Volume Of Distribution Research Articles

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Automated Prediction of Proximal Middle Cerebral Artery Occlusions in Noncontrast Brain Computed Tomography.

Early identification of large vessel occlusion (LVO) in patients with ischemic stroke is crucial for timely interventions. We propose a machine learning-based algorithm (JLK-CTL) that uses handcrafted features from noncontrast computed tomography to predict LVO. We included patients with ischemic stroke who underwent concurrent noncontrast computed tomography and computed tomography angiography in seven hospitals. Patients from 5 of these hospitals, admitted between May 2011 and March 2015, were randomly divided into training and internal validation (9:1 ratio). Those from the remaining 2 hospitals, admitted between March 2021 and September 2021, were designated for external validation. From each noncontrast computed tomography scan, we extracted differences in volume, tissue density, and Hounsfield unit distribution between bihemispheric regions (striatocapsular, insula, M1-M3, and M4-M6, modified from the Alberta Stroke Program Early Computed Tomography Score). A deep learning algorithm was used to incorporate clot signs as an additional feature. Machine learning models, including ExtraTrees, random forest, extreme gradient boosting, support vector machine, and multilayer perceptron, as well as a deep learning model, were trained and evaluated. Additionally, we assessed the models' performance after incorporating the National Institutes of Health Stroke Scale scores as an additional feature. Among 2919 patients, 83 were excluded. Across the training (n=2463), internal validation (n=275), and external validation (n=95) datasets, the mean ages were 68.5±12.4, 67.6±13.8, and 67.9±13.6 years, respectively. The proportions of men were 57%, 53%, and 59%, with LVO prevalences of 17.0%, 16.4%, and 26.3%, respectively. In the external validation, the ExtraTrees model achieved a robust area under the curve of 0.888 (95% CI, 0.850-0.925), with a sensitivity of 80.1% (95% CI, 72.0-88.1) and a specificity of 88.6% (95% CI, 84.7-92.5). Adding the National Institutes of Health Stroke Scale score to the ExtraTrees model increased sensitivity (from 80.1% to 92.1%) while maintaining specificity. Our algorithm provides reliable predictions of LVO using noncontrast computed tomography. By enabling early LVO identification, our algorithm has the potential to expedite the stroke workflow.

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. Patients > 60years of age, who received intravenous linezolid (600mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300mg every 12h).

Simultaneous assessment of blood flow and myelin content in the brain white matter with dynamic [11C]PiB PET: a test-retest study in healthy controls.

Exploring the relationship between oxygen supply and myelin damage would benefit from a simultaneous quantification of myelin and cerebral blood flow (CBF) in the brain's white matter (WM). To validate an analytical method for quantifying both CBF and myelin content in the WM using dynamic [11C]PiB positron emission tomography (PET). A test-retest study was performed on eight healthy subjects who underwent two consecutive dynamic [11C]PiB-PET scans. Three quantitative approaches were compared: simplified reference tissue model 2 (SRTM2), LOGAN graphical model, and standardized uptake value ratio (SUVR). The sensitivity of methods to the size of the region of interest was explored by simulating lesion masks obtained from 36 subjects with multiple sclerosis. Reproducibility was assessed using the relative difference and interclass correlation coefficient. Repeated measures correlations were used to test for cross-correlations between metrics. Among the CBF measures, the relative delivery (R1) of the simplified reference tissue model 2 (SRTM2) displayed the best reproducibility in the white matter, with a strong influence of the size of regions analyzed, the test-retest variability being below 10% for regions above 68 mm3 in the supratentorial white matter. [11C]PiB PET-derived proxies of CBF demonstrated lower perfusion of white matter compared to grey matter with an overall ratio equal to 1.71 ± 0.09 when the SRTM2-R1 was employed. Tissue binding in the white matter was well estimated by the Logan graphical model through estimation of the distribution volume ratio (LOGAN-DVR) and SRTM2 distribution volume ratio (SRTM2-DVR), with test-retest variability being below 10% for regions exceeding 106 mm3 for LOGAN-DVR and 300 mm3 for SRTM2-DVR. SRTM2-DVR provided a better contrast between white matter and grey matter. The interhemispheric variability was also dependent on the size of the region analyzed, being below 10% for regions above 103 mm3 for SRTM2-R1 and above 110 mm3 for LOGAN-DVR. Whereas the 1 to 8-minute standardized uptake value ratio (SUVR1-8) showed an intermediary reproducibility for CBF assessment, SUVR0-2 for perfusion or SUVR50-70 for tissue binding showed poor reproducibility and correlated only mildly with SRTM2-R1 and LOGAN-DVR estimations respectively. [11C]PiB PET imaging can simultaneously quantify perfusion and myelin content in WM diseases associated with focal lesions. For longitudinal studies, SRTM2-R1 and DVR should be preferred over SUVR for the assessment of regional CBF and myelin content, respectively. European Union Clinical Trials Register EUDRACT; EudraCT Number: 2008-004174-40; Date: 2009-03-06; https//www.clinicaltrialsregister.eu ; number 2008-004174-40.

Behind the Non-Uniform Breakup of Bubble Slug in Y-Shaped Microchannel: Dynamics and Mechanisms

Bubble flow in confined geometries is a problem of fundamental and technological significance. Among all the forms, bubble breakup in bifurcated microchannels is one of the most commonly encountered scenarios, where an in-depth understanding is necessary for better leveraging the process. This study numerically investigates the non-uniform breakup of a bubble slug in Y-shaped microchannels under different flow ratios, Reynolds numbers, and initial bubble volumes. Overall, the bubble can either breakup or non-breakup when passing through the bifurcation and shows different forms depending on flow regimes. The flow ratio-Reynolds number phase diagrams indicate a power–law transition line of breakup and non-breakup. The bubble takes longer to break up with rising flow ratios yet breaks earlier with higher Reynolds numbers and volumes. Non-breakup takes less time than the breakup patterns. Flow ratio is the origin of non-uniform breakup. Both the Reynolds number and initial volume influence the bubble states when reaching the bifurcation and thus affect subsequent processes. Bubble neck dynamics are analyzed to describe the breakup further. The volume distribution after breaking up is found to have a quadratic relation with the flow ratio. Our study is hoped to provide insights for practical applications related to non-uniform bubble breakups.

Anesthesia blunts carbon dioxide effects on glymphatic cerebrospinal fluid dynamics in mechanically ventilated rats.

Impaired glymphatic clearance of cerebral metabolic products and fluids contribute to traumatic and ischemic brain oedema and neurodegeneration in preclinical models. Glymphatic perivascular cerebrospinal fluid (CSF) flow varies between anesthetics possibly due to changes in vasomotor tone and thereby in the dynamics of the periarterial CSF-containing space. To better understand the influence of anesthetics and carbon dioxide levels on CSF dynamics, we studied the effect of periarterial size modulation on CSF distribution by changing blood carbon dioxide levels and anesthetic regimens with opposing vasomotor influences - vasoconstrictive ketamine-dexmedetomidine (K/DEX) and vasodilatory isoflurane (ISO). End-tidal carbon dioxide (EtCO2) was modulated with either supplemental inhaled carbon dioxide to reach hypercapnia (EtCO2 80 mmHg) or hyperventilation (EtCO2 20 mmHg) in tracheostomized and anesthetized female rats. Distribution of intracisternally infused radiolabeled CSF tracer 111In-diethylamine pentaacetate was assessed for 86 minutes in 1) normoventilated (EtCO2 40 mmHg) K/DEX, 2) normoventilated ISO, 3) hypercapnic K/DEX, and 4) hyperventilated ISO groups using dynamic whole-body single-photon emission tomography. CSF volume changes were assessed with magnetic resonance imaging. Under normoventilation, cortical CSF tracer perfusion, perivascular space size around middle cerebral arteries (MCAs), and intracranial CSF volume were higher under K/DEX compared with ISO (cortical Cmax ratio 2.33 [95% CI 1.35 to 4.04], perivascular size ratio 2.20 [95% CI 1.09 to 4.45], and intracranial CSF volume ratio 1.90 [95% CI 1.33 to 2.71]). Under ISO, tracer was directed to systemic circulation. Under K/DEX, the intracranial tracer distribution and CSF volume were uninfluenced by hypercapnia compared with normoventilation. Intracranial CSF tracer distribution was unaffected by hyperventilation under ISO despite a 28% increase in CSF volume around MCAs. K/DEX and ISO overrode carbon dioxide as a regulator of CSF flow. K/DEX could be used to preserve CSF space and dynamics in hypercapnia whereas hyperventilation was insufficient to increase cerebral CSF perfusion under ISO.

Effect of hemodialysis practice guideline on dialysis indicators and hemodynamic complications among patients undergoing hemodialysis

To assess the effect of haemodialysis practice guidelines on dialysis indicators and haemodynamic complications, the comparative study was conducted at the dialysis unit of Sheikh Zayed Hospital, Lahore, Pakistan, and comprised patients undergoing haemodialysis who were divided into intervention group A in which updated haemodialysis practice guidelines were used, and control group B in which routine base dialysis was given. Data was collected using a self-structured tool. Data was analysed using McNemar test and Mann-Whitney U-test with p&lt;0.05. Compared to baseline, there was a significant improvement in post-intervention ratio of effective removal of clearance (K) resulting from the treatment characterised by time (t) in the patient with a specific volume of distribution (V), or Kt/V, median &amp; IQR 0.83(0.355) vs 1.21(0.11) and percentage of urea reduction ratio with median &amp; IQR 49(12) vs. 66.5(18.65) (p&lt;0.05). ---Continue

Risk factors for cardio-cerebrovascular events among patients undergoing continuous ambulatory peritoneal dialysis and their association with serum magnesium

Serum magnesium levels exceeding 0.9 mmol/L are associated with increased survival rates in patients with CKD. This retrospective study aimed to identify risk factors for cardio-cerebrovascular events among patients receiving continuous ambulatory peritoneal dialysis (CAPD) and to examine their correlations with serum magnesium levels. Sociodemographic data, clinical physiological and biochemical indexes, and cardio-cerebrovascular event data were collected from 189 patients undergoing CAPD. Risk factors associated with cardio-cerebrovascular events were identified by univariate binary logistic regression analysis. Correlations between the risk factors and serum magnesium levels were determined by correlation analysis. Univariate regression analysis identified age, C-reactive protein (CRP), red cell volume distribution width standard deviation, red cell volume distribution width corpuscular volume, serum albumin, serum potassium, serum sodium, serum chlorine, serum magnesium, and serum uric acid as risk factors for cardio-cerebrovascular events. Among them, serum magnesium ≤0.8 mmol/L had the highest odds ratio (3.996). Multivariate regression analysis revealed that serum magnesium was an independent risk factor, while serum UA (<440 μmol/L) was an independent protective factor for cardio-cerebrovascular events. The incidence of cardio-cerebrovascular events differed significantly among patients with different grades of serum magnesium (χ2 = 12.023, p = 0.002), with the highest incidence observed in patients with a serum magnesium concentration <0.8 mmol/L. High serum magnesium levels were correlated with high levels of serum albumin (r = 0.399, p < 0.001), serum potassium (r = 0.423, p < 0.001), and serum uric acid (r = 0.411, p < 0.001), and low levels of CRP (r = −0.279, p < 0.001). In conclusion, low serum magnesium may predict cardio-cerebrovascular events in patients receiving CAPD.

Understanding the Liver’s Role in the Clearance of Aβ40

The clearance of peripheral beta amyloid (Aβ) is a potential target for the treatment of Alzheimer’s disease (AD). The liver has been implicated in the elimination of Aβ from the peripheral circulation. Here, the single-pass uptake of Aβ40 in perfused livers from young and old rats (6 to 10 rats per group) was investigated with the multiple indicator dilution technique. Aβ40 had volumes of distribution between those of the vascular marker Evans Blue and the extracellular marker sucrose. The hepatic extraction of Aβ40 was negligible, explained in part by the small permeability surface area products consistent with a high endothelial barrier to liver uptake. There were no substantial effects of age on any of these results. In vitro experiments with isolated hepatocytes and liver sinusoidal endothelial cells showed only very small amounts of Aβ uptake consistent with low intrinsic clearance. These results indicate that the hepatic clearance of Aβ is capacity-limited, explained by the low-permeability surface area products and hepatocyte uptake. However, this does not preclude an effect of aging in longer-term in vivo studies where age-related changes in liver blood flow and protein binding influence liver clearance.

#2548 In vitro evaluation of proenkephalin kinetics in hemofiltration and hemodialysis

Abstract Background and Aims Proenkephalin A 119-159 (penKid) is a stable surrogate marker for enkephalins (endogenous opioids regulating kidney function). PenKid plasma concentration correlates to GFR and increases in AKI, for this reason it can be used for prediction and diagnosis of AKI (even subclinical forms) and need of RRT. Furthermore, it seems to be also a reliable biomarker to predict the successful liberation from RRT and may therefore aid in the successful weaning of patients from RRT. PenKid has the perk of maintaining stable its concentration during RRT, suggesting that is barely filtered, in contrast to other biomarkers. However, with its small size of 4.5 kDa, penKid can be assumed to be freely filtered through the glomerulus and dialysis membranes. To address the issue about stable penKid plasma concentrations in RRT (no extracorporeal removal or increased production in response to impaired kidney function), we planned ex vivo experiments simulating different conditions of RRT. The aim of this study is to determine the sieving coefficient and the diffusive clearance of the penKid molecule in conditions of in vitro continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD), respectively. Method The lyophilized peptide was solved in 20 mM Dipotassium phosphate, 6 mM Disodium EDTA [pH 8], avoiding concentrations higher than 1 mg/mL. The compound was diluted in 50 mL of plasma to ensure homogeneous distribution. For each experimental modality, a batch of blood of 1000 mL with adjusted hematocrit at 30% and albumin concentration of 3 g% was utilized. Blood was spiked with lyophilized synthetic penKid to achieve two target concentrations of 150 and 500 pmol/L in CVVH and CVVHD modalities, respectively. Blood was adjusted for a volume of 1000 mL, maintained at 37° and continuously stirred during the experiments. CVVH was performed with blood flow (QB) = 150 mL/min and ultrafiltration rate (QUF) = 20 mL/min to reproduce a filtration fraction of 20%. The ultrafiltrate was reinfused in the venous line to maintain initial volume. This allowed to define convective clearance and solute sieving coefficient in pure convective mode. CVVHD was performed with QB = 150 mL/min and dialysate flow (QD) = 35 mL/min (Net QUF = 0 mL/min). This allowed the calculation of diffusive clearance. A polysulfone dialyzer (AV1000 FMC, Bad Homburg, Germany) was utilized. Samples were taken at 10, 30, 60 minutes from the initiation of the circulation, in both modalities. Results Initial penKid concentrations in blood corresponded to the desired targets in all the experiments. Sieving coefficients displayed values between 0.69 and 1.5 and they appear to remain stable over time (Fig. 1). Diffusive clearance displayed values between 35 and 15.7 mL/min. Values appear to present a slight decrease over time (Fig. 2). The observed variability can be attributed to several factors: difference in plasma protein interference in various moments of the experiments, difference in concentration of penKid in plasma water versus plasma or blood, variability in the sample measurements. Conclusion Significant removal of penKid can be obtained by extracorporeal therapies both in convection (CVVH) and diffusion (CVVHD). Further investigation is needed to assess if these findings are confirmed during in vivo treatments in which penKid kinetics is affected by generation, elimination and changes in distribution volume.

Evolution of Maternal Provisioning and Development in the Ophiuroidea: Egg Size, Larval Form and Parental Care.

The Ophiuroidea is the most speciose class of echinoderms and has the greatest diversity of larval forms, but we know less about the evolution of development (evo-devo) in this group than for the other echinoderm classes. As is typical of echinoderms, evo-devo in the Ophiuroidea resulted in the switch from production of small eggs and feeding (planktotrophic) larvae to large eggs and non-feeding (lecithotrophic) larvae. Parental care (ovoviviparity or viviparity/matrotrophy) is the most derived life history. Analysis of egg data for 140 species (excluding viviparity and facultative planktotrophy) indicated a bimodal distribution in egg volume corresponding to planktotrophy and lecithotrophy+ovoviviparity, with three significant egg size groups due to the very large eggs of the ovoviviparous species. The marked reduction in fecundity in species with extremely large eggs is exemplified by the ovoviviparous species. Egg size in the two species with facultative planktotrophy were intermediate with respect to the two modes. Identifying the ancestral larval life history pattern and the pathways in the switch from feeding to non-feeding larvae is complicated by the two patterns of metamorphosis seen in species with planktotrophic development: Type I (ophiopluteus only) and Type II (ophiopluteus+vitellaria larva). The variability in arm resorption at metamorphosis across ophiuroid families indicates that the Type I and II patterns may be two ends of a morphological continuum. This variability indicates ancestral morphological plasticity at metamorphosis followed by canalization in some taxa to the vitellaria as the metamorphic larva. Vestigial ophiopluteal traits in lecithotrophic ophioplutei and vitellaria indicate evolution from the ancestral (feeding larva) state. Parental care has evolved many times from an ancestor that had a planktonic ophiopluteus or vitellaria and is often associated with hermaphroditism and paedomorphosis. A secondary reduction in egg size occurred in the viviparous species.

#2241 Validation of a new formula for total body water in peritoneal dialysis patients

Abstract Background and Aims Peritoneal dialysis (PD) adequacy, assessed primarily by Kt/V, is crucial in routine clinical practice for detecting issues with PD treatment. This metric relies on urea levels and its volume (V) distribution, classically equivalent to total body water (TBW). TBW estimation, commonly achieved through the Watson and Watson (WW) formula, lacks dialysis patients in its original study, it also excluded patients with water metabolism disturbances, raising concerns about its generalizability to this population. Responding to this need, a new formula (NF) for calculating TBW in PD patients was developed in our center, with the aim of improving the correlation between administered Kt/V and clinical outcomes. Consequently, this study seeks to validate the proposed formula by applying it to a population. Method A prospective study conducted at a single center within PD program involved the collection of data on adequacy and Body Composition Monitoring (BCM) spanning from May 2023 to January 2024. TBW was calculated using the WW formula and the proposed new formula (TBW BI=0.36*Height+0.241*weight−9.675*BSA−26.234 for man and TBW BI=0.36*Height+0.241*weight−9.675*BSA−28.926 for woman). Categorical variables are presented as frequencies and percentages, continuous variables as means and standard deviations, or medians and interquartile ranges for variables with skewed distributions. A p-value &amp;lt; 0.05 was considered significant. Both formulas were subjected to correlation analysis with BCM TBW to assess mean differences using a paired-samples T test. Additionally, the resulting Kt/V values were compared, along with an examination of concordance in the detection of Kt/V values below 1.7. Results 66 measurements were collected from 36 PD patients. 29.2% (n = 10) were female, and the mean age was 59.7 years. Both formulas exhibited strong correlations with BCM TBW (WW: ρ = 0.949 and NF: ρ = 0.953, p &amp;lt; 0.001). BCM TBW showed a significant difference from WW TBW (34.8 vs. 38.1 liters, p &amp;lt; 0.001), but not when compared to the new formula (34.8 vs. 33.9, p = 0.06). The resulting BCM-derived Kt/V significantly differed from both formulas, with a larger mean difference compared to the WW formula (BCM: 2.71 vs. WW: 2.42, p &amp;lt; 0.001, and vs. the new formula: 2.77, p = 0.04). There was a perfect association between the use of NF and identification of BCM derived KtV measurements under the 1.7 target (Phi = 1, p &amp;lt; 0.001), an association that was strong for WW (Phi = 0.69, p &amp;lt; 0.001). Conclusion Errors in quantifying PD adequacy can lead to delayed detection of technical issues or inappropriate adjustments to already adequate prescriptions. We present a novel formula, specific for the PD population, reducing errors in PD quantification, particularly in settings where BCM is not available.

#2234 A new formula for total body water in peritoneal dialysis patients

Abstract Background and Aims Peritoneal dialysis (PD) adequacy, assessed primarily by Kt/V, is crucial in routine clinical practice for detecting issues with PD treatment. This metric relies on urea levels and its volume (V) distribution, classically equivalent to total body water (TBW). TBW estimation, commonly achieved through the Watson and Watson (WW) formula, lacks dialysis patients in its original study, it also excluded patients with water metabolism disturbances, raising concerns about its generalizability to this population. Despite limitations, WW has been widely used in trials assessing optimal dialysis dosage in the PD population. Body composition monitoring (BCM) with bioimpedance (BI) offers a more reliable method for TBW determination, commonly used in dialysis programs for quantifying overhydration. However, its higher cost and limited availability compared to estimate formulas pose challenges. Thereby, this study aims to compare TBW values derived from the WW formula and BCM analysis with BI. Additionally, intends to create a new, patient-specific TBW formula based on biometric measurements for PD. Method We retrospectively analyzed adequacy measurements and BCM data from a Portuguese PD center. Patient information included age, sex, height, weight, and BCM-TBW and Percentage Body Fat (PBF). Derived parameters encompassed WW-derived TBW, Body Surface Area (BSA) via the DuBois formula and Body Mass Index (BMI). Statistical analysis, using Microsoft Excel 2017 and IBM SPSS version 25, with a p-value&amp;lt;0.05 considered significant, followed by a step-wise approach: Results 400 measurements were collected from 90 chronic PD patients. 25.1% (n = 23) were female (101 measurements), with a mean age of 56.2 ± 11.9 years. Mean weight was 74.0 ± 12.5 kg, BMI 26.4 ± 4.1 and BSA 1.80 ± 0.80. BCM TBW obtained was significantly lower compared to WW-TBW (33.7 and 38.4 litters respectively, mean difference −4.65 ± 4.17, P &amp;lt; .001). This difference correlated positively with increased PBF (ρ = 0.73, P &amp;lt; .001). BCM TBW correlated positively with weight, height, BMI and BSA (ρ = 0.62, ρ = 0.68, ρ = 0.28 and ρ = 0.62, respectively, with P &amp;lt; .001 overall), without correlation with age (ρ = 0.0, P = .99). For linear regression analysis, the first step was to exclude outlier values for BCM TBW using median ± 1.5 x interquartile range resulting in 383 measurements comprised between 22.15 and 44.95 L. A multiple linear regression using BSA, height, weight and sex to predict BCM TBW. The overall regression model was statistically significant (R2 = 0.59, F (4 378) = 138.17, P &amp;lt; .001). All the variables significantly contributed to the model at predicting BCM TBW (BSA: β = −0.283, P &amp;lt; .001; Height: β = 0.495, P &amp;lt; .001; Weight: β = 0.56, P &amp;lt; .001; Sex: β = 0.237, P &amp;lt; .001). Two formulas were extrapolated from this regression: Conclusion We present a pivotal formula for TBW calculation in PD patients, aiming to improve the correlation between provided Kt/V and clinical outcomes. This addresses the exclusion of diverse patient characteristics in previous studies. However, given the new evidence challenging the association between Kt/V and clinical outcomes in PD, it becomes imperative to appropriate measures for PD adequacy and subject them to examination in novel randomized clinical trials.

#2545 Hemodialysis for salbutamol intoxication: patient case report

Abstract Background and Aims Salbutamol/albuterol is a moderately selective beta-2-adrenergic receptor agonist that acts as an airway smooth muscle relaxant. It is used to prevent and treat acute bronchospasm in various respiratory conditions. Due to its large volume of distribution, it is not considered dialysable. Method This is a clinical case report of inadvertent parenteral administration of salbutamol resulting in acute intoxication. Salvage renal replacement therapy was implemented due to the severity of the patient's clinical condition and the large amount of salbutamol administered. Multiple plasma measurements of salbutamol were taken during hemodialysis, allowing for a correlation to be made with the patient's clinical presentation. Results This case report presents an elderly patient with sepsis, Down syndrome, and liver cirrhosis. The patient required non-invasive ventilation due to worsening respiratory failure and was prescribed intravenous methylprednisolone. However, the patient inadvertently received 5mg of parenteral salbutamol (albuterol), which resulted in immediate severe arrhythmic tachycardia followed by hemodynamic collapse. After unsuccessful cardioversion and treatment with landiolol infusion, salvage hemodialysis was initiated to reduce the suspected highly elevated serum salbutamol levels. After 30 minutes, sinus rhythm with normocardia was observed. No rebound tachycardia was noted after the hemodialysis termination. However, due to severe septic shock, hypotension persisted, and vasoactive medications were adjusted. However, the measured levels of plasma salbutamol do not support the view that hemodialysis was the cause of the described improvement. The total amount of the drug cleared was exceedingly small, only 2.8% of the total dose. Data from the literature support our findings, even in the case of the life-threatening intoxication described. Conclusion The results confirm a large volume of distribution for salbutamol. The measured half-life time during hemodialysis (3.1 hours) is comparable to observed half-life times in therapeutic settings. The observed clinical benefit associated with dialysis appears to be fortuitous. This case report highlights the potential bias towards positive clinical outcomes and unproven therapies.

#1615 Working without peritoneal dialysate and urine collections during the COVID-19 pandemic: how to assure sufficient small solute removal

Abstract Background and Aims The guidelines of the International Society of Peritoneal Dialysis suggest regular control of small solute removal. During the COVID-19 pandemic we did not perform additional controls of dialysis adequacy in our peritoneal dialysis patients. We judged patients according symptoms and serum urea levels. In this retrospective study, we aimed to evaluate whether the measurement of serum urea alone might indicate sufficient small solute removal in peritoneal dialysis patients. Method In 216 adult PD patients (139 males, 77 females, median age 64 years, median BMI 26.7) Kt/V urea (renal and peritoneal) was registered together with anthropometric and laboratory data during the first two years of PD therapy. Patients presenting urea values between 100 and 250 mg/dl were included in the statistical analysis, thus resulting in the evaluation of 410 measurements (265 in male, 145 in female patients). Urea distribution volume was calculated using the formula of Watson and Watson. The measurement of urea in blood and urine was performed by a standard kinetic test with urease. Results Serum urea correlated significantly to Kt/V urea (r = −0.28, p &amp;lt; 0.01), whereas significance was not reached in female patients (male patients: r = −0.35, p &amp;lt; 0.01; female patients; r = −0.14, p = 0.13). Kt/V urea of at least 1.7 is achieved in male patients presenting serum urea values lower than 160 mg/dl (95% confidence interval), whereas in female patients apparently presenting serum urea values lower than 200 mg/dl (95% confidence interval). This difference is due to the distinct sex specific urea distribution volume (median value: male patients 40.8 liters, female patients 31.8 liters) and to the absence of a significant correlation between serum urea and Kt/V urea in female patients. Conclusion Serum urea values below 160 mg/dl in male peritoneal dialysis patients are roughly indicating sufficient small solute removal, whereas a clear relation between serum urea and Kt/V urea was not present in female patients in our study population.

#1605 Development of an app for a science-based prescription of haemodialysis

Abstract Background and Aims The delivery of an adequate haemodialysis (HD) dose (i.e., a target single-pool Kt/V (spKt/V) of 1.4 per session) is often challenging, especially in patients with huge urea distribution volumes (V). On the other hand, patients with an extremely small V, such as children, are at higher risk of disequilibrium syndrome, which is caused by an excessive or overly rapid correction of urea levels, particularly during the first HD session. The treatment prescription often neglects many elements contributing to the final delivered HD dose, whereas a systematic and comprehensive evaluation of all adjustable parameters could improve the management of patients, not only facilitating the achievement of treatment goals, but also avoiding short- and long-term complications. We aimed at developing a web app capable of predicting the delivered HD dose, given a wide range of parameters, and using renowned kinetic equations relevant to urea clearance in HD. Method The platform used to develop our app is based on Angular, an open-source framework to develop web applications. Specifically, it can be used to realise single-page apps and it is only for frontend. This fits our case, since a backend is not required due to the absence of huge databases or complex operations. The application is grounded on a stepper component, a paradigm to guide the user step-by-step during the data entry process. It consists of three phases, namely (1) patient, (2) haemodialyser, (3) target spKt/V. The last section is also for output. A modification of any input triggers a real-time output change. Results We developed a free access user-friendly web app, through which HD professionals can simulate a treatment prescription and obtain an estimate of the delivered dose in terms of spKt/V. The app is structured in three sections and all calculations are based on validated formulas and kinetic equations applicable to HD: The output “expected spKt/V” changes in real time, after any modification of the input parameters. The result can thus be compared to the treatment goal (i.e., 1.4 for a standard HD session; 0.55 for a first treatment, aiming at reducing the risk of disequilibrium syndrome), as suggested by international guidelines and expert opinions. Conclusion We developed a user-friendly web app, which will be freely accessible online by HD professionals, aimed at predicting the delivered HD dose (spKt/V) considering a wide range of patient- and prescription-related parameters. The application of such a tool in everyday clinical practice, particularly in cases requiring a more accurate definition of the actual delivered dose, could improve the management of patients through a personalisation of the treatment. This could enhance prescription adjustments aimed at achieving an adequate spKt/V in patients receiving an insufficient HD dose; on the other hand, it could help preventing disequilibrium syndrome in patients with very small urea distribution volumes.

#811 Effect of GLP-1 receptor agonists on the weight, urea distribution volume and blood pressure of hemodialysis (HD) patients

Abstract Background and Aims Glucagon-like-peptide-1 receptor agonists (GLP-1) drugs are a class of medications commonly used to treat type-2 diabetes. Diabetes is prevalent in almost 60% of the end stage kidney disease (ESKD) patients and an increasing number of dialysis patients use GLP-1 drugs. It is important to note that GLP-1 drugs may have additional benefits such as weight loss and potential cardiovascular benefits. However, little is known about the effects of these drugs in dialysis patients. We analysed the changes in body weight and blood pressure in hemodialysis (HD) patients who start using these drugs. We also analysed whether there are changes in patients’ urea distribution volume, a proxy of lean body mass, to understand whether these medications affect muscle mass. Method We retrospectively evaluated 236 ESKD patients who were prescribed GLP-1 drugs as part of routine clinical care in October of 2023 at clinics in a large dialysis organization. All patients received dialysis for at least 60 days before and after they started using the medication. We looked at the changes in the average post dialysis weight, urea distribution volume, and pre dialysis systolic blood pressure (pre-SBP) between the 60 days before using GLP-1 drugs (pre-GLP1 period) and 60 days after initiating the drug (post-GLP1 phase). For each metric, we performed a paired t-test to evaluate the changes between pre-GLP1 and post-GLP1. Results The average post dialysis weight pre-GLP1 was 103.98 kg and the average post dialysis weight post-GLP1 was 102.02 kg (difference: −1.96 kg, 95% CI :1.37 to 4.27, p-value &amp;lt;0.001). The average urea distribution volume was 36.0 L pre-GLP1, and 35.6 L post-GLP1 (difference: −0.47 L, 95% CI: −0.99 to 3.56, p-value=0.07). The mean pre-SBP was 147.83 mmHg pre-GLP1 and 149.67 mmHg post-GLP1 (difference: 1.85 mmHg, 95% CI: −5.49 to 24.93, p=0.29). Conclusion Our analysis showed a significant decrease in the average post dialysis weight of HD patients using GLP-1 drugs. While the decline in patients' urea distribution volume, which can be considered as a proxy for lean tissue mass, was not statistically significant, it may be clinically meaningful. We do not see a significant change in pre-SBP. Reductions in weight may suggest reduction in fat and muscle mass but can also be due to “regression to the mean” phenomena as patients who were on these medications tended to be larger. Further studies are necessary to evaluate this association.

Science mapping of the knowledge base on teacher autonomy: a bibliometric study

PurposeThis research sought to document the volume, development trend and geographical distribution of the research on teacher autonomy, identify high-impact journals, authors and documents and reveal the intellectual structure of the field.Design/methodology/approachThis paper analyzed the articles published on the related subject in the Web of Science (WoS) and/or Scopus. Based on certain exclusion criteria, analyses were conducted on a total of 259 articles. The data were then subjected to descriptive analyses and bibliometric analyses.FindingsThe review found that the teacher autonomy knowledge base has grown dramatically since 2004. In the co-citation analysis, it was determined that four clusters focused on the themes of professionalism and professional development, leadership and self-efficacy, autonomy in language teaching and learning and self-determination theory. According to the co-word analysis in this review, the most co-occurring keywords were revealed to be “teacher autonomy,” “autonomy,” “teachers,” “teacher professionalism” and “professional development.”Originality/valueDespite increasing numbers of systematic reviews focusing on educational administration and leadership, this paper represents the first bibliometric review conducted to reveal the development of research on teacher autonomy using both the WoS and Scopus databases. Teacher autonomy can be regarded as an emerging field of study backed up by a theoretical background. Although there are some distinct prominent scholars in the research area, autonomy research still needs more scholars to specialize in the field.

Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication.

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (Ka, 5.41 h-1), volume of distribution (Vd, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication.