Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis.

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc values were <10 ms at the simulated maximum concentration (Cmax) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

Prediction of Human Pharmacokinetic Profiles of the Antituberculosis Drug Delamanid from Nonclinical Data: Potential Therapeutic Value against Extrapulmonary Tuberculosis.

Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration-time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [Css-MRT] and physiologically based pharmacokinetic [PBPK] modeling). In Css-MRT, allometric scaling predicted the distribution volume at steady state based on data from mice, rats, and dogs. Total clearance was predicted by in vitro-in vivo extrapolation using a scaled albumin amount. A simulated human pharmacokinetic profile using a combination of human-predicted Css and MRT was almost identical to the observed profile after single oral administration, which suggests that the pharmacokinetic profile of delamanid could be predicted by allometric scaling from these animals and metabolic capacity in vitro. The PBPK model was constructed on the assumption that delamanid was metabolized by albumin in circulating plasma and tissues, to which the simulated pharmacokinetic profile was consistent. Moreover, the PBPK modeling approach demonstrated that the simulated concentrations of delamanid at steady state in the lung, brain, liver, and heart were higher than the in vivo effective concentration for Mycobacterium tuberculosis. These results indicate that delamanid may achieve similar concentrations in various organs to that of the lung and may have the potential to treat extrapulmonary tuberculosis.

Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0-24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0-24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0-24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0-24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia's formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

Factors associated with functional rehabilitation outcomes of non-operative treatment for hip fractures: a retrospective study.

[Purpose] Limited data are available regarding the outcomes of non-operative treatment for hip fractures. We investigated the factors associated with functional rehabilitation outcomes in patients undergoing non-operative treatment for hip fractures. [Participants and Methods] We investigated 57 patients with hip fractures who underwent non-operative treatment. We retrospectively analyzed medical or rehabilitation outcomes and functional outcomes (assessed using the Functional Independence Measure tool). We examined the association between functional outcomes and other factors and compared the medical and rehabilitation outcomes between mobile and immobile patients at the time of discharge. [Results] Of the 57 patients investigated, 15 (26.3%) were mobile at discharge. We observed a significant association between the Functional Independence Measure subscores (Motor and Cognitive) and serum albumin levels. Serum albumin levels and the Functional Independence Measure subscores (Motor and Cognitive) were significantly higher in mobile than in immobile patients. [Conclusion] We observed that functional outcomes at discharge in patients undergoing non-operative treatment for hip fractures were associated with serum albumin ratios and the Functional Independence Measure-Cognitive score.

Polydimethylsiloxane-coated partitioning sample collection device for the precise quantification of polycyclic aromatic hydrocarbons in air.

A novel partitioning collection device comprising a glass cartridge packed with poly(dimethylsiloxane)-coated macroporous silica particles was developed for the precise quantification of polycyclic aromatic hydrocarbons in air. The analyte collection and elution performances achieved using different amounts of poly(dimethylsiloxane) coating were quantitatively evaluated. The sample retention power increased with increasing the coating, and more than 250 L of air could be collected without analyte breakthrough at a sampling temperature of 35°C. During the air collection, the moisture in the air was not retained on the particles due to the hydrophobic surface of the sorbent. A complete and rapid elution of the collected analytes from the device was accomplished by the passage of only 10 mL of acetone with ultrasonication for 1 min. The proposed method was successfully applied for the determination of airborne polycyclic aromatic hydrocarbons in tunnel air.

Partitioning sample collection/solvent extraction cartridge packed with octadecyl-derivatized macroporous silica particles for the analysis of sesquiterpenes in air samples.

A novel sampling device based on the partition of target analytes to the extraction medium was developed for the determination of sesquiterpenes in air samples. The extraction medium was prepared by the chemical derivatization of a specially prepared macroporous silica, with a specific surface area of 2.0 m2 /g. Taking advantage of the sample extraction, which was mainly based on the partition of sesquiterpenes between air and a C18 -bonded phase, the extracted analytes were rapidly and quantitatively desorbed just by passing a small amount of desorption solvent for subsequent analysis by gas chromatography with mass spectrometry. Several experimental conditions, such as the sampling volume and temperature, were systematically evaluated. Under optimized conditions, desorption of the extracted analytes was completed within 1 min with a desorption efficiency of more than 99.9%, achieved using 5 mL of acetone for all the evaluated sesquiterpenes. The applicability of the developed device was confirmed by the determination of several sesquiterpenes from coniferous trees. Although further improvements of the device are required for collecting large volumes or high-temperature air samples, the potential of the developed sampling device was confirmed by determining traces of semivolatile organic compounds in air samples.

Quantitative estimation of the parameters for self-motion driven by difference in surface tension.

Quantitative information on the parameters associated with self-propelled objects would enhance the potential of this research field; for example, finding a realistic way to develop a functional self-propelled object and quantitative understanding of the mechanism of self-motion. We therefore estimated five main parameters, including the driving force, of a camphor boat as a simple self-propelled object that spontaneously moves on water due to difference in surface tension. The experimental results and mathematical model indicated that the camphor boat generated a driving force of 4.2 µN, which corresponds to a difference in surface tension of 1.1 mN m(-1). The methods used in this study are not restricted to evaluate the parameters of self-motion of a camphor boat, but can be applied to other self-propelled objects driven by difference in surface tension. Thus, our investigation provides a novel method to quantitatively estimate the parameters for self-propelled objects driven by the interfacial tension difference.

Factors Associated With Ambulation Status and Survival One Year After Conservative Management of Hip Fracture.

PURPOSE: Few studies have investigated the factors associated with ambulation and survival over one year. Therefore, this study aimed to examine the factors that influence ambulation and survival rates in elderly patients who have undergone conservative management for hip fractures. MATERIALS AND METHODS: This retrospective study included 74 ambulatory individuals aged 65 years or older prior to their injuries. One-year mortality and ambulatory status were assessed. Statistical comparisons of background and medical characteristics between groups of independent and non-independent walkers, as well as between survivors and mortalities, were performed using the Pearson chi-squared, Fisher exact, and Mann-Whitney U tests. RESULTS: The numbers of older patients able to walk independently, those not able to walk independently, and those with mortality at one-year post-injury after conservative management of hip fractures were 13 (18.3%), 35 (49.3%), and 23 (32.4%), respectively. Independent walkers one year after conservative treatment for hip fracture were younger (p=0.04) and less likely to have cognitive impairment (p=0.04) than non-independent walkers. The proportion of individuals with cognitive impairment was found to be lower among survivors than among mortalities (p=0.0098). CONCLUSION: Cognitive decline may contribute to difficulties in walking independently and mortality at one year post-injury in this population.

Knockout of Brca1-interacting factor Ola1 in female mice induces tumors with estrogen suppressible centrosome amplification.

Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1+/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1+/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1+/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1+/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1.

In Situ Observation of Bubbles and the Effect of Ultrasonic Vibration on Bubble Behavior in EDM.

Accumulation and concentration of debris in deep hole electrical discharge machining (EDM) significantly hinder its machining efficiency and accuracy. It is believed that the movement of bubbles associated with the discharge gap flow field play a pivotal role in debris removal and influence the discharge conditions. Ultrasonic vibration (USV) of the electrode is thought to be an effective method for improving EDM-generated bubbles and debris exclusion. In this study, we first elucidated the behavior of bubbles during EDM of holes with varying aspect ratios. Subsequently, USV was introduced to EDM. The behavior of dielectric fluid flow under the influence of ultrasonic vibration was analyzed using computational fluid dynamics (CFD), which revealed time-varying changes in discharge gap flow pressure and velocity. The velocity of the dielectric flow field near the electrode's side face was found to reach a maximum of approximately 15.2 m/s, greatly facilitating debris removal. High-speed camera observations revealed that bubbles were dispersed within the side gap, with most of them adhering to the electrode's wall. Furthermore, the bubbles exhibited a tendency to continuously break up and coalesce near the hole's outlet before escaping in the USV-assisted EDM. These observed characteristics of bubble behavior under the influence of USV are expected to significantly enhance debris removal and promote efficient dielectric exchange.

Safety and Effectiveness of Exercise-Based Cardiac Rehabilitation for Patients With Atrial Fibrillation Following Radiofrequency Catheter Ablation Therapy: A Systematic Review and Meta-Analysis.

Despite the potential of cardiac rehabilitation (CR) to reduce atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA), its prescription is not routine. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of CR in this setting. Inclusion criteria comprised randomized controlled trials (RCTs) comparing CR with usual care in patients with AF following RFCA. We performed a comprehensive search of six databases up to August 17, 2023, and conducted a thorough risk of bias assessment. We synthesized safety outcomes using AF recurrence rates to calculate relative risks (RR). Furthermore, we conducted a meta-analysis on peak oxygen uptake (VO2 peak) and the six-minute walk test (6MWT) to gauge efficacy, utilizing mean differences (MD) for comparison. The GRADE framework was employed to determine the certainty of evidence, with two independent reviewers completing all processes. Our analysis encompassed eight studies with 772 participants aged 55-70 years engaged in moderate-intensity CR for a median of six months. Results showed no significant difference in AF recurrence after CR (RR = 0.69 (0.41-1.14)), with low evidence certainty due to heterogeneity. Subgroup analyses suggested a poor risk reduction effect in patients with obesity and persistent AF. Significant improvements were observed in VO2 peak and 6MWT outcomes (VO2 peak; MD = 2.53 (0.78-4.28), 6MWT; MD = 38.81 (0.65-76.97)), with moderate-certainty evidence. While CR may decrease AF recurrence after RFCA, its effectiveness varies, potentially diminishing in patients with obesity or persistent AF. Moderate gains in physical performance were achieved with minimal adverse events. Further RCTs are warranted to confirm these findings.

Stress Dependence on Relaxation of Deformation Induced by Laser Spot Heating.

This paper deals with a non-destructive analysis of residual stress through the visualization of deformation behaviors induced by a local spot heating. Deformation was applied to the surface of an aluminum alloy with an infrared spot laser. The heating process is non-contact, and the applied strain is reversible in the range of room temperature to approximately +10 °C. The specimen was initially pulled up to elastic tensile stress using a tensile test machine under the assumption that the material was subject to the tensile residual stress. The relaxation behaviors of the applied strain under tensile stress conditions were evaluated using contact and non-contact methods, i.e., two strain gauges (the contact method) and a two-dimensional electronic speckle pattern interferometer (non-contact method). The results are discussed based on the stress dependencies of the thermal expansion coefficient and the elasticity of the materials.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.

OBJECTIVES: In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. METHODS: Telmisartan was orally administered at MD condition (100 µg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. RESULTS: No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. CONCLUSION: The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients.

Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h)=2.85×(creatinine clearance/60.9)0.618×0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.

Herbal Medicine Containing Licorice May Be Contraindicated for a Patient with an HSD11B2 Mutation.

Licorice ingestion, as well as mutations in the HSD11B2 gene, inhibits 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and an HSD11B2 mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutant HSD11B2 genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine. Molecular analysis showed that she carried a missense mutation, c.40C>T, in HSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation in HSD11B2. Carrying a mutation in HSD11B2 is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with an HSD11B2 mutation.

New dopamine agonist pramipexole improves parkinsonism and depression in Parkinson's disease.

Previous studies have shown that pramipexole might have the potential to improve depressive symptoms in patients with Parkinson's disease. To provide more evidence, in five Japanese patients at Hoehn & Yahr stage 1-3 we evaluated the Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Montgomery Asberg Depression Rating Scale (MADRS) at our hospital. After the pramipexole treatment, each total score of UPDRS, HAMD and MADRS significantly decreased compared with that before the treatment. Our data indicate that pramipexole improves depressive symptoms in patients with Parkinson's disease.

Dynamic ESPI Evaluation of Deformation and Fracture Mechanism of 7075 Aluminum Alloy.

The deformation and fracture mechanism in 7075 aluminum alloy is discussed based on a field theoretical approach. A pair of peak-aged and overaged plate specimens are prepared under the respective precipitation conditions, and their plastic deformation behaviors are visualized with two-dimensional electronic speckle pattern interferometry (ESPI). The in-plane velocity field caused by monotonic tensile loading is monitored continuously via the contour analysis method of ESPI. In the plastic regime, the peak-aged specimen exhibits a macroscopically uniform deformation behavior, while the annealed specimen exhibits non-uniform deformation characterized by a localized shear band. The occurrence of the shear band is explained by the transition of the material's elastic resistive mechanism from the longitudinal force dominant to shear force dominant mode. The shear force is interpreted as the frictional force that drives mobile dislocations along the shear band. The dynamic behavior of the shear band is explained as representing the motion of a solitary wave. The observed decrease in the solitary wave's velocity is accounted for by the change in the acoustic impedance with the advancement of plastic deformation.

Quantification of 23 Volatile Organic Compounds with a Single Reference Material Using Post-column Reaction Gas Chromatography Combined with a Stainless-steel Heating Furnace.

We built a heating furnace using stainless-steel instead of aluminum in gas chromatography combined with an oxidation/reduction system; it increased the oxidation temperature to 650°C. At 600°C, it completely oxidized five organochlorine compounds. This system was applied to a standard solution of 23 volatile organic compounds. The analytical results of 20 hydrocarbon and organochlorine compounds showed good agreement with the expanded uncertainty (k = 2) of the reference values. Three organobromine compounds obtained values higher than the reference; this was investigated further.

Deformation Wave Theory and Application to Optical Interferometry.

A method to diagnose the deformation status of solid objects under loading is discussed. The present method is based on a recent field theory of deformation and fracture and optical interferometry known as the Electronic Speckle-Pattern Interferometry (ESPI). Using one of the most fundamental principles of physics referred to as symmetry in physics, this field theory formulates all stages of deformation and fracture on the same theoretical basis. In accordance with the formalism, the theory has defined the criteria for different stages of deformation (linear elastic, plastic and fracturing stages) expressed by certain spatiotemporal features of the differential displacement (the displacement occurring during a small time interval). The ESPI is used to visualize the differential displacement field of a specimen as two-dimensional, full-field interferometric fringe patterns. This paper reports experimental evidence that demonstrates the usefulness of the present method. A tensile load is applied to an aluminum-alloy plate specimen at a constant pulling rate and the resultant in-plane displacement field is visualized with a two-dimensional ESPI setup. The differential displacement field is obtained at each time step and the interferometric fringe patterns are interpreted based on the criterion for each stage of deformation. It has been found that the criteria of linear elastic deformation, plastic deformation and fracturing stage are clearly observed in the corresponding fringe patterns and that the observations are consistent with the loading characteristics.

Effects of exercise on kidney and physical function in patients with non-dialysis chronic kidney disease: a systematic review and meta-analysis.

Patients with non-dialysis chronic kidney disease (CKD) are at greater risk of early mortality and decreased physical function with an advance in the stage of CKD. However, the effect of exercise in these patients is unclear. This meta-analysis aimed to determine the effects of physical exercise training on the risk of mortality, kidney and physical functions, and adverse events in patients with non-dialysis CKD. The meta-analysis conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the Cochrane Handbook recommendations. On 16 August 2019, the PubMed, CINAHL, Cochrane Library databases, and Embase were electronically searched, with no restrictions for date/time, language, document type, or publication status, for eligible randomized controlled trials (RCTs) investigating the effects of exercise on mortality and kidney and physical function in patients with non-dialysis CKD. Eighteen trials (28 records), including 848 patients, were analyzed. The effects of exercise on all-cause mortality and estimated glomerular filtration rate were not significantly different from that of usual care. Exercise training improved peak/maximum oxygen consumption compared to usual care. Regular exercise improves physical and walking capacity for patients with non-dialysis CKD. Effect on leg muscle strength was unclear.