Multitarget mechanisms of Origanum vulgare L. essential oil against clinically isolated carbapenem-resistant Acinetobacter baumannii.

Green tea, a commonly consumed beverage worldwide, is extensively used as dietary supplements for cancer prevention. However, the interaction between green tea and paclitaxel is still unknown. This study aimed to systematically investigate the herb-drug interaction of green tea consumption on the pharmacodynamics and pharmacokinetics of paclitaxel. The ATP assay results indicated that green tea extract (GTE) significantly enhanced the cytotoxicity of paclitaxel in both human and murine breast cancer cells. Further, the 4T-1 tumor model testified that daily green tea consumption could improve the therapeutic effects of paclitaxel on breast carcinoma. The pharmacokinetic profiles revealed that in the group with short-term green tea consumption (0.5 h), there was a more than 55.87% increase in the maximum plasma concentration (Cmax) of paclitaxel and a 38.49% increase in the area under the plasma concentration curve (AUC). In the long-term green tea consumption group (2 weeks), there was a 23.80% increase in the Cmax of paclitaxel and a 28.29% increase in the AUC. Moreover, long-term green tea consumption significantly reduced hepatic microsomal protein level. Taken together, green tea consumption enhances the anticancer efficacy and increases the pharmacokinetic profile of paclitaxel, which provides information to study the interaction between herbs and chemotherapy.

BackgroundCervical cancer poses a severe public health burden in Uganda, which has one of the world’s highest incidence rates. Despite commitments to Universal Health Coverage (UHC), screening utilization remains critically low and inequitable. This study assessed vertical equity in the awareness and utilization of cervical cancer screening services among women in Uganda, evaluating whether distribution aligns with differential need.MethodsWe conducted a cross-sectional analysis of the 2022 Uganda Demographic and Health Survey (UDHS), including 18,251 women aged 15–49. The primary outcomes were self-reported screening utilization and awareness. Socioeconomic status was measured using the DHS wealth index. Equity was assessed using concentration curves and indices (CIs), with a positive CI indicating pro-rich inequality. P.value of 0.05 (95% confidence interval) was used to test for significance of study findings.ResultsWe found significant pro-rich inequity in both screening utilization (CI = 0.125, p < 0.000) and awareness (CI = 0.178, p < 0.000), demonstrating that wealthier women had a disproportionate advantage. The pro-rich inequality in utilization was more pronounced in the urban (CI = 0.125) than rural (CI = 0.049) areas. Awareness was distributed almost equitably in rural areas (CI = −0.007, p = 0.165) but showed significant pro-rich inequality in urban settings (CI = 0.014, p < 0.016).ConclusionUganda’s cervical cancer screening services demonstrate significant vertical inequity, disproportionately favoring wealthier and urban women rather than being allocated according to greater need. To achieve elimination goals, deliberate policies must prioritize resource allocation and awareness for the poorer and rural women who bear the highest burden.

ABSTRACTIn population pharmacokinetics (PopPK), non‐linear mixed effects (NLME) models are used to simultaneously describe a drug's pharmacokinetics (PK) and dynamics (PD) in a patient population using systems of ordinary differential equations. In this field, machine learning is mainly used for data preparation, hypothesis generation, predictive modeling, and model validation. Some approaches to integrate artificially generated information have already been explored, but real‐world application is still limited. We therefore conducted a proof‐of‐concept study to analyze the ability of generative artificial intelligence (AI) to create artificial patient profiles to augment PopPK data sets and assess their influence on parameter estimates. We defined the pharmacokinetic parameters of a hypothetical drug and simulated the concentration curves of 20 patients. We then trained Wasserstein Generative Adversarial Networks (WGANs) with gradient penalty (GP) to generate artificial patients. The data distribution of original and artificial patients was statistically indistinguishable as shown by the Maximum Mean Discrepancy test. Therefore, the WGAN‐GP is neither overfitted, that is producing only single instances of artificial patients, nor underfitted, that is producing unrealistic artificial patients. We then combined different shares of original and artificial patients in separate data sets to build and compare PopPK model estimates. Addition of artificial patients led to narrower confidence intervals, indicating more robust parameter estimates, and accentuated the allometric effect of weight on the volume of distribution. In conclusion, we provide a proof‐of‐concept that generative AI can be used to augment pharmacokinetic data sets, with preliminary evidence suggesting improved parameter estimation.

Voriconazole is a broad-spectrum antifungal agent belonging to the triazole class, exhibiting significant efficacy against a diverse array of pathogenic organisms. This study aimed to assess the pharmacokinetic properties, bioequivalence, and safety profiles of two oral formulations of voriconazole tablets. An open-label, randomized, two-period, two-sequence crossover, Phase I bioequivalence trial was conducted involving healthy Chinese volunteers under fasting conditions. During each study period, participants were administered a single 200mg dose of either the generic (test) or branded (reference) voriconazole tablet, with treatment sequences assigned randomly. Blood samples were collected at various time points before and after administration to determine plasma voriconazole concentrations. The study assessed bioequivalence by calculating the maximum concentration (Cmax) and the area under the concentration-time curve (AUC). Adverse events (AEs) were systematically documented. A total of seventy healthy volunteers were recruited, with 68 participants who received voriconazole included in the final analysis. The geometric mean ratios (GMR) of the test tablet to the reference for Cmax, the area under the concentration curve from time 0 to the last measurable time point (AUC0-t), and the area under the concentration curve from time 0 extrapolated to infinity (AUC0-inf) were determined to be 1.03, 0.98, and 0.97, respectively, under fasting conditions. These values met the established criteria for bioequivalence acceptance. Furthermore, both the test and reference formulations of voriconazole were well tolerated. The findings indicate that the test and reference voriconazole tablets are bioequivalent and possess similar safety profiles in healthy Chinese volunteers.

Exploring socio-economic inequalities in measles immunisation in Lao People's Democratic Republic, Thailand, and Viet Nam.

To report the global, regional, and national burden of breast cancer (BC) and its attributable risk factors between 1990 and 2021, by age, sex, and sociodemographic index. Using data from the Global Burden of Disease Study 2021, we analyzed BC prevalence, deaths, disability-adjusted life years (DALYs), and attributable risk factors across 204 countries and territories from 1990 to 2021. Age-standardized prevalence, deaths, and DALYs rates were estimated, and temporal trends were assessed using the estimated annual percentage change. Geographical and sociodemographic inequalities were further evaluated using decomposition analysis, concentration curves, and sociodemographic index (SDI)-based modeling. Attributable risk factors for deaths and DALYs were quantified using the comparative risk assessment framework. Globally, BC presents a starkly diverging landscape. While the age-standardized prevalence has climbed to 239 per 100,000 (a 9.3% increase since 1990), the death and DALYs rates have actually declined by 13.7% and 9.8%, respectively. This global trend, however, masks a critical geographical shift. High-income regions maintain the highest prevalence, yet the most rapid increases in burden are now concentrated in resource-limited areas such as North Africa and the Middle East. The "triple threat" in low-SDI regions defines this transition. Decomposition analysis revealed that while population growth and aging lead to absolute mortality everywhere, high-SDI regions successfully offset this pressure through favorable epidemiological changes and advancements in screening and treatment. In contrast, low-SDI regions face a deteriorating epidemiological profile that actively contributes to rising deaths. Our inequality analysis further underscores this systemic shift; concentration curves confirm that BC mortality is becoming disproportionately concentrated in lower-SDI countries over time. Additionally, the disease follows a nonlinear, inverted U-shaped relationship with socioeconomic development, peaking at an SDI of 0.75. Finally, we identified a distinct sex-based etiological divide: while female risk patterns are multifaceted, male BC is almost singularly driven by metabolic dysregulation, with high body mass index emerging as the leading global driver of the disease. Despite progress in reducing the BC burden, it remains a global public health challenge. The prevalence is high in developed countries, while the burden is rapidly increasing in low- and middle-income countries.

Exploring methane phenotypes and their relationship with productive traits in the Spanish Holstein Population.

To describe cancer incidence, mortality, and mortality-to-incidence ratios (MIRs) in Africa in 2022 by age and country to inform cancer control planning. We conducted a descriptive analysis of GLOBOCAN 2022 estimates, summarizing age-standardized incidence rate (ASIR), mortality (ASMR) per 100,000, and MIR (ASMR/ASIR). Two lenses were applied: age bands (0-19, 20-44, 45-69, ≥70 years) and country concentration curves, which identify the smallest set of countries accounting for 50% and 80% of the burden. In 2022, there were 1,154,584 new cancer cases and 754,574 deaths. Breast, cervix uteri, prostate, colorectal, and liver cancers dominated incidence, whereas liver, lung, cervix uteri, breast, and stomach cancers dominated mortality. Around 80% of incident cases occurred in 15 countries. MIR increased with age and was highest at ≥70 years. Liver, lung, stomach, and brain/central nervous system cancers showed consistently high MIR. Cancer site profiles differed by life stage, with hematologic cancers predominating in childhood and adolescence and breast, cervix, prostate, and colorectal cancers predominating from mid-adulthood onward. Cancer mortality in Africa is high, rises with age, and is concentrated in few countries. Age-band and country-concentration lenses identify priorities for human papillomavirus and hepatitis B vaccination, tobacco control, and oncology packages in high-burden settings.

Extracorporeal membrane oxygenation (ECMO) systems for permanent respiratory support are currently under development as an alternative to lung transplantation. Direct oral anticoagulants are a promising alternative to heparin due to their oral administration and predictable pharmacology. The efficacy of rivaroxaban for artificial surface anticoagulation was evaluated using 3 studies that determined (1) the pharmacological behavior of 0.25, 0.5, and 1 mg/kg doses of rivaroxaban in sheep; (2) the artificial surface anticoagulation efficacy of these 3 doses compared with heparin in a short-term mini-ECMO model; and (3) the efficacy of the optimal dose from study 2 with simulated oral pharmacokinetics in an extended-duration mini-ECMO model. Study 1 found that sheep have a higher volume of distribution (2.2 ± 0.4 L/kg) and a shorter half-life (1.4 ± 0.1 h) for rivaroxaban than humans but a similar linear relationship between prothrombin time and rivaroxaban plasma concentration. In study 2, device survival time in the heparin group (57.5 ± 13.0 min) was most similar to the 0.5 mg/kg rivaroxaban group (51.3 ± 8.8 min; P = 0.287). This dose was selected for study 3, and no difference was found in device survival time between heparin (6.3 ± 1.3 h) and the 0.5 mg/kg rivaroxaban infusion (6.3 ± 1.6 h; P = 0.837). Furthermore, the calculated rivaroxaban exposure was similar to the clinically approved oral rivaroxaban doses (24-h area under the plasma concentration curve = 2074 µg h/L). These results demonstrate that rivaroxaban has artificial surface anticoagulation efficacy similar to that of heparin at dosages that are feasible for oral administration in humans. Future studies will evaluate rivaroxaban anticoagulation using a 10-d full-scale ovine ECMO model.

Minimum Dietary Diversity (MDD) is a crucial factor for children, as it enhances energy and nutrient intake, promoting optimal nutritional status, growth, and development. It consists of consuming a variety of food groups as the foundation for a healthy transition from infancy to adulthood. Only 23% of the children aged 6–23 months consumed MDD; therefore, the remaining children do not have MDD due to socioeconomic inequalities among households in India. Therefore, we aim to measure socioeconomic inequality in MDD and identify the contributing factors of inequality using the cross-sectional data of 8,156 children aged 6–23 months from the National Family Health Survey of India. We utilize several descriptive statistics, confidence intervals, and chi-squared tests for baseline analysis. Furthermore, we utilize Erreyger’s concentration index (ECI) and concentration curve to represent the MDD inequality, and subsequently, the ECI is decomposed to identify the contributing factors to inequality. The ECI value for inequality in MDD due to wealth status was 0.057. Decomposition analysis revealed that 47% of the inequality was contributed by wealth index, 34.07% by region, 32.8% by sanitation facility, 7.86% by birth order, and 3.06% by mother’s BMI. Similarly, the ECI value for MDD inequality due to maternal education was 0.034, and 56.70% of the inequality was attributed to region, 36.45% to wealth index, 22.81% to sanitation facility, and 5.06% to maternal education. To minimize the MDD inequality among children, nutrition-sensitive interventions should be integrated with efforts to address economic deprivation, maternal education, access to healthcare, safe sanitation, and informational reach.

The maternal continuum of care (CoC) is comprehensive healthcare provided for women during pregnancy, childbirth, and postpartum. Equitable maternal CoC can reduce the risk of maternal and neonatal mortality. We examined inequalities in the completion of maternal continuum of care, and factors associated with CoC among reproductive age women in Ethiopian using the 2019 mini-Ethiopian Demographic and Health Survey (mini-EDHS). The concentration curve and concentration curve index were used to examine socioeconomic inequalities in maternal CoC.Odds ratios were used to assess associations, with significance at p < 0.05. Overall, 23.97% (95% CI 21.63-26.48) of women completed maternal continuum of care. There was pro-rich inequality in the completion of maternal CoC in Ethiopia (Concentration index: 0.244 (95% CI 0.177-0.311, p ≤ 0.001)), rural resident (Concentration index: 0.146 (95% CI 0.087-0.205, p ≤ 0.001)), and urban resident (Concentration index: 0.154 (95% CI 0.045-0.263, p ≤ 0.01)). Being urban resident (adjust odds ratio (AOR) = 1.59, 95% CI 1.09-2.33), attaining secondary (AOR = 1.67, 95% CI 1.19-2.33), or higher education (AOR = 1.93, 95% CI 1.30-2.87), and early initiation of antenatal care (AOR = 1.97, 95% CI 1.61-2.41) were positively associated with the completion of maternal CoC. However, belonging to pastoral region (Afar or Somali) (AOR = 0.46, 95% CI 0.28-0.77), belonging to poorest (AOR = 0.58, 95% CI 0.37-0.92) or middle (AOR = 0.62, 95% CI 0.40-0.96) wealth quintile, not being informed about obstetric danger signs (AOR = 0.54, 95% CI 0.43-0.66), and blood pressure not being measured (AOR = 0.53, 95% CI 0.32-0.85) were negatively associated with maternal CoC. The results of this study revealed that completion of the maternal continuum of care was low in Ethiopia and there was a significant inequality in the completion of maternal CoC across wealth status, place of residence, and educational status. Targeted strategies are needed to improve maternal healthcare utilization among disadvantaged women, particularly those in rural areas, with low education, and from poor households. Interventions should focus on improving access, promoting early and high-quality ANC, and providing culturally tailored services.

Doxazosin, a selective α1-adrenergic receptor antagonist, is widely used to treat hypertension and benign prostatic hyperplasia and is available in immediate-release (IR) and extended-release (ER) formulations. However, quantitative tools for predicting pharmacokinetic (PK) differences between formulations and changes in drug exposure in patients with impaired liver function remain unestablished. Therefore, this study aims to develop a physiologically based pharmacokinetic (PBPK) model for doxazosin IR and ER formulations and to predict PK patterns under various dosing scenarios and levels of liver disease severity. The model was developed using PK-Sim® and subsequently validated and optimized using clinical data obtained from multiple published sources. Key parameters included the physicochemical properties of doxazosin, absorption and metabolism coefficients, and organ-specific distribution coefficients. The model also incorporated physiological changes associated with liver disease, such as altered blood flow and enzyme activity. The model prediction results showed a significant difference in maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) between the IR and ER formulations after single dose administration. Additionally, the variation between maximum plasma concentration at steady-state (Cpeak) and minimum plasma concentration at steady-state (Ctrough) was greater for the IR formulation in multiple doses. However, the area under the plasma concentration curve (AUC) and systemic clearance (CL/F) were similar between the IR and ER formulations, accounting for the dose. In patients with liver disease, plasma doxazosin concentrations increased following the Child-Pugh (CP) grade, with doxazosin exposure rising progressively from CP-A to CP-C. The PBPK model developed in this study serves as a practical tool for quantitatively predicting the PK of doxazosin across different formulations and varying degrees of liver impairment. It holds potential for supporting the development of patient-tailored treatment strategies in the future.

Protection against financial risk is an essential pillar of Universal Health Coverage (UHC), particularly through the reduction of out-of-pocket payments that can lead to catastrophic health expenditure (CHE). This study aims to identify the determinants of CHE among households in Côte d&amp;apos;Ivoire. We conducted a cross-sectional analytical study using data from the 2021 Harmonized Household Living Conditions Survey (HLCS) (secondary analysis). The survey is based on a two-stage probability sampling method; 1,084 clusters and 13,008 households were initially selected, and 12,965 households were retained after validation. CHE was defined according to the &amp;quot;ability to pay&amp;quot; approach: a dichotomous variable (CHE=1) when OOPCAP = OOP/CAP ≥ 40%, otherwise CHE=0. Descriptive statistics, a bivariate Chi² test and binary logistic regression were used (Stata 17). Households spend more than half of their consumption expenditure on food (52.2%). The frequency of CHE is low: 0.11% in the total sample (14 households) and 0.35% among those who received direct payments. The concentration curve indicates a relatively homogeneous distribution (Gini = 0.187). The logistic model is significant (Chi² = 38.38; p &amp;lt; 0.001; pseudo-R² = 0.094). The risk of CHE decreases significantly with household size (OR = 0.07 for 6–7 members; OR = 0.03 for &amp;gt;7). Conversely, households headed by a married person have an increased risk (OR = 5.27), as do those residing in rural areas (OR = 4.72). With regard to standard of living, the upper quintiles show odds ratios below 1 (Q2 to Q5), suggesting better financial protection, although some associations are of marginal significance. No significant link is observed for the gender of the head of household or for residence in Abidjan. CHE are rare, but their distribution remains socially differentiated: increased risk in rural areas, increased vulnerability when the head of household is married, and a protective effect of household size, linked to intra-family mutualization. A socioeconomic gradient also appears, with wealthier households being less exposed, but the significance is marginal. These results call for strengthening financial protection, especially in rural areas, and interpreting CHE with caution, given their rarity and sensitivity to methodological choices.

BackgroundDifferentiated thyroid cancer (DTC) is the most commonly diagnosed endocrine cancer. Diagnosis of DTC metastases is possible with the use of ultrasound, RAI scintigraphy, [18F]FDG PET/CT, or contrast-enhanced CT; however, the use of iodine contrast factors (ICF) delays potential RAI treatment. Dual energy computed tomography (DECT) is a variant of computed tomography that enables the detection and calculation of iodine concentration in tissues. The study aimed to evaluate the potential use of non-contrast DECT in diagnosing DTC metastases.Materials and methodsThis prospective study enrolled 37 patients who had undergone thyroidectomy for DTC and were found to have lesions suspected of being metastatic. DECT was performed at least six months after the last administration of RAI or ICF. Group differences were analyzed using statistical tests, including the Student’s t-test and the Mann-Whitney U test. Receiver operating characteristic (ROC) curves were utilized to assess the sensitivity and specificity of selected parameters.ResultsIn 31 of 37 patients, non-contrast DECT confirmed increased accumulation of endogenous iodine. Per patient, DECT sensitivity was 93.5%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 71.4%. Statistically higher values of iodine concentration (IC), effective atomic number (Zeff), and Hounsfield Unit (HU) were observed for DTC metastases compared to normal lymph nodes. The area under the curve (AUC) for endogenous iodine concentration was 0.992, and a threshold of endogenous IC >250 µg/cm3 provided a sensitivity of 96.6% and a specificity of 87.0% for detecting DTC metastases.ConclusionsNon-contrast DECT is useful in the diagnosis of DTC metastases, demonstrating high sensitivity and specificity. A key advantage is the lack of necessity for ICF, which prevents delay in potential radioiodine therapy and is safer for patients with an allergy to such factors.

The hydrodynamic and sediment processes in the Yellow River are profoundly amplified during the flood season, significantly influencing the habitat suitability of aquatic species. This study evaluates the impact of these processes on the habitat of two indicator species, Cyprinus carpio and Misgurnus anguillicaudatus, using a 2D hydrodynamic and sediment transport model, MIKE 21, coupled with the habitat suitability model (HSM). Habitat suitability curves (HSCs) for water depth (SId ), velocity (SIv ), water temperature (SIt ) and suspended sediment concentration (SSC) (SISSC ) were developed to assess the habitat suitability based on weighted usable area (WUA) and overall suitability index (OSI). Three model configurations were tested: (1) Conventional SSC (SId, SIv, SIt, SISSC ). (2) Incorporation of the severity of ill effect (SEV) index (SId, SIv, SIt, SISEV ) and (3) Excluding sediment stress (SId, SIv, SIt ). The results indicate that habitat suitability is significantly decreased by sediment stress under maximum discharge. The SEV-based test showed a slightly increased OSI compared to the conventional method by 1% under maximum discharge, reflecting more physiologically realistic sediment stress effects. Although OSI was higher at minimum discharge across all methods, excluding the sediment variable improved OSI by 13% to 27%, resulting in a higher WUA, representing substantial but unrealistic improvements. Hydrodynamic indices showed both species thrived at a depth of (5–8 m) and velocities between 0.8 and 2 m/s. These findings highlight the significance of managing sediment and hydrodynamic conditions for biodiversity conservation in the Yellow River during flood conditions.

Bacterial infections pose a significant threat to public health, primarily driven by the increasing prevalence of antibiotic resistance due to their overuse. Therefore, the development of novel antibacterial materials as alternatives to conventional antibiotics is urgently needed. In this context, metal-organic frameworks (MOFs) and polyoxometalates (POMs) are gaining recognition as potential antibacterial agents. In this study, developed a novel antibacterial compound, α-SiW11Zn@ZIF-8, was synthesized via a hydrothermal reaction of α-SiW11Zn with ZIF-8. Its antibacterial efficacy was then evaluated by minimum inhibitory concentration (MIC), disk diffusion, and bacterial growth curve assays. Experimental results show that α-SiW11Zn@ZIF-8 exhibits significant antibacterial activity, with minimum inhibitory concentration (MIC) values of 32 μg mL−1 against Escherichia coli (E. coli)and 64 μg mL−1 against Staphylococcus aureus (S. aureus), while producing inhibition zones of approximately 2.95 cm and 2.43 cm, respectively. The principal antibacterial mechanism involves the generation of reactive oxygen species and the release of metal ions, which disrupt bacterial physiological functions and ultimately lead to cell death. This study provides valuable insights for the development of highly efficient antibacterial materials and highlights the significant potential of α-SiW11Zn@ZIF-8 in combating drug-resistant bacterial infections.

Remdesivir (REM) and its parent drug, GS-441524 (GS-44), are used to treat cats with feline infectious peritonitis (FIP), resulting in a survival rate of circa 85% (range 77-96%). Cats suffering from FIP exhibit complex and variable clinical presentations, which will cause concurrent variations in the pharmacokinetics (PK) of GS-44. In turn, this will vary the ability of target cells (monocytes and tissue macrophages) to absorb GS-44 in sufficient quantities to achieve optimal antiviral efficacy, resulting in full recovery. Sparse data exists to guide treatment regimens optimized for every presentation of FIP. Therapeutic Drug Monitoring (TDM) measured the GS-44 concentration in 728 blood samples from 263 cats undergoing treatment and generated 173 PK graphs. These identified individuals varied in their ability to absorb GS-44, leading to sub-optimal (11%) and supra-optimal (12%) dose-normalized plasma concentrations. Dosage alterations were suggested to guide subsequent dosages to ensure optimum GS-44 concentrations for individual cats (the clinical outcome report will be published separately). Proposed TDM target values are: area under the concentration vs. time curve (AUC), at least 220 µM·h, time per day that plasma concentration exceeds 3 µM, at least 23 h, time per day plasma concentration exceeds 10 µM, and at least 9 h.

Gene networks that control gene expression play a primary role in determining the epigenetic and biochemical properties of cells. At the same time, the interconnectedness of gene networks with networks of other types and levels requires approaches that consider this complexity. The article addresses this problem by examining the nesting of gene networks within cells, which themselves are nodes of a higher-level network, namely, a cell ensemble. Information models (object, relational, and object-relational) of the control gene network over genetic blocks are created, as well as a model of the cell ensemble as a network over cell control gene networks. The combined two-level model describes the gene network structures within cell ensembles with the dynamic characteristics of the main molecular genetic processes. Based on these models, the SETIES platform was developed for in silico studies of molecular genetic systems controlling gene expression in prokaryotes and eukaryotes. The platform includes software components for the design and visualization of cell and intercell gene networks, the automatic construction of their mathematical models, and the simulation of network dynamics in cell-free systems, cell lines, and clonal cell populations, as well as in cell ensembles with constant and dynamic structure. The computational modules implement the formalism of generalized threshold models, combining the advantages of discrete and continuous methods for modeling these systems. Among the tasks addressed are the construction of gene activity diagrams over time, the calculation of kinetic curves for mRNA and protein concentrations, the identification of gene expression patterns as functional states of the gene network, the assessment of parametric stability of regimes, and the simulation of mechanisms of epigenetic inheritance, phenotypic heterogeneity, and morphogenetic positioning. Overall, the platform implements the "network of networks" paradigm, which serves as the basis for advanced research in systems and synthetic biology.

Tuberculosis (TB) is a major cause of morbidity and mortality in children globally. This study developed models to describe population pharmacokinetics (PK) of pyrazinamide (PZA) and ethambutol (EMB) in children with TB with or without human immunodeficiency virus (HIV) coinfection. Ghanaian children with TB with or without HIV coinfection receiving first-line antituberculosis therapy for at least 4 weeks had blood samples collected at time 0 (pre-dose), 1-, 2-, 4-, 8-, and 12-h post-dose. PZA and EMB concentrations were quantified using liquid chromatography tandem mass spectrometry. Nonlinear mixed-effects models were applied to describe the population PK using Monolix2024R1. Maximum concentrations (Cmax) and 24-h area under the time concentration curve (AUC0-24) were compared to published values in adults. A total of 85 children (41 TB, 44 TB/HIV) were included. The median (range) age was 5 years (0.3-14.5), and 61.2% were male. Median (range) doses for PZA and EMB were 31.6 (21.4-49.7) and 21.4 mg/kg (14.3-34.2), respectively. PZA was best described using a one-compartment model and EMB by a two-compartment model. Allometric scaling improved both model fits. Children with TB/HIV coinfection had approximately 18.5% faster PZA clearance and 25% faster EMB clearance. Optimized dosing to achieve adult-equivalent exposures required higher-than-currently recommended doses, particularly among children in the lowest weight bands and those with HIV. The population PK of PZA and EMB was well described by the final models, but the higher-than-currently recommended doses needed to achieve adult-equivalent exposures raise concerns regarding risks for drug-associated toxicities and will require further evaluation.