multi-omics-based molecular classification and effective targeted therapies. In this study, we performed proteomic and phosphoproteomic analyses of NPC and non-cancerous nasopharyngeal tissues to identify key dysregulated proteins and phosphorylation networks. Based on these profiles, we classified NPC into two distinct molecular subtypes: S1 and S2, which exhibit significant clinical heterogeneity. Notably, the S2 subtype displayed stronger immune suppressive characteristics. By leveraging proteomic data from both cancerous and non-cancerous tissues, as well as from the two molecular subtypes, we developed robust diagnostic and prognostic models. Through computational drug repurposing and experimental validation, we identified Panobinostat, a pan-histone deacetylase inhibitor, as a potent anti-tumor agent for NPC, demonstrating efficacy in both in vitro and in vivo models. Mechanistically, Panobinostat inhibits MYC expression, thereby suppressing the transcriptional activation of key components in the homologous recombination (HR) DNA repair pathway. This reduction in transcriptional activation impairs HR repair efficiency and leads to the accumulation of DNA double-strand breaks (DSBs). Furthermore, combination therapy with Panobinostat and radiotherapy produced a synergistic effect, significantly enhancing NPC suppression. Additionally, we predicted and validated potential drugs for targeting the S2 subtype of NPC. In conclusion, we identified molecular subtypes of NPC, constructed preliminary diagnostic and prognostic marker panels, and observed the therapeutic potential of Panobinostat, as a monotherapy and in combination with radiotherapy. These findings provide a solid foundation for precision diagnosis, prognostic stratification, and personalized treatment strategies for NPC.
This study reports the fabrication of pH-sensitive hydrogel beads composed of β-cyclodextrin-ionic liquid/chitosan modified with glycidyl methacrylate/sodium alginate (CD-IL/CTS-GMA/Alg), cross-linked by calcium chloride (CaCl2) to improve the loading and delivery of poorly soluble drug amlodipine (AML). Chitosan was first modified with glycidyl methacrylate to obtain CTS-GMA, while CD-IL was synthesized by reacting mono-6-(p-toluenesulfonyl)-6-deoxy-cyclodextrin (CD-OTs) with vinyl imidazole. An aqueous solution of alginate containing AML was mixed with CD-IL/CTS-GMA copolymer, and the final solution was added dropwise into CaCl2 (3%) to form hydrogel beads at room temperature via the "egg-box" gelation model. Structural and morphological characterization was performed using FTIR, 1H NMR, and SEM. The CD-IL/CTS-GMA/Alg beads exhibited significantly enhanced AML loading efficiency (~99%) compared to Alg/CTS beads (~67%). The β-cyclodextrin moiety facilitated inclusion complexation with AML, improving solubility and stability, while the ionic liquid component further enhanced drug incorporation. Electrostatic interactions between alginate and chitosan imparted pH sensitivity. Drug release was limited under acidic conditions (pH 1.2, ~20% after 96 h) but markedly higher under near-neutral conditions (pH 7.4, ~86% after 96 h), demonstrating controlled and pH-dependent release. Cytotoxicity assays confirmed biocompatibility across 10-1000 μM. Overall, CD-IL/CTS-GMA/Alg hydrogel beads show strong potential as effective carriers for hydrophobic drugs.
Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent intestinal ulceration. The rising global incidence of IBD in recent years has increased disease burden and highlighted the urgent need for more effective and safer treatments. Small-molecule therapeutics targeting critical pathogenic pathways represent a rapidly advancing area of IBD drug development, offering the advantages of stronger target binding affinity, better specificity, and more favorable pharmacokinetic performance compared to conventional therapies. This review summarizes the progress made in IBD small-molecule drugs in the past 5 years, covering the association between related targets and IBD pathogenesis, a series of new compounds acting on distinct molecular targets, including those that have advanced recently to clinical trials as well as those demonstrating promising anti-IBD activity in preclinical studies. The targets include key proteins (BRD4, PDE4, NLRP3), kinases (JAK, RIPK, SIK, IRAK), and G protein-coupled receptors (CCR6, CXCR4). For preclinical compounds, we highlighted the key structural modification process and structure-activity relationship (SAR) studies, summarizing their anti-inflammatory and intestinal protective activities demonstrated in both in vitro and in vivo experiments. Overall, this review aims to facilitate the rational development of next-generation, more effective, and safer small-molecule therapeutics for IBD.
This retrospective study evaluated the clinical value of fractional exhaled nitric oxide in predicting glucocorticoid response in patients with acute exacerbations of chronic obstructive pulmonary disease. Based on the critical value of fractional exhaled nitric oxide (FeNO) levels ≥25 ppb at admission, patients were categorized into two groups: the high FeNO group (n = 61) and the low FeNO group (n = 61). All patients received standard basic treatment, which included inhaled corticosteroids (ICS), short-acting β2 receptor agonists (SABA), and short-acting anticholinergic drugs (SAMA). The treatment subgroup was administered additional systemic glucocorticoid therapy. The primary outcomes of this study were improvements in forced expiratory volume in 1 s (FEV1% pred) and the COPD Assessment Test (CAT) score. Secondary outcomes included changes in the duration of hospital stay and levels of exhaled nitric oxide. Baseline exhaled nitric oxide (FeNO) levels were positively correlated with blood eosinophil counts. In the high-level FeNO group, patients in the treatment group showed significant improvements in lung function, a reduction in the COPD Assessment Test (CAT) score, and lower exhaled nitric oxide levels compared with the control group. Conversely, in the low-level FeNO group, no significant differences were observed between the treatment and control subgroups. These findings indicate that baseline fractional exhaled nitric oxide can identify eosinophilic airway inflammation and predict responsiveness to glucocorticoid therapy, supporting personalized glucocorticoid treatment selection in acute exacerbations of chronic obstructive pulmonary disease. This retrospective study shows that baseline fractional exhaled nitric oxide identifies eosinophilic airway inflammation and predicts glucocorticoid response in acute exacerbations of chronic obstructive pulmonary disease, supporting personalized treatment and reducing hospital stay.
Doxorubicin (DOX) remains a foundation of cancer treatment; however, its clinical utility is seriously restricted by measurements of subordinate and frequently irreversible cardiotoxicity. In spite of the fact that dexrazoxane is as of now the as it were affirmed cardioprotective specialist, its limited viability and clinical restrictions highlight the require for elective methodologies. Developing prove shows that DOX-induced cardiotoxicity could be a systems-level clutter driven essentially by mitochondrial brokenness, metabolic resoluteness, disabled quality control, and controlled cell passing pathways. This audit fundamentally looks at rising cardioprotective methodologies past dexrazoxane, with a center on sodium glucose cotransporter 2 (SGLT2) inhibitors, medicate repurposing approaches, and mitochondrial-targeted treatments. We synthesize unthinking bits of knowledge and translational prove to compare these techniques in terms of robotic breadth and clinical status. SGLT2 inhibitors rise as the most clinically developed and robotically integrator choice, though repurposed drugs and mitochondrial-directed mediations offer complementary but variable potential. Finally, we highlight future bearings emphasizing combination treatments and accuracy cardioprotection to realize solid cardiac conservation in anthracycline-treated patients.
This study aims to estimate the rate of recruitment of participants. This is a pilot, multicentre, double-blind, placebo-controlled, randomised controlled trial of oral oxycodone and sublingual placebo vs sublingual buprenorphine and oral placebo for postoperative pain management for 7 days after pelvic exenteration. Patients will be recruited from three metropolitan quaternary referral centres that offer advanced gastrointestinal surgery in Australia. The inclusion criteria will be patients over the age of 18 years undergoing pelvic exenteration surgery and exclusion criteria are previous adverse events related to the study drugs, currently requiring monoamine oxidase inhibitor medications and if epidural analgesia is planned in the perioperative period. Enrolled patients will undergo pelvic exenteration surgery and be initiated postoperatively on patient-controlled analgesia. In the postoperative period, when clinically appropriate to take oral medications, patients will be commenced on trial analgesia for 7 days. Participants will be randomised to receive either oral active oxycodone 5-10 mg up to 3 hourly as required (with sublingual placebo) or sublingual active buprenorphine 200-400 mcg 3 hourly as required (with oral placebo). The primary outcome measure is the rate of recruitment over a 6-month period. Secondary outcomes include an assessment of missing data, protocol adherence and acceptability of the trial to participants. The trial received ethics approval from Sydney Local Health District, Royal Prince Alfred Hospital Human Research Ethics Committee (No: X25-0128 & 2025/ETH01058). The results of the study will be disseminated by publication and presentation at local annual scientific meetings in Australia. The study protocol is prospectively registered at the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.anzctr.org.au; ACTRN12625000901404).
Objective: To analyze the age-specific differences and temporal trends in triggers of pediatric anaphylaxis from 2015 to 2024, aiming to provide evidence for optimizing clinical diagnosis, treatment, and allergy management strategies. Methods: This was a single-center retrospective study. Patients who attended the Department of Allergy, Beijing Children's Hospital, from January 2015 to December 2024 were initially screened based on based on the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes and clinical diagnoses. Cases meeting the diagnostic criteria for anaphylaxis were included after secondary verification by allergy specialists. A total of 635 children were included. According to age at first onset, they were divided into infant/toddler group (0-2 years, n=227), preschool group (3-6 years, n=143), school-age group (7-12 years, n=211), and adolescent group (13-17 years, n=54). Basic demographic data, suspected clinical triggers, and comorbid allergic diseases were collected. Suspected triggers were determined by integrating clinical history with allergen-specific immunoglobulin E (sIgE) results and skin prick test findings. The chi-square test and Cochran-Armitage trend test were employed for intergroup comparisons and trend analyses. Results: A total of 635 pediatric patients were enrolled, with the highest incidence of onset in the 0-2 years age group (227 cases, 35.7%). Males accounted for 64.6% (410/635) and females 35.4% (225/635). The most common comorbid allergic disease was allergic rhinitis/allergic conjunctivitis (303 cases, 47.7%), followed by bronchial asthma (145 cases, 22.8%). A total of 845 episodes of anaphylaxis were analyzed, with food being the predominant trigger (81.1%, 685/845), followed by food-dependent exercise-induced anaphylaxis/exercise-induced anaphylaxis (11.6%, 98/845), idiopathic causes (3.8%, 32/845), and suspect drugs (2.5%, 21/845). The leading food triggers were cow's milk (11.2%, 95/845), wheat (9.6%, 81/845), and hen's egg (8.5%, 72/845); fruits/vegetables and nuts/seeds accounted for 20.9% (177/845) and 10.1% (85/845), respectively. Overall trigger analysis showed that the proportion of food-induced anaphylaxis decreased significantly with increasing age, from 95.8% in the 0-2 years group to 52.7% in the 13-17 years group (Z=-10.718, P<0.001). In contrast, the proportion of food-dependent exercise-induced/exercise-induced anaphylaxis increased significantly with age, from 0.4% (1/284) in the 0-2 years group to 35.1% (26/74) in the 13-17 years group (Z=10.881, P<0.001). Age-trend analysis for specific food triggers revealed that allergies to cow's milk, hen's egg, and wheat all showed a significant downward trend with age (Z=-9.518, -9.797, -9.233, respectively; all P<0.001), while allergies to fruits/vegetables increased significantly with age (Z=5.909, P<0.001). Buckwheat and nut/seed allergies were most prevalent in the 3-6 years age group, with no statistically significant age-related trend (P=0.518 and P=0.174, respectively). Comparison of trigger proportions between the periods 2015-2019 and 2020-2024 demonstrated a significant decrease in the overall proportion of food triggers, from 88.0% to 79.0% (χ2=8.209, P=0.004). The proportion of food-dependent exercise-induced anaphylaxis/exercise-induced anaphylaxis increased significantly (χ2=16.758, P<0.001), while the proportion of drug-induced anaphylaxis decreased significantly (χ2=9.827, P=0.002). No statistically significant changes were observed in the proportions of idiopathic and other triggers (both P>0.05). Among specific food triggers, the proportions of nuts/seeds (χ²=12.46, P<0.001) and fruits/vegetables (χ2=7.636, P=0.006) increased significantly, whereas the proportions of cow's milk (χ2=24.999, P<0.001), wheat (χ2=5.891, P=0.015), legumes (χ2=7.394, P=0.007), and seafood/fish (χ2=4.161, P=0.041) decreased significantly. Conclusion: Based on this single-center 10-year retrospective data, triggers of pediatric anaphylaxis from 2015 to 2024 show age-related differences and temporal trends. Clinically, stratified and individualized allergy management strategies should be implemented, taking into account age-specific characteristics and period evolution, to provide evidence for precise prevention and control of pediatric anaphylaxis. 目的： 探讨2015—2024年儿童严重过敏反应诱因的年龄差异性及变化趋势。 方法： 采用横断面研究，选择2015年1月至2024年12月于北京儿童医院过敏反应科就诊，根据《疾病和有关健康问题的国际统计分类》第十次修订版（ICD-10）编码及临床诊断初步筛选病例，经过敏反应专科医师二次审核确认符合严重过敏反应诊断标准的患儿，共纳入635例患儿，根据第1次起病年龄划分，其中婴幼儿（0~2岁）227例、学龄前组（3~6岁）143例、学龄组（7~12岁）211例、青春期组（13~17岁）54例。收集患儿基本信息、临床可疑诱因及合并过敏性疾病等资料；病史结合过敏原特异性IgE（specific IgE，sIgE）、皮肤点刺试验判定可疑诱因。采用χ2检验、Cochran-Armitage趋势检验进行组间比较及趋势分析。 结果： 在纳入的635例患儿中，起病年龄以0~2岁组最多（227例，35.7%），男性占64.6%（410/635），女性占 35.4%（225/635）。过敏共病中最常见者为过敏性鼻炎/过敏性结膜炎（303例，47.7%），其次为支气管哮喘（145例，22.8%）。共纳入845次严重过敏反应，诱因以食物为主，占81.1%（685/845），其次为食物联合运动/运动占11.6%（98/845），特发性严重过敏反应、疑似药物诱因分别占3.8%（32/845）和2.5%（21/845）。主要食物诱因依次为牛奶11.2%（95/845）、小麦9.6%（81/845）、鸡蛋8.5%（72/845）；水果/蔬菜20.9%（177/845），坚果/种子10.1%（85/845）。总体诱因分析显示，食物诱发严重过敏反应比例随年龄增长呈现显著下降趋势，由0~2岁组95.8%降至13~17岁组52.7%（Z=-10.718，P<0.001）；食物联合运动/运动诱发过敏比例随年龄显著上升趋势，从0~2岁组的0.4%（1/284）上升至13~17岁组的35.1%（26/74）（Z=10.881，P<0.001）；具体食物诱因年龄趋势分析显示，牛奶、鸡蛋、小麦过敏均随年龄增长呈显著下降趋势（Z=-9.518、-9.797、-9.233，均P<0.001）；水果/蔬菜过敏随年龄呈显著上升趋势（Z=5.909，P<0.001）。荞麦、坚果/种子过敏以3~6岁组多见，年龄变化趋势无统计学意义（P=0.518、P=0.174）。对 2015—2019年与 2020—2024年两个时段诱因占比进行比较，结果显示，总体食物诱因占比由88.0%降至79.0%，差异有统计学意义（χ2=8.209，P=0.004）。食物联合运动/运动诱因占比显著升高（χ2=16.758，P<0.001）；疑似药物诱因占比显著降低（χ2=9.827，P=0.002）；特发性诱因及其他诱因占比变化均无统计学意义（均P>0.05）。具体食物诱因中，坚果/种子（χ2=12.46，P<0.001）和水果/蔬菜（χ2=7.636，P=0.006）占比显著升高；牛奶（χ2=24.999，P<0.001）、小麦（χ2=5.891，P=0.015）、豆类（χ2=7.394，P=0.007）及海鲜/鱼（χ2=4.161，P=0.041）占比显著降低。 结论： 2015—2024年北京儿童医院儿童严重过敏反应诱因呈现年龄差异及年度变化趋势。.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), enters host cells via interaction between the receptor-binding domain of the spike protein (RBDSP) and the peptidase domain (PD) of the host angiotensin-converting enzyme 2 (ACE2). However, no drugs that directly inhibit this interaction have been clinically approved. To discover novel inhibitors, we developed an artificial intelligence (AI)-guided virtual screening approach focused on medium-sized synthetic compounds ≥500 Da. One hit compound inhibited the RBDSP-PDACE2 interaction and suppressed SARS-CoV-2 infection. Nuclear magnetic resonance (NMR) titration revealed direct binding to PDACE2, not RBDSP. ACE2 forms dimers that interconvert between tight and loose conformations, with the tight form stabilized by inter-subunit hydrogen bonds. Extensive NMR analysis using isotopically-labeled PDACE2 identified a putative compound-binding region near the PDACE2 dimer interface, distinct from the RBDSP-binding site. Docking simulations and infection assays using ACE2 mutants deficient in inter-subunit hydrogen bonding provided further evidence for a model in which compound binding is compatible with the loose dimer conformation and may shift the conformational equilibrium away from the tight dimer state, thereby impairing viral entry. These findings uncovered a previously unrecognized allosteric regulatory region within ACE2, which can be targeted by medium-sized molecules to modulate ACE2 conformational equilibrium to inhibit SARS-CoV-2 infection.