A Quantitative Prediction Method for the Human Pharmacokinetics of Fc-Fusion Proteins.

BACKGROUND AND OBJECTIVE: Fc fusion is an effective strategy for extending the half-lives of therapeutic proteins. This study aimed to evaluate the applicability of a human pharmacokinetics prediction method for Fc-fusion proteins by extending on reported methods for monoclonal antibodies (mAbs). METHODS: To predict human pharmacokinetic profiles following intravenous (IV) dosing, the pharmacokinetic data for 11 Fc-fusion proteins in monkeys were analysed by two approaches: a species-invariant time method with a range of allometric exponents in clearance (CL, 0.7-1.0) and a two-compartment model reported for mAbs. The pharmacokinetic profiles following subcutaneous (SC) dosing were predicted by simple dose normalisation from monkeys or using the geometric means of the absorption rate constant (Ka) and bioavailability (BA) for mAbs or Fc-fusion proteins in humans and compared. RESULTS: In the case of IV administration, the area under the curve could be predicted for more than 85% of Fc-fusion proteins within a twofold difference from the observed value using the species-invariant time method (scaling exponent for CL, 0.95). For SC dosing, incorporating the geometric means of absorption parameters for both mAbs (BA 68.2%, Ka 0.287 day-1) and Fc-fusion proteins (BA 63.0%, Ka 0.209 day-1) in humans provided better accuracy than simple normalisation from monkeys. CONCLUSION: We have successfully predicted the human pharmacokinetic profiles of Fc-fusion proteins for both IV and SC administration within twofold of the observed value from monkey pharmacokinetic data by extending on reported methods for mAbs. This method will facilitate drug discovery and development of Fc-fusion proteins.

Prognostic Nutritional Index (PNI) as a Potential Prognostic Tool for Exacerbation of COPD in Elderly Patients.

Purpose: In COPD, exacerbation of the disorder causes a deterioration in the quality-of-life and worsens respiratory dysfunction, leading to a poor prognosis. In recent years, nutritional indices have been reported as significant prognostic factors in various chronic diseases. However, the relationship between nutritional indicators and prognosis in elderly subjects with COPD has not been investigated. Patients and methods: We enrolled 91 subjects who received COPD assessment tests (CAT), spirometry, blood tests, and multidetector computed tomography (MDCT). We divided the subjects into two groups according to age (<75 years (n=57) and ≥ 75 years (n=34)). The prognostic nutritional index (PNI) was used to assess immune-nutritional status and was calculated as 10 x serum albumin + 0.005 x total lymphocyte count. We then examined the relationship between PNI and clinical parameters, including exacerbation events. Results: There was no significant correlation between the PNI and CAT, the FEV1%pred, or low attenuation volume percentage (LAV%). In the elderly group, there were significant differences between the groups with or without exacerbation in the CAT and PNI (p=0.008, p=0.004, respectively). FEV1%pred, neutrophil-to-lymphocyte ratio (NLR) and LAV% did not differ between the two groups. The analytical model combining CAT and PNI improved the prediction of exacerbations in the elderly subjects (p=0.0068). Conclusion: In elderly subjects with COPD, CAT were associated significantly with the risk of COPD exacerbation, with PNI also a potential predictor. The combined assessment of CAT and PNI may be a useful prognostic tool in subjects with COPD.

Training cessation and subsequent retraining of a world-class female Olympic sailor after Tokyo 2020: A case study.

Olympic sailing is a complex sport where sailors are required to predict and interpret weather conditions while facing high physical and physiological demands. While it is essential for sailors to develop physical and physiological capabilities toward major competition, monitoring training status following the competition is equally important to minimize the magnitude of detraining and facilitate retraining. Despite its long history in the modern Olympics, reports on world-class sailors' training status and performance characteristics across different periodization phases are currently lacking. This case study aimed to determine the influence of training cessation and subsequent retraining on performance parameters in a world-class female sailor. A 31-year old female sailor, seventh in the Women's Sailing 470 medal race in Tokyo 2020, completely stopped training for 4 weeks following the Olympics, and resumed low-intensity training for 3 weeks. Over these 7 weeks, 12.7 and 5.3% reductions were observed in 6 s peak cycling power output and jump height, respectively, with a 4.7% decrease in maximal aerobic power output. Seven weeks of training cessation-retraining period induced clear reductions in explosive power production capacities but less prominent decreases in aerobic capacity. The current findings are likely attributed to the sailor's training characteristics during the retraining period.

The Mediating Role of Sense of Coherence and Striving for Work-Life Balance on Intention to Leave From Nurses' Burnout.

High turnover and understaffing are significant issues plaguing the healthcare system. Some of the leading reasons of turnover include child-bearing and -rearing, stress related to working, and health concerns. With the onset of the coronavirus (COVID-19) pandemic, this problem of turnover worsened due to increased risk of infection and escalating workload. This study aimed to clarify and validate the effect of burnout on intention to leave among full-time nursing professionals and the structural relationship with sense of coherence (SOC) and striving for work-life balance (S-WLB). Secondary analyses of data obtained from a previous study was carried out; a hypothesized model was tested for goodness of fit and a final model was developed. Burnout directly affected intention to leave (P < .001). It also affected intention to leave through SOC and S-WLB (P < .01); SOC lessened the effect of burnout on S-WLB, therefore reducing its impact on intention to leave. Effective strategies need to be developed to improve the SOC and WLB of nurses to alleviate the effects of burnout and thus reduce the likelihood of turnover. Improving their ability to grasp and deal with emergencies and ambiguous situations, as well as providing emotional and tangible support can be other ways to retain nursing professionals.

Dynamic Quantitative Magnetic Resonance Imaging Assessment of Areas of the Lung During Free-Breathing of Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE AND OBJECTIVES: Changes in the geometry of the chest wall due to lung hyperinflation occur in COPD. However, the quantitative assessment of impaired lung motions and its association with the clinical characteristics of COPD patients are unclear. This study aimed to investigate the respiratory kinetics of COPD patients by dynamic MRI. MATERIALS AND METHODS: This study enrolled 22 COPD patients and 10 normal participants who underwent dynamic MRI and pulmonary function testing (PFT). Changes in the areas of the lung and mediastinum during respiration were compared between the COPD patients and the normal controls. Relationships between MRI, CT parameters, and clinical measures that included PFT results also were evaluated. RESULTS: Asynchronous movements and decreased diaphragmatic motion were found in COPD patients. COPD patients had a larger ratio of MRI-measured lung areas at expiration to inspiration, a smaller magnitude of the peak area change ratio, and a smaller mediastinal-thoracic area ratio than the normal participants. The lung area ratio was associated with FEV1/FVC, predicted RV%, and CT lung volume/predicted total lung capacity (pTLC). The lung area ratio of the right lower and left lower lungs was significantly correlated with emphysema of each lower lobe. The expiratory mediastinal-thoracic area ratio was associated with FEV1% predicted and RV/TLC. CONCLUSION: Changes in the lung areas of COPD patients as shown on MRI reflected the severity of airflow limitation, hyperinflation, and the extent of emphysema. Dynamic MRI provides essential information about respiratory kinetics in COPD.

Influence of Striving for Work-Life Balance and Sense of Coherence on Intention to Leave Among Nurses: A 6-Month Prospective Survey.

The increase in the elderly population in need of healthcare services has led to a serious shortage in the nursing workforce. To retain a large nursing workforce, a strong work-life balance among nurses is needed along with a healthy work environment. This prospective study investigates the influence of work-life balance and sense of coherence on intention to leave among hospital nurses. A questionnaire survey was conducted with 2239 nurses as a baseline. The explanatory variables included striving for work-life balance behavior, a sense of coherence in terms of personal resources, and work-, organizational-, and individual-related factors. Using a cohort of 1368 valid responses, we measured intention to leave among 975 nurses with whom we were able to follow up 6 months after the baseline survey. We then performed multiple regression analysis. The behavior striving for work-life balance was shown to influence nurses' intention to leave. Nurses who exhibited less striving for work-life balance behavior showed higher intentions to leave. The sense of coherence was not identified as a factor affecting intention to leave. Securing a comfortable work-life balance would reduce the nurses' desire to quit the hospital. To reduce nurse turnover, nurse managers should develop support programs that can help nurses achieve a better work-life balance.

A causal model on assertiveness, stress coping, and workplace environment: Factors affecting novice nurses' burnout.

AIM: This study aimed to develop and test a causal model focused on assertiveness, stress coping, and workplace environment as factors affecting burnout among novice nurses. DESIGN: Cross-sectional study was conducted with novice nurses of 17 hospitals. METHODS: The Novice Nurse Assertiveness Scale and the Japanese version of Maslach Burnout Inventory. RESULTS: Data from 645 female novice nurses were analysed. The mean age, Novice Nurse Assertiveness Scale and Maslach Burnout Inventory were 22.6 ± 3.0, 67.4 ± 10.3 and 13.7 ± 2.5. For the final model, the study adopted a model that includes indirect influences; inappropriate assertiveness and inappropriate coping affected the dissatisfaction with the job and then affected the burnout. The goodness of fit index was GFI = 0.94, AGFI = 0.91, RMSEA = 0.66, and R2 was .86. The findings validated this as a causal model of assertiveness, stress coping, and the work environment as factors affecting burnout for novice nurses.

PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung.

Excessive release of neutrophil extracellular traps (NETs) has been implicated in several organ fibrosis, including pulmonary fibrosis. NETs constitute a phenomenon in which decorated nuclear chromatin with cytosolic proteins is released into the extracellular space. PAD4 (peptidylarginine deiminase 4) plays an important role in the formation of NETs. However, the role of NETs in the pathogenesis of pulmonary fibrosis remains undefined. Here, we identified NETs in the alveolar and interstitial lung space of mice undergoing bleomycin (BLM)-induced lung fibrosis, which was suppressed by a pan-PAD inhibitor, Cl-amidine. In vitro, BLM directly induced NETs in blood neutrophils, which was also inhibited by Cl-amidine. Furthermore, Padi4 gene knockout (PAD4-KO) in mice led to the alleviation of BLM-induced NETs and pulmonary fibrosis and to the expression of inflammatory and fibrotic genes. PAD4 deficiency prevented decreases in alveolar epithelial and pulmonary vascular endothelial cell numbers and increases in ACTA2-positive mesenchymal cells and S100A4-positive fibroblasts in the lung. Hematopoietic cell grafts from PAD4-KO mice, not wild-type mice, resolved BLM-induced lung fibrosis and fibrotic gene expression in wild-type and PAD4-KO mice, suggesting that expression of PAD4 in hematopoietic cells may be involved in the development of lung fibrosis. These data suggest that PAD4 deficiency could ameliorate BLM-induced formation of NETs and lung fibrosis, suggesting that this pathway could serve as a therapeutic target for pulmonary fibrosis treatment.

Characteristics of Japanese elderly patients with pulmonary arterial hypertension.

Previous nationwide Japanese data suggested that pulmonary arterial hypertension (PAH) predominantly affects young women. However, the number of elderly patients diagnosed with PAH has been increasing in western countries. There have been no reports on elderly PAH patients in Asian countries. This study aimed to investigate the clinical characteristics of elderly PAH patients in a Japanese cohort. Idiopathic/heritable PAH (I/H-PAH) was included in the national research project on intractable diseases. The patients were required to submit a clinical research form completed by their attending physicians. We analyzed the characteristics of Japanese I/H-PAH using the newly registered forms in 2013 (Study 1, n = 148). Also, we did a retrospective, observational cohort study at Chiba University Hospital (Study 2, n = 42). We compared the characteristics of elderly PAH patients (≥65 years old) with younger patients (<65) in both studies. Study 1 revealed a predominance of males (51% male), better hemodynamics and poorer exercise capacity in the elderly group (n = 72), compared with the younger group (n = 76) in study 1. In Study 2, elderly patients showed a male predominance (63% male), a higher ratio of smokers, a lower % carbon monoxide diffusing capacity, and poorer exercise tolerance. Elderly patients in Study 2 showed less improvement in hemodynamics with therapy. There was no significant difference in disease-specific survival between elderly and younger patients. Japanese elderly patients with I/H-PAH showed poorer exercise capacity and impaired gas exchange, but better pulmonary hemodynamics than younger patients.

S100A12 inhibits fibroblast migration via the receptor for advanced glycation end products and p38 MAPK signaling.

The migration of lung fibroblasts plays a pivotal role in wound repair and fibrotic processes in the lung. Although the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of lung diseases, its role in lung fibroblast migration is unclear. The current study examined the effect of three different RAGE ligands, namely, high mobility group box 1 (HMGB1), S100A12, and N-epsilon-(carboxymethyl) lysine (CML), on human fibronectin-directed human fetal lung fibroblast (HFL-1) migration. HMGB1 augmented, whereas S100A12 inhibited, HFL-1 migration in a concentration-dependent manner. CML did not affect HFL-1 migration. The effect of HMGB1 was not through RAGE. However, the effect of S100A12 was mediated by RAGE, but not Toll-like receptor 4. S100A12 did not exert a chemoattractant effect, but inhibited HFL-1 chemotaxis and/or chemokinesis. Moreover, S100A12 mediated HFL-1 migration through p38 mitogen-activated protein kinase (MAPK) but not through nuclear factor-kappa B, protein kinase A, phosphatase and tensin homolog deleted on chromosome 10, or cyclooxygenase. In addition, western blot analysis showed that S100A12 augmented p38 MAPK activity in the presence of human fibronectin. In conclusion, S100A12 inhibits lung fibroblast migration via RAGE-p38 MAPK signaling. This pathway could represent a therapeutic target for pulmonary conditions characterized by abnormal tissue repair and remodeling.

Mucosa-associated lymphoid tissue lymphoma with metachronous involvement of the palpebral conjunctiva and bronchus: A case report.

A 61-year-old woman with a history of palpebral conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma, treated with rituximab, was referred to the authors' hospital after follow-up positron emission tomography/computed tomography revealed 18F-fluoro-2-deoxy-d-glucose uptake in a tumor located in the left main bronchus. The diagnosis of MALT lymphoma was made by pathological and immunohistochemical findings homologous to previous palpebral conjunctival lesion via bronchoscopic biopsy. The disease was controlled with rituximab, cyclophosphamide, oncovin, and prednisolone (i.e., R-COP) chemotherapy. Although MALT lymphoma occurs in several organs, metachronous occurrence in the palpebral conjunctiva and bronchus is especially rare, and careful check-up is required to monitor for occurrence of systemic relapse.

Validity and reliability of the Japanese version of the Rathus assertiveness schedule in day psychiatric care users with schizophrenia.

Objective: This study aimed to investigate the validity and reliability of the Japanese version of the Rathus assertiveness schedule (J-RAS) in psychiatric day care users with schizophrenia. Subjects and Methods: We examined 715 psychiatric day care users with schizophrenia by conducting the test twice between September 2007 and February 2008 using a questionnaire-based survey. We examined construct validity and used the internal reliability test, split-half method, and test-retest method to examine reliability. The questionnaires were distributed and collected by post via the director of each facility. Results: Of the 1272 psychiatric day care users, 715 users (56.2%) were enrolled in the study. Seven factors were extracted for construct validity. The cumulative contribution rate of these factors was 49.4% and the internal consistency of 30 items of the J-RAS was α = 0.72. The split-half method revealed a significant correlation between the total scores of the odd- and even-numbered items (r = 0.64, p < 0.01). The test-retest method revealed a significant difference between the total scores of the first and second tests of the 30 items of the J-RAS (r = 0.73, P < 0.01). Conclusion: We confirmed the validity and reliability of the J-RAS in psychiatric day care users with schizophrenia and demonstrated its efficacy in evaluating psychiatric day care users.

Proposed selection strategy of surrogate matrix to quantify endogenous substances by Japan Bioanalysis Forum DG2015-15.

It is important to select an appropriate surrogate matrix for preparing calibration standards and quality control samples while quantitatively assaying for endogenous substances, because a blank matrix that does not contain the endogenous substance cannot be derived from the species from which the target study samples are collected. This is because the assay results might be affected, depending on the characteristics of the analyte in the surrogate matrix. Our discussion group that participated in the Japan Bioanalysis Forum discussed the recommended selection strategies, focusing on large and small molecules in ligand binding assays and LC-MS, respectively. We established an efficient selection strategy for a surrogate matrix, with simple compositions as the first candidates stated in this article.

Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain-Fused Anticalin Protein.

Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the risk of cardiovascular events in a clinical context, PCSK9 inhibition is thought to be an attractive therapy for dyslipidemia. In the present study, we created a novel small biologic alternative to PCSK9 antibodies called DS-9001a, comprising an albumin binding domain fused to an artificial lipocalin mutein (ABD-fused Anticalin protein), which can be produced by a microbial production system. DS-9001a strongly interfered with PCSK9 binding to low-density-lipoprotein receptor (LDL-R) and PCSK9-mediated degradation of LDL-R. In cynomolgus monkeys, single DS-9001a administration significantly reduced the serum LDL-C level up to 21 days (62.4% reduction at the maximum). Moreover, DS-9001a reduced plasma non-high-density-lipoprotein cholesterol and oxidized LDL levels, and their further reductions were observed when atorvastatin and DS-9001a were administered in combination in human cholesteryl ester transfer protein/ApoB double transgenic mice. Additionally, their reductions on the combination of atorvastatin and DS-9001a were more pronounced than those on the combination of atorvastatin and anacetrapib. Besides its favorable pharmacologic profile, DS-9001a has a lower molecular weight (about 22 kDa), yielding a high stoichiometric drug concentration that might result in a smaller administration volume than that in existing antibody therapy. Since bacterial production systems are viewed as more suited to mass production at low cost, DS-9001a may provide a new therapeutic option to treat patients with dyslipidemia. In addition, considering the growing demand for antibody-like drugs, ABD-fused Anticalin proteins could represent a promising new class of small biologic molecules.

Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics.

BACKGROUND AND OBJECTIVE: Human in vitro and dog in vitro/in vivo researches indicate that the drug-drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to evaluate the utility of this animal model and the clinical relevance of the DDI mechanism. METHODS: VPA and VPA-G concentrations in plasma, urinary excretion of VPA-G and APEH activity in humanized livers were measured after co-administration of VPA with meropenem (MEPM) to chimeric mice. RESULTS: After co-administration with MEPM to the chimeric mice, plasma VPA concentration more rapidly decreased than without the co-administration. An increase in plasma AUC and urinary excretion of VPA-G was also observed. APEH activity in humanized livers was strongly inhibited even at 24 h after co-administration of MEPM to the chimeric mice. CONCLUSION: The DDI of VPA with carbapenems was successfully observed in chimeric mice with humanized livers. The DDI was caused by long-lasting inhibition of hepatic APEH-mediated VPA-G hydrolysis by carbapenems, which strongly supports the APEH-mediated mechanism of the clinical DDI. This is the first example showing the usefulness of chimeric mice with humanized livers for evaluation of a DDI via non-cytochrome P450 enzyme.

Pharmacokinetics, distribution, and disposition of esaxerenone, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist, in rats and monkeys.

1. Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys. 2. Following intravenous dosing of esaxerenone at 0.1-3 mg/kg, the total body clearance and the volume of distribution were 3.53-6.69 mL/min/kg and 1.47-2.49 L/kg, respectively, in rats, and 2.79-3.69 mL/min/kg and 1.34-1.54 L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0-127% in rats and 63.7-73.8% in monkeys. 3. After oral administration of [14C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [14C]esaxerenone the main excretion route of the radioactivity was feces. 4. Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.

Factors related to the burnout of Japanese female nurses with children under 3 years old.

AIM: Burnout is a common feature among healthcare professionals; however, little systematic research exists on burnout among nurses who are raising children. The burnout-related factors among female nurses with children under the age of 3 years were identified in order to ascertain potential burnout prevention methods. METHODS: In total, 1681 nurses with children who worked at nine city hospitals in Kanagawa Prefecture, Japan, were sent the Maslach Burnout Inventory-Human Services Survey; 1173 nurses responded in June 2014. They were divided according to their sex and children's ages. A data analysis was undertaken for those female nurses with children who were aged under 3 years who provided valid responses (n = 158). RESULTS: A number of factors related to burnout in female nurses with children aged under 3 years was found via a multiple regression analysis: irritation at being unable to attend to their own affairs, over 4-6 h of overtime work per week, having a child aged under 3 years as the first or second child, little sense of work fulfillment, using a childcare facility outside the workplace, dissatisfaction with their salary, feeling ill-qualified as a parent, and a sense of inadequate support. CONCLUSIONS: Child care occurs during a limited period and appropriate support is needed. A workplace environment with no overtime work, a childcare facility in the workplace, and mental health support to reduce "feelings of irritation" and "feeling ill-qualified as a parent" could help to prevent burnout in female nurses with toddlers and infants.

In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs.

1. Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug-drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs. 2. More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were observed after co-administration with MEPM compared with those after without co-administration, whereas the plasma level and bile excretion of VPA-G showed no change. 3. Dog VPA-G hydrolase activity, inhibited by carbapenems, was mainly located in cytosol from both the liver and kidney. APEH-immunodepleted cytosols lacked VPA-G hydrolase activity. Hepatic and renal APEH activity was negligible even at 24 h after dosing of MEPM to a dog. 4. In conclusion, DDI of VPA with carbapenems in dogs is caused by long-lasting inhibition of APEH-mediated VPA-G hydrolysis by carbapenems, which could explain the delayed recovery of plasma VPA levels to the therapeutic window even after discontinuation of carbapenems in humans.