Background Marketing regulations for natural products (NPs), such as herbal supplements, are less stringent than for prescription or over‐the‐counter medications. This paucity of regulations and widespread use demonstrates the need to better understand potential safety risks of NPs. The aim of this disproportionality analysis was to use the FDA Adverse Event Reporting System (FAERS) database to identify cardiac adverse event (AE) signals associated with NPs. Methods FAERS reports (2004 Q1–2021 Q3) were searched for cardiac AEs and NP use. Reporting odds ratios (ROR) were calculated for each cardiac AE–NP pair. Pairs with ≥ 3 reports and a 95% confidence interval for the ROR ≥ 2.0 underwent further analysis using the observed‐to‐expected (OE) ratio with shrinkage. Signals with an OE ratio 95% credibility interval > 1.0 were considered significant safety signals. Detailed assessments of each report were conducted for content validity based on clinical interpretation. Results A total of 2484 spontaneous reports listing cardiac AEs and NPs were identified, resulting in 705 preliminary NP–AE pairs for 74 unique NPs. Subsequent OE ratio calculations identified 10 significant safety signals for 8 unique NPs. Conclusion Several AE signals for NPs had a disproportionate number of reports when compared to all other product reports within FAERS. After a literature search for supporting evidence, we found that four NPs are likely associated with cardiac AEs (guarana, hemp extract, licorice, and ginkgo) and four require further investigation (seawrack, soybean, celery, and Panax ginseng ). Despite limitations inherent to spontaneous reporting systems, this study highlights potential cardiac safety risks associated with NP use.
BackgroundWe aimed to establish the prevalence of adverse reactions associated with the use of deoxycholate and/or liposomal amphotericin B and to determine adherence to World Health Organization (WHO) recommendations to minimize the risk of toxicity.MethodsClinical data were collected from records of 143 patients over 18 years of age who were under treatment with amphotericin B (deoxycholate and/or liposomal) for at least 5 days from January 2016 to March 2019 at National Institute of Respiratory Diseases "Ismael Cos & iacute;o Villegas" in Mexico City. We used MeSH terms to name each formulation of amphotericin B, adverse reactions, and diagnoses. Definitions and classification of the adverse reactions were made in accordance with the Common Terminology Criteria for Adverse Events Version 5.0 and other bibliographic references. Preventability assessment was evaluated using the Schumock and Thornton scale. To determine adherence to WHO recommendations, we evaluated intravenous preemptive hydration, electrolyte supplementation, and laboratory test monitoring.Results105 patients (73.4%) were exposed to deoxycholate amphotericin B, 25 patients (17.5%) to liposomal amphotericin B, and 13 patients (9.1%) to both amphotericin B types. Hypokalemia was the most common adverse reaction (76.2%), followed by hypomagnesemia (47.6%), acute kidney injury (40.6%), infusion reactions (33.6%), anemia (20.3%), thrombocytopenia (7%), and neutropenia (4.9%). Electrolyte supplementation was the WHO recommendation that was less performed (28%), while preemptive hydration and laboratory test monitoring were well applied (82.5% and 84.6%).ConclusionThis study highlights the need to adhere to amphotericin B toxicity prevention recommendations as some of the most common adverse reactions are mostly preventable.
Presently, the incidences of colorectal cancer (CRC) are significantly increasing and there is a need for new therapeutics that better treat CRC. The current treatments for CRC, such as surgery, chemotherapeutics, immunotherapies, and radiotherapies, lack specificity and are cytotoxic to cells. Plant‐derived exosome‐like nanoparticles (PELNs) may provide a new and more natural strategy for enhancing colon health. PELNs are stable, exhibit low immunogenicity, and are highly biocompatible. PELNs may reduce inflammation, repair the intestinal barrier of the gut, and control the composition of the gut microbiota. PELNs and their miRNAs may ameliorate many of the causes of CRC that includes chronic inflammation, dysbiosis of the gut microbiota, and the degradation of the intestinal epithelium by maintaining the homeostasis of the intestinal microenvironment. However, there is a need for more research studies that examine the effects of PELNs on the gut microbiota and on the mechanisms of PELN miRNAs within the intestines. This review will provide support for the immense potential of PELNs and their miRNAs to prevent and treat CRC by discussing their ability to control the composition of bacteria in the gut microbiota and their miRNA regulation of cancer‐causing and inflammatory‐based gene expression in the colon.
Aims This study aimed to assess the association between estimated glomerular filtration rate (eGFR) levels and the prevalence of potentially inappropriate medications (PIMs) based on three criteria: the Beers (2019 version), Chinese, and Screening Tool of Older Persons’ Prescriptions (STOPP) criteria. Methods This retrospective cross‐sectional study analyzed 191 inpatients aged ≥ 65 years. Using the Beers, Chinese, and STOPP criteria, we assessed the prevalence of PIMs across stratified eGFR levels. Nonparametric analyses (Mann–Whitney U test), chi‐square tests, and logistic regression analysis were employed to evaluate the association between eGFR and PIMs exposure. Results Participants were stratified into three groups based on eGFR: Group I (≥ 90 mL/min/1.73 m 2 ), Group II (60–89 mL/min/1.73 m 2 ), and Group III (< 60 mL/min/1.73 m 2 ). Prevalence rates of PIMs were 72.25% by Beers criteria, 60.73% by Chinese criteria, and 28.80% by STOPP criteria, with STOPP demonstrating significantly lower PIMs detection rates than the other two criteria. Analysis by eGFR stratification revealed escalating PIMs prevalence with declining kidney function under Beers criteria: 67.35% in Group I, 74.29% in Group II, and 86.96% in Group III ( p < 0.05). Notably, Group III (eGFR < 60 mL/min/1.73 m 2 ) exhibited higher proportions of patients with ≥ 2 PIMs across all criteria. By Beers criteria, 56.52% of Group III patients had ≥ 2 PIMs versus 22.45% (Group I) and 25.71% (Group II). Similar trends were observed by Chinese and STOPP criteria ( p < 0.05). Logistic regression analysis identified polypharmacy and eGFR decline as independent risk factors for PIMs exposure. Conclusion The prevalence of PIMs gradually increases with the decline of eGFR in older adults, particularly when compounded by polypharmacy.
Background Immune checkpoint inhibitors (ICIs) have improved the survival rates of cancer patients. However, ICIs often cause gastrointestinal adverse events (AEs). This study aims to assess the risk of gastrointestinal AEs associated with ICIs. Methods A comprehensive search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library databases to identify eligible phase III or phase IV, double‐blind randomized controlled trials (RCTs) investigating gastrointestinal AEs (nausea, vomiting, colitis, abdominal pain, constipation, and diarrhea) in cancer patients treated with ICIs, published before December 3, 2024. References were managed using EndNote X21, and all statistical analyses were performed in R (Version 4.3.3). The pooled incidence of gastrointestinal AEs was estimated using a random‐effects model. Subgroup analyses were performed according to predefined study designs. Results After excluding studies that did not meet the criteria, 10 RCTs were eligible for the meta‐analysis. Diarrhea was the most common low‐grade gastrointestinal AE, with an incidence of 18.862% (95% confidence interval [CI] = 14.920%–23.845%), followed by nausea (10.798% [95% CI = 7.781%–14.983%]) and vomiting (6.454% [95% CI = 3.945%–9.527%]). Among high‐grade gastrointestinal AEs, diarrhea and colitis were the most common, with incidences of 3.719% (95% CI = 1.788%–6.314%) and 2.668% (95% CI = 1.590%–4.479%), respectively. Additionally, cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) inhibitors, either alone or in combination with PD‐1 inhibitors, were associated with a significantly higher risk of diarrhea and colitis compared to programmed cell death protein 1 (PD‐1) inhibitors alone. Conclusion Gastrointestinal AEs are relatively common during ICI therapy. Monitoring and managing these events, especially diarrhea and colitis, are crucial to improving treatment efficacy in cancer patients, especially those receiving CTLA‐4 inhibitors.
ObjectiveTo develop a population pharmacokinetic model for colistin sulfate in Chinese critically ill patients, identify factor multifactorial determinants of pharmacokinetic variability including extracorporeal support modalities, and establish a precision dosing framework guided by quantitative pharmacodynamic targets.MethodsThis study enrolled 59 critically ill adult patients with microbiological evidence of infection caused by carbapenem-resistant Gram-negative organisms and antimicrobial susceptibility or empirical treatment. A nonlinear mixed-effects modeling (NONMEM) approach incorporating 278 concentration measurements was employed to characterize covariate effects, explicitly evaluating ECMO/CRRT impacts. Model robustness was validated through goodness-of-fit (GOF), bootstrap, normalized prediction distribution errors (NPDEs), and external clinical verification. Monte Carlo simulations were conducted to quantify target attainment probabilities for fAUC/MIC >= 20 under varying renal function and MIC scenarios (0.5 similar to 2 mg & centerdot;L-1).ResultsA one-compartment model with first-order elimination demonstrated superior fit, identifying creatinine clearance (CrCl) as the primary covariate influencing clearance. The integrated validation paradigm confirmed model reliability. The simulation revealed critical limitations of conventional dosing: 1.0 similar to 1.5 MU a day is insufficient for patients with normal renal function or those infected with pathogens with an MIC >= 1.0 mg & centerdot;L-1. Therefore, the dosing regimen of colistin sulfate should be tailored according to renal function and the MIC.ConclusionTo our knowledge, this study establishes the first PPK model integrating dynamic renal function and extracorporeal support effects for colistin sulfate in Chinese critically ill patients. The developed model-to-clinic pipeline, combining Monte Carlo simulation-derived breakpoints and Bayesian forecasting, provides a paradigm for individualized antimicrobial dosing in complex critical care scenarios.
ObjectivesMyocardial infarction (MI) is the most severe manifestation of coronary artery disease. Guanxinning (GXN), a traditional Chinese medicinal compound, is used to treat stable coronary artery disease. However, the potential benefits of GXN in MI and its precise molecular mechanisms remain unclear. This study aimed to explore the effects and therapeutic mechanisms of GXN in MI by network pharmacology, molecular docking, and experimental validation.MethodsUsing "myocardial infarction" as a search term, we retrieved relevant disease targets from multiple databases, including the Human Mendelian Genetic Disease Database, Drug Database, DisGeNET Database, and GeneCards Human Genetic Synthesis Database. Protein-protein interaction (PPI) networks for the intersecting targets were constructed using the STRING database, and core targets were identified. These were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses using the Metascape software. Putative active ingredients and core targets were further analyzed by docking and binding energy calculations using AutoDock Vina (Version 1.2.0), and visualization was performed using PyMOL 2.3.0. Additionally, an acute MI rat model was constructed to verify the results of network pharmacology through in vivo experiments.ResultsNetwork pharmacology analysis predicted 330 potential therapeutic targets of GXN for the treatment of MI, 26 of which were identified as central to its therapeutic effects. GO enrichment analysis identified 1885 relevant biological processes, whereas KEGG enrichment analysis revealed 154 associated signaling pathways. Imaging studies, enzyme-linked immunosorbent assays, Western blot analysis, Masson's trichrome staining, and TUNEL assays demonstrated that GXN mitigated adverse ventricular remodeling by suppressing oxidative stress through activation of the PI3K/AKT/GSK3 beta signaling pathway.ConclusionGXN effectively suppressed oxidative stress following MI by activating the PI3K/AKT/GSK3 beta signaling pathway, thereby enhancing cardiac function postinfarction. This study established a theoretical foundation for the potential clinical use of GXN.
BackgroundThe optimization of therapeutic safety in oncology requires precise biomarkers to stratify patients and anticipate treatment interactions. While dysregulation of the Wnt pathway is a hallmark of colon cancer, the clinical and immunological significance of noncanonical Wnt ligands, particularly WNT10B, remains poorly defined, limiting their utility in personalized risk assessment.MethodsWe conducted an integrative bioinformatics analysis using The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohort (n = 478). WNT10B expression was analyzed for its association with clinicopathological features, overall survival (OS), and disease-specific survival (DSS). Multivariate Cox regression was used to determine its independent prognostic value. Immune cell infiltration was estimated using CIBERSORTx and ssGSEA algorithms. A prognostic nomogram incorporating WNT10B was developed and validated.ResultsWNT10B was significantly upregulated in tumor tissues and associated with advanced T stage (p = 0.022). High WNT10B expression predicted inferior OS (HR = 3.304, p = 0.010) and DSS (HR = 3.879, p = 0.014), remaining an independent prognostic factor after adjusting for age and TNM stage. Tumors with high WNT10B exhibited an immunosuppressive microenvironment, characterized by increased M2 macrophage infiltration and reduced CD8+ T cell abundance, which has been well-acknowledged as a phenotype with reduced immunotherapy response in previous studies. The WNT10B-incorporated nomogram showed robust calibration for predicting 1-, 3-, and 5-year survival.ConclusionOur study establishes WNT10B as a novel, independent prognostic biomarker in colon cancer, directly linked to an immunosuppressive tumor microenvironment.
Background: Cancer cachexia (CAC) is a prevalent and debilitating complication in gastric cancer. However, specific tumor-derived biomarkers for the screening and diagnosis of CAC remain largely unidentified. This study was designed to screen cachectic factors secreted by tumors and to investigate the value of regenerating islet-derived family member 4 (REG4) in CAC. Methods: We enrolled 91 gastric cancer patients, stratified into a CAC group (n = 34) and a noncachectic (NC) group (n = 57). To identify cachectic factors differentially expressed by tumor tissues, bulk RNA sequencing was performed. REG4 expression was validated in tumor tissues and plasma using immunohistochemistry and enzyme-linked immunosorbent assay, respectively. CT imaging was utilized to evaluate body composition parameters, specifically the skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI). The relationships among plasma REG4 levels, nutritional status, and body composition were analyzed. Logistic regression analysis was employed to identify risk factors for CAC, and receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of REG4. Results: RNA sequencing revealed significantly elevated REG4 gene expression in the gastric cancer tumors from the CAC group compared with the NC group. Plasma REG4 levels in the CAC group were significantly higher (p < 0.001). Correlation analysis demonstrated that elevated plasma REG4 was significantly associated with lower SMI (r = -0.24, p = 0.02), SATI (r = -0.26, p = 0.01), BMI (r = -0.26, p = 0.01), and prealbumin (r = -0.22, p = 0.04), as well as increased 6-month weight loss (r = 0.36, p < 0.001). Multivariate logistic regression and ROC curve analysis identified high REG4 levels as an independent risk factor (OR = 7.54, 95% CI: 2.63-21.65) and a potential predictor for CAC (AUC = 0.728, 95% CI: 0.626-0.831, p < 0.001). Conclusion: In patients with gastric cancer, tumor-derived REG4 is released into the circulation, resulting in elevated plasma levels that correlate with poor nutritional status and compromised body composition. Circulating REG4 holds promise as a novel predictor for the clinical diagnosis of CAC.
Aim: Penicillin allergy (Pen A) is the most commonly reported drug allergy worldwide, with approximately 10% of the population carrying this label. However, over 90% of these labels are inaccurate. A Pen A label is associated with increased morbidity, mortality, antibiotic resistance and healthcare costs. Pen A delabelling has become a clinical and public health priority, with recent focus on tools like PenFAST for risk stratification in nonspecialist settings. The aim of this work is to determine the prevalence of Pen A among adult inpatients at a large UK teaching hospital and to stratify their risk of allergic reactions using the validated PenFAST tool. Materials and methods: A cross-sectional point prevalence survey was conducted over two days in June 2024 across two hospital sites of the University Hospital of North Midlands. All adult inpatients (excluding maternity wards) were screened for Pen A using demographic data and drug charts. Patients with a Pen A label were assessed using PenFAST. Statistical analysis was performed to determine prevalence and identify risk categories. Results: Among 1136 inpatients, 16.3% (n = 185, 95% CI: 14.2-18.5) were labelled penicillin allergic. Older patients (> 65 years), women and those admitted to medical wards were more likely to carry the label. Pen A label increased the likelihood of diagnosis with other antibiotic allergies (RR: 3.56, 95% CI: 2.52-5.03). Risk stratification identified 55.6% (n = 85) of patients as low risk (PenFAST <= 2), suggesting they could be safely delabelled by nonspecialists. Conclusion: Pen A prevalence amongst adult inpatients was higher than expected in this study. A significant proportion of inpatients with Pen A are at low risk of true allergy and can potentially be delabelled by nonspecialists using validated clinical history-based tools.
Objective: To compare the pharmacokinetic and pharmacodynamic (PK/PD) profiles after a single dose of chiglitazar sodium in healthy rats and the rats with hypoalbuminemia. Method: Single doses of 3.33 mg/kg chiglitazar sodium were administered by gavage in all rats. Serial blood samples were collected for the determination of plasma concentrations of chiglitazar sodium by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and blood concentrations of glucose by glucometer. The PK parameters were derived based on the measured plasma concentration data. Both PK parameters and the blood glucose levels were summarized and statistically compared between healthy rats and the rats with hypoalbuminemia. Results: The PK analysis revealed that, compared to healthy rats, only T-max in the rats with hypoalbuminemia was significantly earlier by 34.3% (p < 0.001), while other PK parameters showed no significant differences. The PD analysis indicated that blood glucose levels remained stable in both healthy rats and rats with hypoalbuminemia during the 0.25-10-hour monitoring period. Conclusion: There were no significant differences in the PK/PD parameters between healthy rats and rats with hypoalbuminemia, except for T-max. Blood glucose levels remained stable in the two groups of rats after a single oral dose of 3.3 mg/kg of chiglitazar sodium. The experimental results in rats suggest that, under normal conditions, hypoalbuminemia does not alter the PK and PD profiles of chiglitazar sodium.
IntroductionCombination chemotherapy regimens are the mainstay of treatment for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Their narrow therapeutic indices often result in adverse drug reactions (ADRs) that can interrupt therapy, increase resource utilization, and worsen patient outcomes. Data on the burden and characteristics of systemic cancer therapy-related ADRs among lymphoma patients in Kenya are scarce. Hence, this study aimed to assess the prevalence, types, severity, preventability, and clinical outcomes of systemic cancer therapy-related ADRs among adult HL and NHL patients treated at Kenyatta National Hospital (KNH).MethodsThis retrospective cohort study involved 100 adult patients (>= 18 years) diagnosed with HL or NHL who received systemic cancer therapy at KNH between January 2020 and December 2024. Data were extracted using a structured abstraction tool and included patient demographics, lymphoma subtype, systemic cancer therapy, ADR types, severity, preventability, and associated clinical outcomes. Statistical analysis was conducted using SPSS Version 29.0.01 software.ResultsSystemic cancer therapy-related ADRs occurred in 98% of patients, demonstrating a very high burden in this population. The most frequently observed ADRs were anemia (31%), followed by nausea/vomiting (24%) and neutropenia (14%). Most ADRs were mild (51%) or moderate (33%), though 14% were classified as severe. Preventability analysis showed that 57% of ADRs were definitely preventable and 27% probably preventable. Clinical consequences included treatment interruptions (47%), hospital admissions (19%), and ADR-related mortality in 8% of patients.ConclusionThe prevalence of systemic cancer therapy-related ADRs among lymphoma patients at KNH is extremely high. While many reactions are not severe, most are preventable, indicating gaps in monitoring and regimen optimization. Strengthening pharmacovigilance, early toxicity detection, and individualized regimen selection could help reduce toxicities and improve outcomes for lymphoma patients in Kenya.
IntroductionAntibody-drug conjugates (ADCs) targeting the human epidermal growth factor receptor 2 (HER2), including trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), have already altered the treatment landscape for HER2-positive malignancies. Interstitial lung disease (ILD) associated with ADCs presents as a fatal adverse reaction, yet it remains inadequately characterized in real-world contexts.AimThis study was to refine the risk profiles of these agents using ILD cases drawn from the FDA Adverse Event Reporting System (FAERS) to examine the clinical features.MethodILD cases were extracted from FAERS. Disproportionality analyses and survival analyses were used to assess risk signals, onset kinetics, and mortality.ResultsT-DXd exhibited stronger ILD signals and shorter time-to-onset than T-DM1 (acute respiratory distress syndrome [73d vs. 403d, p = 0.033], pneumonitis [62.5d vs. 106d, p = 0.035]). No statistically significant differences were observed in fatal cases.ConclusionT-DXd exhibits more reporting cases and an earlier onset time of ILD compared to T-DM1. Proactive monitoring, including earlier radiographic screening, is warranted, particularly for patients at risk of acute respiratory distress syndrome and pneumonitis.Impact StatementsThis study provides crucial evidence through large-scale real-world data that T-DXd is associated with a significantly higher number of reported cases of ILD and a shorter time to onset compared to T-DM1. This comprehensive characterization of ILD signals and timing in real-world clinical practice provides direct evidence for clinicians to conduct risk-benefit assessments and highlights the importance of early detection strategies starting within months of T-DXd therapy.
AimsWe previously identified a strong association between seven rare DPYD variants (Ser199Asn, Ile245Phe, Thr305Lys, Glu386Ter, Ser556Arg, Ala571Asp, and Trp621Cys) and fluoropyrimidine-related toxicity in Japanese cancer patients. Herein, we reported clinical and molecular functional analyses of these seven rare DPYD variants.MethodsMutant dihydropyrimidine dehydrogenase (DPD) enzymes were expressed in HEK293 cells. DPD activity was measured by quantifying dihydro-5-FU using high-performance liquid chromatography-tandem mass spectrometry. DPD levels and dimerization were analyzed via western blotting and blue native PAGE. In addition, three-dimensional (3D) structural modeling was performed to evaluate the effects of these mutations on enzyme structure and function.ResultsTransient expression of DPD variant enzymes in HEK293 cells showed that the Ser199Asn, Ala571Asp, and Glu386Ter variants caused profound reductions in activity compared to the wild type (27%, 5.0%, and undetectable, respectively), while Thr305Lys, Trp621Cys, Ile245Phe, and Ser556Arg retained partial to normal activity (49%, 58%, 118%, and 113%). The results of 3D structural analysis supported the functional findings from HEK293 cell experiments. Clinical evaluation revealed that carriers with the five variants (Ser199Asn, Ile245Phe, Glu386Ter, Ala571Asp, and Trp621Cys) presented with adverse reactions Graded 3 or higher according to the Common Terminology Criteria for Adverse Events. Retrospective assessment of DPD activity in peripheral blood mononuclear cells revealed that patients carrying Ser199Asn, Ala571Asp, or Glu386Ter exhibited reduced DPD activity, correlating with findings from HEK293 cell experiments.ConclusionsExpression studies demonstrated that the rare DPYD variants Ser199Asn, Ala571Asp, and Glu386Ter were associated with decreased DPD enzyme activity and 5-FU toxicity, even in the heterozygous state.
Background Therapeutic drug monitoring (TDM) is recommended by measurement of blood trough concentrations (Cmin) for optimizing voriconazole (VRZ) therapy. This study aims to investigate and compare potential factors associated with supratherapeutic and subtherapeutic VRZ trough levels under steady-state conditions. Methods We retrospectively analyzed the clinical data of patients aged >= 13 years who were hospitalized and received VRZ treatment from January 2022 to December 2024. Contributing factors for VRZ Cmin >= 5.5 mg/L and VRZ Cmin <= 1.0 mg/L were identified by binary logistic regression analysis. The diagnostic performances of the final models were assessed using receiver operating characteristic (ROC) curves. Values of the identified independent variables were stratified, and the proportions of supratherapeutic and subtherapeutic VRZ trough concentrations were analyzed. Results Significant factors associated with VRZ Cmin >= 5.5 mg/L included older age (OR 1.026 per year; p < 0.001), higher daily VRZ dose (OR 1.250 per 50 mg; p = 0.001), and elevated C-reactive protein (CRP) (OR 1.503 per 50 mg/L; p < 0.001). For VRZ Cmin <= 1.0 mg/L, significant contributors were younger age (OR 0.959 per year; p < 0.001), lower daily VRZ dose (OR 0.620 per 50 mg; p < 0.001), decreased CRP (OR 0.540 per 50 mg/L; p = 0.015), and nasogastric administration (OR 4.807; p = 0.001). The areas under the ROC curves for predicting VRZ Cmin >= 5.5 and <= 1.0 mg/L were 0.722 (95% CI 0.673-0.770) and 0.823 (95% CI 0.749-0.898), respectively. Nonlinear patterns were observed in the incidences of supratherapeutic VRZ trough concentrations across the entire ranges of the variables, with proportions changing sharply at specific threshold levels. Conclusions Our analysis identified age, daily VRZ dose, and CRP as common contributors to both supratherapeutic and subtherapeutic VRZ trough concentrations; meanwhile, the nasogastric administration route was found to have an independent association with subtherapeutic VRZ trough levels, suggesting that the contributing factors for these two types of off-target concentrations may not be identical. The findings may facilitate targeted interventions to maintain therapeutic concentrations, thereby potentially preventing suboptimal treatment outcomes or adverse events.
Background Burn injuries are a significant public health concern in low- and middle-income countries, associated with high morbidity and mortality due to infections and antimicrobial resistance (AMR). However, data on these aspects from Nepal remain limited. The study aimed to assess antibiotic utilization patterns and cost analysis among burn patients at a tertiary care hospital in Nepal. Methods A retrospective cross-sectional study was conducted using medical records of 249 burn patients admitted to a tertiary care hospital between June 2018 and May 2019. Antibiotic consumption was assessed using the WHO Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology. A generalized linear model (GLM) with a gamma distribution and log-link function was employed to identify factors influencing antibiotic costs. Results Total antibiotic consumption was 2213.38 DDDs, corresponding to 82.47 DDDs per 100 bed-days. Cephalosporins were the most frequently prescribed class (57.6%), with ceftriaxone being the most commonly used agent. Empirical therapy was initiated in 55% of cases, and 96.4% of antibiotics were administered parenterally. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections were identified in 35.3% and 14.5% of patients, respectively. The median antibiotic cost per patient was US$18.18 (IQR: US$63.90). Higher costs were significantly associated with age between 15 and 44 years, greater total body surface area (TBSA) involvement, third-degree burns, and the presence of MDR/XDR infections (p < 0.001). Conclusion The study reveals a high rate of empirical antibiotic use and substantial costs in burn care, primarily driven by resistant infections and burn severity. These findings underscore the urgent need for implementing antimicrobial stewardship interventions and culture-guided therapy to improve clinical outcomes and reduce the financial burden.
Renal cell carcinoma is the most common type of kidney cancer, accounting for approximately 90% of all cases. Pazopanib, a tyrosine kinase inhibitor, has emerged as an effective treatment option for advanced and metastatic renal cell carcinoma, demonstrating progression-free survival benefits compared to placebo or interferon in previous Phase 3 clinical trials. However, real-world data on its safety profile remain limited, underscoring the need for observational studies to assess the efficacy and safety of approved treatments in clinical practice. This retrospective observational study aims to evaluate the real-world safety of pazopanib in patients with advanced renal cell carcinoma, providing clinical safety data from a hospital unit in the Alentejo region, Portugal, between 2015 and 2024. A total of 22 patients were included in the study, with a median age of 69 years (range: 45-86); the majority were male. The results revealed a higher incidence of adverse drug reactions compared to clinical trials, with hematological and hepatic toxicities being the most common. Thrombocytopenia was observed in 81.8% of patients, while hepatic impairment was reported in 68.2%. Dose adjustments due to analytical intolerance were required in 54.5% of cases. The study also assessed drug interactions in eligible participants within a real-world clinical setting, revealing a high prevalence of potential drug interactions. On average, 1.36 interactions per patient were identified, with 73.3% classified as high-risk (Category X). These findings highlight the importance of active pharmacovigilance in optimizing drug safety and treatment outcomes. Strategies such as personalized dosing, medication reconciliation, and close monitoring by clinical pharmacists are essential to mitigate risks and improve patient care. The safety profile and tolerability were found to be consistent with that reported in previous pivotal and real-world evidence studies, underscoring the need for further research to refine treatment protocols and enhance patient outcomes.
Objective: Easily accessible predictors of early mortality and complications in influenza A pneumonia remain inadequately defined. This investigation was undertaken to determine the prognostic significance of the lactate-to-albumin ratio (LAR) for 28-day all-cause mortality among hospitalized patients with influenza A pneumonia. Methods: We performed a retrospective study encompassing 105 individuals with confirmed influenza A pneumonia. The principal outcome measure was 28-day all-cause mortality. Clinical parameters differentiating survivors from nonsurvivors were systematically evaluated through Cox analysis, receiver operating characteristic (ROC) curve analysis, and Kaplan-Meier survival analysis. Results: LAR was identified as an independent prognostic indicator for 28-day mortality in patients with influenza A pneumonia. The area under curve value for LAR in predicting 28-day mortality exceeded those of lactate and albumin individually. LAR achieved diagnostic sensitivity and specificity values of 84.4% and 86.7%, respectively, for 28-day mortality prediction. The LAR levels deviated only slightly in survivors but remained elevated during the first week of admission in the nonsurvivors. Compared with patients with low LAR (< 50.91 & times; 10(-3)), those with high LAR (>= 50.91 & times; 10(-3)) had significantly (p < 0.001) higher incidence of acute respiratory distress syndrome and extrapulmonary complications as well as significantly shorter survivals (p < 0.001). Conclusion: Elevated LAR exhibits significant correlation with unfavorable clinical complications and constitutes a highly effective prognostic biomarker for 28-day mortality in influenza A pneumonia. The integration of LAR into clinical practice may facilitate early risk stratification and enhance disease surveillance.
ObjectivesLinezolid is administered at a fixed dose of 600 mg twice daily for the treatment of Gram-positive infections. However, recent population pharmacokinetic studies reveal considerable interpatient variability, resulting in subtherapeutic or supratherapeutic drug exposures. This study aimed to describe the pharmacokinetics of linezolid in hospitalized infectious patients across varying degrees of renal function and propose optimized dosing strategies.MethodsPopulation pharmacokinetic modeling was performed using Monolix Version 2024R1. The model was evaluated using goodness-of-fit plots, bootstrap analysis, and prediction-corrected visual predictive checks. Appropriate dosing regimens for different levels of renal function and minimum inhibitory concentrations were proposed by Monte Carlo simulations.ResultsFifty-five adult patients with a total of 178 linezolid concentration measurements were included. A two-compartment model with first-order absorption and linear elimination best described the pharmacokinetic data. Volume of distribution and clearances were scaled using an allometric weight model. In addition, creatinine clearance (CLcr) significantly affected linezolid clearance. Simulation results suggested that patients with CLcr <= 30 mL/min may require reduced doses (600-900 mg daily), whereas those with CLcr >= 110 mL/min may benefit from increased doses (600 mg every 8 h).ConclusionsIndividualization of linezolid dosing based on renal function is warranted. Therapeutic drug monitoring is recommended for patients with impaired or augmented renal clearance to optimize the therapeutic efficacy and minimize the risk of toxicity.
BackgroundProstate adenocarcinoma (PRAD) exhibits marked heterogeneity in its immune microenvironment, which influences tumor progression and therapeutic response. However, a comprehensive delineation of immune infiltration patterns and their prognostic relevance in PRAD remains incomplete.MethodsWe analyzed TCGA-PRAD transcriptomes using ssGSEA, CIBERSORT, ESTIMATE, and complementary deconvolution frameworks (xCell, TIMER, EPIC, and MCPcounter). Immune subtypes were derived by unsupervised clustering of immune-related gene expression. Differential immune characteristics, clinical associations, and putative immune-evasion features were examined. Prognostic immune genes were identified via univariate Cox and LASSO-Cox regression using biochemical recurrence-free survival (BCRFS) as the primary endpoint (PFI/OS exploratory). A multigene risk score was constructed and evaluated by Kaplan-Meier analysis, time-dependent ROC, calibration, and a nomogram integrating clinical covariates.ResultsTwo immune subtypes-Immunity_H and Immunity_L-were identified with distinct tumor microenvironment (TME) features. Immunity_H displayed higher stromal/immune scores, enhanced antigen presentation and interferon signaling, upregulated HLA expression, enrichment of CD8+ T cells, activated memory CD4+ T cells, and M1 macrophages, whereas Immunity_L was characterized by increased M2 macrophages and resting immune populations. A multigene signature stratified patients into high- and low-risk groups with significantly different BCRFS. The risk score correlated negatively with antitumor immune cells (e.g., memory B cells and CD8+ T cells) and positively with immunosuppressive components (e.g., cancer-associated fibroblasts). Incorporation of the risk score with PSA, Gleason/ISUP grade, and pathologic T/N stage in a nomogram improved individualized recurrence-risk prediction.ConclusionThis study delineates the immune heterogeneity of PRAD and proposes a robust immune-related prognostic model that supports risk stratification and may inform immunotherapeutic decision-making.
