Clearance Ratio Research Articles

Effects of Cimetidine and Dolutegravir on the Endogenous Drug-Drug Interaction Biomarkers for Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Protein 1 in Healthy Volunteers.

This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m1A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CLr) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CLr ratio (CLrR) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CLrR of m1A was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CLr of creatinine was significantly decreased only by cimetidine 800 mg. Individual CLrR of 1-NMN and m1A showed a positive correlation with the corresponding CLrR of metformin with r2 of 0.58 and 0.55, respectively. When evaluated individually, m1A showed a better correlation during cimetidine periods (r2 0.64) than 1-NMN (r2 0.36), but vice versa during dolutegravir periods (r2 1-NMN, 0.80; m1A, 0.32). These results suggest that 1-NMN and m1A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CLrR change.

The Influence of Perspective on Perception: Assessing Residue Across Planes of Videofluoroscopy.

(1) To determine whether perception of pharyngeal residue severity differs by view plane on videofluoroscopy. (2) To explore whether the Bolus Clearance Ratio (BCR) can be reliably applied in the anterior-posterior (AP) plane. (3) To investigate the relationship between perception of residue severity and BCR measures across view planes. Images of the same bolus condition in lateral and AP were rated using a simple 5-point ordinal descriptive scale (none, trace, mild, moderate, severe) by 225 speech-language pathologists via electronic survey. BCR measures were obtained for the same set of images from four trained raters. Wilcoxon signed-rank tests and cumulative mixed modeling were used to compare ratings by plane. BCR reliability was calculated using intraclass correlation coefficients. Perceptual ratings were compared with BCR measures using Spearman correlations. (1) Perception of residue severity was not consistent across plane in 9/10 image pairs (p < 0.05), with a significant fixed effect of plane on severity rating (β = 0.41; z = 7.27; p < 0.001). The directionality of differences varied by case. (2) Inter-rater reliability for BCR measures was good across lateral (intraclass correlation coefficient [ICC] = 0.82) and AP (ICC = 0.87) planes, with superior intra-rater reliability in AP (lateral ICC = 0.85; AP ICC = 0.98). (3) There was a strong positive correlation between perceptual ratings and BCR measures in both planes. Perception of pharyngeal residue severity differs between lateral and AP planes with inconsistent directionality raising important questions about the clinical implications of single plane studies. The BCR shows good-excellent reliability and strong correlation with perception across planes, offering a promising method for cross-plane quantification. Level III, diagnostic study with a gold standard Laryngoscope, 2024.

Research on working mechanism and structural optimization of high speed bearing of tricone bits based on finite difference method

Abstract In order to analyze the working mechanism of the floating sleeve bearing of the cone bit, the life of floating sleeve bearing was tested. The experimental results show that adhesive wear will form on the bearing surface with the increase of temperature, which is the main cause of bearing failure. And this paper establishes the Reynolds equation and energy equation of the oil film based on the theory of dynamic pressure lubrication of sliding bearings. The equation was numerically solved based on the finite difference method. It determines the rotational speed ratio at the equilibrium based on the trend of the frictional torque. And then corrects the eccentricity in the iterative calculation process so as to analyze the tribological performance of the bearings in equilibrium under different clearance ratios. Among them, the improper configuration of the internal and external clearance ratio leads to the increase of the friction torque and the reduction of the bearing capacity. For floating sleeve bearings, the configuration with large internal clearance and small external clearance should be adopted. Finally, the bearing structure is optimized and numerical calculations show that the tribological performance of the new type bearings is significantly improved compared with that of ordinary cone bit bearings.

The Effect of Nerolidol on Renal Dysfunction following Bilateral Ureteral Obstruction.

Background/Objectives: Obstructive uropathy is a common cause of renal impairment. Recently, there has been a burgeoning interest in exploring natural products as potential alternative remedies for many conditions due to their low toxicity, affordability and wide availability. Methods: We investigated the effect of nerolidol in a rat model of bilateral ureteral obstruction (BUO) injury. Nerolidol, dissolved in a vehicle, was administered orally as a single daily dose of 200 mg/kg to Wistar rats. Sham group (n = 12) underwent sham surgery, whereas the BUO (n = 12) and BUO/NR groups (n = 12) underwent reversible 24-h BUO and received the vehicle or nerolidol, respectively. The treatment started 9 days prior to the BUO/sham surgery and continued for 3 days after reversal. Renal functions were assessed before starting the treatment, just prior to the intervention and 3 days after BUO reversal. Results: Neither nerolidol nor the vehicle affected the basal renal functions. Nerolidol resulted in a significant attenuation in the BUO-induced alterations in renal functional parameters such as serum creatinine and urea, creatinine clearance and urinary albumin-creatinine ratio. Nerolidol also attenuated the changes in several markers associated with renal injury, inflammation, apoptosis and oxidative stress and mitigated the histological alterations. Conclusions: The findings of this study demonstrated the potent reno-protective effects of nerolidol in mitigating the adverse renal effects of bilateral ureteral obstruction. This is attributed to its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-oxidant properties. These effects were reflected in the partial recovery of renal functions and histological features. These findings may have potential therapeutic implications.

Swallowing Kinematics in Male Patients with Total Laryngectomy.

The present study aimed to investigate the symptomatic swallowing complaints in individuals with total laryngectomy (TL) and reveal how swallowing kinematics differs between those with and without symptomatic dysphagia complaints. A total of 34 subjects with TL were included in the study. Swallowing kinematics of those with symptomatic swallowing complaints (Group 1) were compared to those without (Group 2). Kinematic parameters including pharyngeal transit duration (PTD), maximum pharyngeal constriction ratio (MPCR), upper esophageal sphincter opening ratio (UESOR), upper esophageal sphincter opening duration (UESOD), and bolus clearance ratio (BCR) were investigated from Videofluoroscopic Swallowing Study (VFSS) records via ImageJ software. Symptomatic swallowing complaints were determined in 47.1% of the subjects (n = 16). Difficulty while swallowing solid foods and pills, diminished pleasure of eating, food getting stuck in the throat, and increased level of stress during swallowing were among the major swallowing complaints in the present cohort. PTD, MPCR, and BCR parameters were significantly higher in subjects with symptomatic swallowing complaints than those without. These preliminary findings indicate that almost half of individuals with TL may have symptomatic swallowing complaints. The underlying pathophysiology of this phenomenon may be the devianced kinematic parameters including PTD, MPCR, and BCR in this population. Therefore, it is recommended to include the kinematic measurements in the dysphagia evaluation protocol in individuals with TL, most notably in those with symptomatic swallowing complaints. 3 Laryngoscope, 2024.

7752 Navigating Hypercalcemia in Pregnancy: A Case Report

Abstract Disclosure: J. Gabbay: None. S. Steinmetz-Wood: None. Introduction: Primary hyperparathyroidism (PHPT) in pregnancy is rare but presents many diagnostic and therapeutic challenges. Prompt diagnosis and treatment are important due to associated maternal and fetal risks, however evaluation of urine calcium to differentiate from Familial Hypocalciuric Hypercalcemia (FHH) becomes less reliable due to physiologic changes in pregnancy, sestamibi scans. CT scans require radiation, parathyroidectomy introduces surgical risk, and medical alternatives like bisphosphonates can interfere with fetal skeletal development. Clinical Case: A 24-year-old woman who presented to the emergency room for progressive nausea and abdominal pain was found to be pregnant with elevated serum calculated calcium to 11.4 mg/dL (2.84 mmol/L). She had a history of renal stones, longstanding hypercalcemia of unknown etiology and a remote family history of parathyroid “issues”. Follow up laboratory work showed a PTH of 75.8 pg/ml (8.04 pmol/L) with an elevated 24-hour urine calcium and a low 25OH vitamin D. Given her history of kidney stones and overt symptoms it was our clinical judgement that this was not a case of FHH. She was started on IV fluids twice weekly. After an unrevealing neck ultrasound, an MRI neck showed a 7 mm lesion along the posterior aspect of the left thyroid suggestive of a parathyroid adenoma. Sestamibi scan was avoided due to the risks of radiation to the developing fetus. Given the presumptive diagnosis of parathyroid adenoma, the lack of response to aggressive hydration, and the maternal and fetal risks of hypercalcemia during pregnancy, parathyroidectomy was pursued in her second trimester. Intra-operative inspection and biopsy showed the lesion to be only a lymph node. She underwent 4-gland exploration and the left inferior parathyroid gland, which appeared abnormal and enlarged, was removed. The intra-operative PTH dropped only from 98 to 80 (10.4 to 8.5 pmol/L). She otherwise had an unremarkable hospital course and at discharge her calcium was normal with an undetectable PTH, which can be an expected finding in pregnancy. On follow up she was feeling well with sustained normocalcemia and low PTH levels. Given the age at which her hyperparathyroidism started, she was referred to genetics for further evaluation. Clinical Lessons/Conclusion: There were significant biochemical and radiological limitations in the management of this case. Normally an inappropriately normal PTH with elevated serum calcium and normal urine calcium/creatinine clearance ratio confirms the diagnosis of PHPT, however in pregnancy it should be noted that FHH could also present with normal or elevated urine calcium due to absorptive hypercalciuria in pregnancy. Additional clinical history and reasoning was needed for management as well as a skilled surgeon, where preoperative localization was limited and was not ultimately helpful. Presentation: 6/2/2024

A-125 Difference Between the Results of Vitros® Dry Biochemistry and Wet Biochemistry with Kinetic Method in Diagnosing the Comorbidity of Lung Adenocarcinoma and Aacroamylasemia: Case Report

Abstract Background Amylase (AMY) is a biomarker that comes mainly from the pancreas and salivary glands. Macroamylasemia is a condition often accompanied by malignant tumors and clinical features that include: (i) recurrent abdominal pain, no abnormality in the salivary glands, serum amylase (AMY) level ≥2 to 3 times higher than the normal value and poor patient response to treatments for pancreatitis; (ii) normal serum creatinine and urea levels, increased serum AMY level, and urine AMY level within the normal range or slightly lower. Because macroamylasemia may cause abnormally increased serum AMY levels for a long period of time, misdiagnosis of pancreatitis and delayed diagnosis/treatment of the disease may occur. We report a case of lung adenocarcinoma with macroamylasemia that was co-diagnosed using wet chemistry with kinetic method and dry chemistry to measure AMY. Methods A 47-year-old male patient was previously diagnosed with “acute pancreatitis and lung infection” after initial admission to a local hospital with paroxysmal cough and abdominal pain without obvious cause. To further diagnose the patient, we determined the blood AMY level by using the wet chemistry with kinetic method and the Vitros® dry chemistry test, in addition to conducting a physical exam, abdominal and chest computed tomography (CT), and other lab tests. Two methods, calculation of amylase/creatinine clearance ratio (Cam/Ccr ratio) and protein precipitation by polyethylene glycol (PEG), were also performed to validate assumed interference by serum macroamylase (MAMS) in the wet chemistry method compared to the dry chemistry method, which has technology to capture large molecules and minimize the impact of interferents. MAMS is a high-molecular-weight AMY complex that is synthesized by normal serum AMY bound with macromolecular substances (eg, immunoglobulins and carbohydrates). Results The final diagnosis was a stage IIB cT3N0M0 adenocarcinoma of the upper lobe of the right lung and macroamylasemia. Symptoms and radiologic findings were atypical in terms of pancreatitis. Serum AMY was 2,178U/L when measured with the wet chemistry with kinetic method. When the specimen was re-tested with Vitros dry chemistry, the AMY level was 369 U/L. After precipitation with 25% PEG 6000 solution, the blood AMY level from wet chemistry decreased from 2395.1 U/L to 246.7 U/L, yielding a precipitation rate of 89.7%. Cam/Ccr ratio was calculated as 0.23% (&amp;lt;1%). The calculated PEG precipitation rate and Cam/Ccr ratio from this study were consistent with the ranges considered for macroamylasemia, which are ≥73% and Cam/Ccr ratio &amp;lt;1%, respectively. Conclusions High serum AMY levels do not necessarily indicate pancreatitis or parotitis; wet chemistry results can be impacted by the presence of serum macroamylase. Instead of relying solely on blood AMY in diagnosing acute pancreatitis, clinicians should also consider the correlations of blood AMY with urine AMY and blood lipase. In patients with prolonged blood AMY elevation but normal lipase and urine AMY, re-testing of AMY with a more interference-resistant methodology (e.g. Vitros dry chemistry) may be requested. Accordingly, Cam/Ccr ratio calculation and PEG precipitation can be performed to validate the diagnosis of macroamylasemia.

An Overview of Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is one of the rare reasons for hypercalcemia. FHH is an autosomal dominant disease that is inheritable. The most common calcium sensitive receptors (CaSR) develop because of the inactivation of. In addition, they also develop due to the function loss of AP2S1 and GNA11. The FHH sickness is characterized by hypercalcemia, hypocalciuria, the regular or increased level of the parathyroid hormone, and normal renal function. The symptoms of hypercalcemia are usually not observed. It is often diagnosed by calculating the calcium/creatine clearance ratio of a 24-hour urine sample, and then genetically looking at it. FHH is usually a benign disorder, and when symptomatic and rarely complications develop, calcimimetics are used or parathyroidectomy can be performed. In conclusion, FHH is a benign and genetically transmitted, moderate cause of hypercalcemia. It is rare and usually asymptomatic.

Three-dimensional visualization technology for guiding one-step percutaneous transhepatic cholangioscopic lithotripsy for the treatment of complex hepatolithiasis.

Biliary stone disease is a highly prevalent condition and a leading cause of hospitalization worldwide. Hepatolithiasis with associated strictures has high residual and recurrence rates after traditional multisession percutaneous transhepatic cholangioscopic lithotripsy (PTCSL). To study one-step PTCSL using the percutaneous transhepatic one-step biliary fistulation (PTOBF) technique guided by three-dimensional (3D) visualization. This was a retrospective, single-center study analyzing, 140 patients who, between October 2016 and October 2023, underwent one-step PTCSL for hepatolithiasis. The patients were divided into two groups: The 3D-PTOBF group and the PTOBF group. Stone clearance on choledochoscopy, complications, and long-term clearance and recurrence rates were assessed. Age, total bilirubin, direct bilirubin, Child-Pugh class, and stone location were similar between the 2 groups, but there was a significant difference in bile duct strictures, with biliary strictures more common in the 3D-PTOBF group (P = 0.001). The median follow-up time was 55.0 (55.0, 512.0) days. The immediate stone clearance ratio (88.6% vs 27.1%, P = 0.000) and stricture resolution ratio (97.1% vs 78.6%, P = 0.001) in the 3D-PTOBF group were significantly greater than those in the PTOBF group. Postoperative complication (8.6% vs 41.4%, P = 0.000) and stone recurrence rates (7.1% vs 38.6%, P = 0.000) were significantly lower in the 3D-PTOBF group. Three-dimensional visualization helps make one-step PTCSL a safe, effective, and promising treatment for patients with complicated primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for patients with complicated primary hepatolithiasis. This minimally invasive method has the potential to be used as a substitute for hepatobiliary surgery.

Human Proenkephalin A 119-159 (penKid) in Extracorporeal Therapies: Ex vivo Sieving Coefficient, Diffusive Clearance, and Hemoadsorption Kinetics

Introduction: Enkephalins, endogenous opioid peptides, are involved in the regulation of renal function. One derived molecule, proenkephalin A, also known as penKid, has been demonstrated to be a reliable biomarker for kidney function and its plasma concentration correlates with measured glomerular filtration rate. penKid is used for prediction and diagnosis of AKI and need of renal replacement therapy (RRT). penKid has also been used to predict the successful weaning from RRT in patients with AKI. Whether the concentration of penKid is affected or not by RRT is a controversial point and there are no studies describing the kinetics of the molecule in such conditions. The low molecular weight (4.5 kDa) would imply free removal by the glomerulus and the dialysis membranes. During RRT, this reduction could not be detected in clinical practice due to the complex kinetics involving either low dialytic clearance or increased production in response to impaired kidney function. The aim of this study was 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, and also the penKid removal ratio in conditions of in vitro hemoadsorption (HA) using a synthetic microporous resin. Methods: Blood spiked with a lyophilized penKid peptide solved in 20 mm dipotassium phosphate and 6 mm disodium EDTA [pH 8] to reach target concentrations is used as testing solution. In each experiment, the blood batch was adjusted at a volume of 1,000 mL, maintained at 37°, and continuously stirred. Samples were collected from blood, ultrafiltrate, and spent dialysate at different times during the experiments. Sieving, clearance, and removal ratio were calculated. Results: Significant removal of penKid was observed in CVVH (sieving 1.04 ± 0.27), in CVVHD (clearance 23.08 ± 0.89), and in HA (removal ratio 76.1 ± 1% after 120 min). Conclusion: penKid is effectively removed by extracorporeal therapies. In presence of anuria, penKid generation kinetics can be calculated based on extracorporeal removal and volume variation. In steady state conditions, declining values may be the result of an initial renal function recovery and may suggest discontinuation and successful liberation from RRT.

Wing-to-Wall Distance Effect On The Large-Scale Turbulent Structures Interacting With A Wall

We experimentally investigate the effect of the wing-to-wall distance, also called ground clearance, on the three-dimensional flow generated by a wing at a 4° angle of attack and a chord Reynolds number of 1400. We perform 3D velocity measurements using Particle tracking velocimetry to characterize the wake downstream of the wing, evaluate the evolution of the intensity and the size of the wingtip and secondary counter-rotating vortices, and finally compute the aerodynamic coefficients using momentum balance equations. We extended the control volume method for drag and lift calculation to the case where the transverse plane downstream of the wing does not contain the whole wake. The secondary flow's vorticity isocontours and velocity vectors show a decrease in the downwash and vortex size with the ground clearance ratio (i.e., as we approach the ground). The computation of the circulation shows that this latter decays rapidly streamwise as we get closer to the wall, indicating a dissipation of the kinetic energy contained in the trailing vortices. The aerodynamic coefficients' results based on the control volume method show that the tested wing manifests a two-force regime evolution of the drag coefficient with the ground clearance ratio, as it first decreases when moving far from the ground before increasing as we move farther from the ground. A noteworthy high lift is generated when too close to the ground. Further application of the extended control volume method on DNS data is needed to validate the method.

Numerical and experimental investigation of a solar air heater duct with circular detached ribs to improve its efficiency

A solar air heater duct (SAH-duct) SAH-duct has low thermal performance due to the low heat transfer coefficient of air which is the working fluid. Proper mixing of relatively hot and cold air with respect to the hot absorber plate of the SAH-duct can enhance heat transfer. It can be achieved by placing suitable hindrances in the path of airflow like detached ribs. This study presents the numerical investigation of an asymmetrically heated 2D rectangular SAH-duct with in-line arranged circular detached ribs. In the geometrical configurations of the detached ribs; blockage ratio d/H, clearance ratio c/d, and relative longitudinal pitch ratio P/d are varied as 0.04–0.48, 0.1–1.2, and 05–50 respectively at Reynolds number Re 3000–15000 to study their effect on the thermal-hydraulic performance of the SAH-duct. Local and space-averaged thermal-fluid properties like heat transfer coefficient, and friction factor, Nusselt number, pressure coefficient, etc. are discussed through the graphical illustrations and contour plots. The various dimensions of the ribs are varied to find the optimum geometrical configuration of the detached ribs.

Simultaneous alleviating oxidative stress and scavenging uric acid via Janus polyethersulfone hemodialysis membrane loaded with urate oxidase-like nanoenzyme

The decline of renal function for the patients with end-stage kidney disease (ESKD) leads to the loss of uric acid excretion, which may reduce the prognosis of patients and increase mortality. Although hemodialysis could remove most uric acid, the long-term hemodialysis patients commonly face the problems of exacerbating oxidative stress and subsequent complications such as inflammation effects. In this work, urate oxidase-like (UOD-like) nanoenzyme is added to the blood side of polyethersulfone (PES) hemodialysis membrane by a simple double-casting phase inversion method, aiming to simultaneously achieve antioxidation and scavenge uric acid. The results demonstrate that the Janus PES/UOD membrane exhibits the ability to scavenge RNS (ABTS+, 59.75 %) and ROS (H2O2, 97.76 %; OH, 74.45 %), while efficiently clears 54.62% uric acid. In addition, the membrane has good blood compatibility and does not cause hemolysis, complement activation, or coagulation. Furthermore, the membrane exhibits the water flux of 56.83 mL/m2·h·mmHg, the urea clearance ratio of 95.33 %, and the BSA retention ratio of 99 %. Overall, we develop a promising hemodialysis membrane with antioxidant, and it opens a new route to fabricate multifunctional hemodialysis membranes.

Kidney Outcomes and Trajectories of Tubular Injury and Function in Critically Ill Patients With and Without COVID-19.

COVID-19 may injure the kidney tubules via activation of inflammatory host responses and/or direct viral infiltration. Most studies of kidney injury in COVID-19 lacked contemporaneous controls or measured kidney biomarkers at a single time point. To better understand mechanisms of acute kidney injury in COVID-19, we compared kidney outcomes and trajectories of tubular injury, viability, and function in prospectively enrolled critically ill adults with and without COVID-19. The COVID-19 Host Response and Outcomes study prospectively enrolled patients admitted to ICUs in Washington State with symptoms of lower respiratory tract infection, determining COVID-19 status by nucleic acid amplification on arrival. We evaluated major adverse kidney events (MAKE) defined as a doubling of serum creatinine, kidney replacement therapy, or death, in 330 patients after inverse probability weighting. In the 181 patients with available biosamples, we determined trajectories of urine kidney injury molecule-1 (KIM-1) and epithelial growth factor (EGF), and urine:plasma ratios of endogenous markers of tubular secretory clearance. At ICU admission, the mean age was 55 ± 16 years; 45% required mechanical ventilation; and the mean serum creatinine concentration was 1.1 mg/dL. COVID-19 was associated with a 70% greater occurrence of MAKE (relative risk 1.70; 95% CI, 1.05-2.74) and a 741% greater occurrence of KRT (relative risk 7.41; 95% CI, 1.69-32.41). The biomarker cohort had a median of three follow-up measurements. Urine EGF, secretory clearance ratios, and estimated glomerular filtration rate (eGFR) increased over time in the COVID-19 negative group but remained unchanged in the COVID-19 positive group. In contrast, urine KIM-1 concentrations did not significantly change over the course of the study in either group. Among critically ill adults, COVID-19 is associated with a more protracted course of proximal tubular dysfunction and reduced eGFR despite similar degrees of kidney injury.

Four-dimensional impedance manometry volume metrics for predicting abnormal bolus retention.

The objective measurement for esophageal bolus volume and bolus clearance could classify abnormal high-resolution manometry (HRM) beyond the current Chicago classification. We aimed to compare the novel four-dimensional impedance manometry (4D HRM) volume metrics with timed barium esophagram (TBE). Adults with esophageal symptoms undergoing HRM and TBE were included. A custom-built program for 4D HRM analysis measured esophageal luminal cross-sectional area (CSA) from impedance and subsequently derived esophageal bolus volume and clearance. 4D HRM volume metrics included pre-swallow residual volume, maximal volume, retention volume, and clearance ratio defined as 1.0-retention volume divided by the maximal volume. An abnormal TBE was defined as a column height >5 cm at 1 min or 5 min. A total of 95 patients (normal motility: 33%; ineffective esophageal motility: 12%; absent contractility: 10%; esophagogastric junction outflow obstruction: 30%; type I achalasia: 5%; type II achalasia: 12%) were categorized into normal TBE (58%), abnormal TBE at 1 min (17%), and abnormal TBE at 5 min (25%). The AUROC demonstrated that, among all 4D HRM volume metrics, the clearance ratio had the best performance in predicting abnormal TBE at 5 min (AUROC, 95% confidence interval: 0.89, 0.82-0.96), and exhibited a strong negative correlation with TBE at 5 min (r = -0.65; p < 0.001). Novel 4D HRM volume metrics provide objective measurement of esophageal bolus volume and bolus clearance. The clearance ratio has a strong correlation with TBE and could potentially serve as a substitute for TBE to measure esophageal retention.

Using the Dynamic Well-Stirred Model to Extrapolate Hepatic Clearance of Organic Anion-Transporting Polypeptide Transporter Substrates without Assuming Albumin-Mediated Hepatic Drug Uptake.

Extrapolating in vivo hepatic clearance from in vitro uptake data is a known challenge, especially for organic anion-transporting polypeptide transporter (OATP) substrates, and the well-stirred model (WSM) commonly yields systematic underpredictions for those anionic drugs, hypothetically due to "albumin-mediated hepatic drug uptake". In the present study, we demonstrate that the WSM incorporating the dynamic free fraction (f D), a measure of drug protein binding affinity, performs reasonably well in predicting hepatic clearance of OATP substrates. For a selection of anionic drugs, including atorvastatin, fluvastatin, pravastatin, rosuvastatin, pitavastatin, cerivastatin, and repaglinide, this dynamic well-stirred model (dWSM) correctly predicts hepatic plasma clearance within 2-fold error for six out of seven OATP substrates examined. The geometric mean of clearance ratios between the predicted and the observed values falls in the range of 1.21-1.38. As expected, the WSM with unbound fraction (f u) systematically underpredicts hepatic clearance with greater than 2-fold error for five out of seven drugs, and the geometric mean of clearance ratios between the predicted and the observed values is in the range of 0.20-0.29. The results suggest that, despite its simplicity, the dWSM operates well for transporter-mediated uptake clearance, and that clearance under-prediction of OATP substrates may not necessarily be associated with the chemical class of the anionic drugs, nor is it a result of albumin-mediated hepatic drug uptake as currently hypothesized. Instead, the superior prediction power of the dWSM confirms the utility of the dynamic free fraction in clearance prediction and the importance of drug plasma binding kinetics in hepatic uptake clearance. SIGNIFICANCE STATEMENT: The traditional well-stirred model (WSM) consistently underpredicts organin anion-transporting polypeptide transporter (OATP)-mediated hepatic uptake clearance, hypothetically due to the albumin-mediated hepatic drug uptake. In this manuscript, we apply the dynamic WSM to extrapolate hepatic clearance of the OATP substrates, and our results show significant improvements in clearance prediction without assuming albumin-mediated hepatic drug uptake.

Management Changes After Echocardiography Are Associated With Improved Outcomes in Critically Ill Children.

To evaluate management changes and outcomes in critically ill children after formal echocardiography. Retrospective cohort study between January 1, 2011, and December 31, 2020. Tertiary care children's hospital. Patients from 1 to 18 years who had formal echocardiography within 72 hours of ICU admission and who were intubated and on vasoactive infusions at the time of the study. Patients were stratified into two cardiac function groups: 1) near-normal cardiac function and 2) depressed cardiac function. Clinical variables were abstracted from the electronic medical record and placed in time sequence relative to echocardiography. Vasoactive and fluid management strategies in place before echocardiography were associated with markers of tissue perfusion and volume overload. Management changes after echocardiography were characterized and associated with outcomes. None. Among patients eventually found to have depressed cardiac function, the use of vasoconstrictors was associated with worse lactate clearance and oxygen extraction ratio. Use of vasoconstrictors in this cohort was also associated with a more liberal fluid management strategy, evidence of increased lung water, and a worse Sp o2 /F io2 . An echocardiogram demonstrated depressed cardiac function was likely to be followed by management changes that favored inotropes and more conservative fluid administration. Patients with depressed cardiac function who were switched to inotropes were more likely to be extubated and to wean off vasoactive support compared with those patients who remained on vasoconstrictors. Among patients with depressed cardiac function, alterations in management strategy after echocardiography are associated with shortened duration of intensive care interventions.

Hemocompatible polyethylenimine-grafted poly (glycidyl methacrylate) based microspheres for effective endotoxin removal

Endotoxin (also known as lipopolysaccharide, LPS), the major component in the outer cell wall of Gram-negative bacteria, is considered to be a main cause of sepsis. To reduce the mortality of sepsis, adsorbents with positively charged surfaces like polyethylenimine (PEI) are commonly employed to adsorb endotoxins; however, there are hidden dangers in binding stability and hemocompatibility of PEI-grafted materials. Herein, poly (glycidyl methacrylate) microspheres prepared by electro-spraying are chosen as the substrate, the surface epoxy groups are utilized to chemically immobilize PEI molecules. Then, heparin coatings are introduced through electrostatic interaction to obtain composite microspheres as hemoperfusion adsorbent. As a result, the hemocompatibility of the microspheres is significantly improved after the introduction of the heparin coatings. Compared to the microspheres only grafting PEI, the hemolysis ratio has a huge decrease from 4.6% to 1.0%. The adsorption process of the composite microspheres is more consistent with Sips isotherm model with a theoretical maximum endotoxin adsorption capacity of 2659.1 EU/g in normal saline solution. And the microspheres exhibit high endotoxin clearance ratio of 81.3% in static plasma (C0 = 12.6 EU/mL, exceeding critical illness level). In vitro dynamic adsorption experiments also indicate that the microspheres remove 86.6% of endotoxin in septic plasma (C0 = 7.2 EU/mL, exceeding critical illness level) within 1 h. We hope that the composite microspheres could have good application potential as an efficiency endotoxin adsorbent in sepsis treatment.

Biparatopic Nanobody-Based Immunosorbent for the Highly Selective Elimination of Tumor Necrosis Factor-α.

Removing the overexpressed TNF-α by hemoperfusion positively affects clinical treatments for diseases such as autoimmune disease and sepsis. However, clearance ratios of adsorbents targeting TNF-α were limited by the extremely low concentration of TNF-α (mostly <1000 ng/L in sepsis) and hydrophobic interactions. In this work, biparatopic nanobodies (NbC21) with a high affinity of 19.9 pM, which bind to two distinct sites of TNF-α, were constructed as high-affinity ligands for the immunosorbent. The theoretical maximum adsorption capacity estimated from the Langmuir isotherm was up to 18.22 mg/g gel. The prepared immunosorbent (NbC21-sorbent) had an outstanding TNF-α clearance ratio of approximately 96% during the dynamic adsorption test, with a sorbent-to-serum ratio of 1:1000. Additionally, it demonstrated favorable hemocompatibility and a prolonged storage capability. The results indicated that the biparatopic nanobody immunosorbent exhibited significant potential for clinical applications as it met the stringent criteria for both efficacy and safety.

PURIFIED GAMBIR (UNCARIA GAMBIR (HUNTER) ROXB.) ATTENUATE RENAL FUNCTION IN ALLOXAN-INDUCED DIABETIC MALE RATS

Objective: Diabetes and its vascular complications could prevent by antioxidants. Purified gambir is the purified extract of Uncaria gambir (Hunter) Roxb, which contains more than 90% catechins and scientifically work as antioxidant. This study aimed to determine the effect of purified gambir on renal function in alloxan-induced diabetic Wistar Kyoto rats.&#x0D; Methods: Diabetic rats were induced by alloxan 125 mg/kgBW by intraperitoneal injection. Forty-five diabetic rats were divided into five groups, diabetic control group treated with vehicle, a positive control group treated with glibenclamide at dose 0.45 mg/kgBW, and treatment groups of purified gambir at doses of 2.50, 5, and 10 mg/kgBW for 14 d. Blood glucose, water intake, urine volume, creatinine clearance, renal ratio, and urine density were measured on day 3, 7, and 14. All data were analyzed by two-way ANOVA followed by Duncan Multiple Range Test.&#x0D; Results: Purified gambir significantly lower blood glucose (p&lt;0.05) and had a significant effect (p&lt;0.05) on renal function parameters in diabetic rats. Duration of treatment purified gambir in diabetic rats had a significant effect (p&lt;0.05) on water intake, urine volume, creatinine clearance and renal ratio.&#x0D; Conclusion: This result show that purified gambir at dose 2.5 mg/kgBW increased the renal function of diabetic rats, in contrast, purified gambir at dose 5 and 10 mg/kgBW attenuate renal function of diabetic rats