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How neural representations preserve information about multiple stimuli is mysterious. Because tuning of individual neurons is coarse (e.g., visual receptive field diameters can exceed perceptual resolution), the populations of neurons potentially responsive to each individual stimulus can overlap, raising the question of how information about each item might be segregated and preserved in the population. We recently reported evidence for a potential solution to this problem: when two stimuli were present, some neurons in the macaque visual cortical areas V1 and V4 exhibited fluctuating firing patterns, as if they responded to only one individual stimulus at a time (Jun et al., 2022). However, whether such an information encoding strategy is ubiquitous in the visual pathway and thus could constitute a general phenomenon remains unknown. Here, we provide new evidence that such fluctuating activity is also evoked by multiple stimuli in visual areas responsible for processing visual motion (middle temporal visual area, MT), and faces (middle fundus and anterolateral face patches in inferotemporal cortex – areas MF and AL), thus extending the scope of circumstances in which fluctuating activity is observed. Furthermore, consistent with our previous results in the early visual area V1, MT exhibits fluctuations between the representations of two stimuli when these form distinguishable objects but not when they fuse into one perceived object, suggesting that fluctuating activity patterns may underlie visual object formation. Taken together, these findings point toward an updated model of how the brain preserves sensory information about multiple stimuli for subsequent processing and behavioral action.

The neural mechanisms through which neurons represent simultaneously presented stimuli are not well understood. Here the authors demonstrate that the two stimuli are alternately encoded through fluctuations in the activity patterns of single neurons.

Objectives: It is recommended to adjust the dose of vancomycin (VCM) with a target area under the concentration-time curve (AUC) of 400-600 μg·h/mL. Factors that affect the deviation between AUCs are estimated from the trough value alone and the trough and peak values using practical AUC-guided therapeutic drug monitoring (PAT) for vancomycin. In this study, factors that affect AUC were evaluated., Methods: AUCs were estimated from a single trough value and trough and peak values, and the patients were classified into those who showed a 10% or greater deviation (deviation group) and those in whom the deviation was less than 10% (no-deviation group). Risk factors related to ≥ 10% deviation of AUC were identified by univariate and multivariate analysis., Results: As a result of univariate and multivariate analysis of 30 patients in the deviation group and 344 patients in the no-deviation group, a creatinine clearance (CLcr) of ≥ 110 mL/min (odds ratio (OR) = 3.697, 95% confidence interval (CI) = 1.616-8.457, p = 0.002), heart failure with a brain natriuretic peptide (BNP) of ≥ 300 pg/mL (OR = 4.854, 95%CI = 1.199-19.656, p = 0.027), and the concomitant use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (ACE-I/ARB) (OR = 2.544, 95%CI = 1.074-6.024, p = 0.034) were identified as risk factors of ≥ 10% deviation of AUC., Conclusions: Estimation of AUC by two-point blood sampling for the trough and peak values rather than one-point blood sampling for the trough value is suggested to improve the prediction accuracy in patients with enhanced renal function, severe heart failure, and patients using ACE-I/ARB., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC 24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC 24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC 24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC 24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC 24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC 24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC 24-48h ≥600 μg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC 24-48h <500 μg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI., Importance: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus . However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets., Competing Interests: K.M. received grant support funding from Meiji Seika Pharma Co., Ltd., Sumitomo Pharma Co., Ltd. and Shionogi & Co., Ltd., and speaker honoraria from Meiji Seika Pharma Co., Ltd. The other authors declare no conflicts of interest.

Introduction: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients., Methods: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUC follow-up ) and target AUC follow-up achievement was defined as an AUC of 400-600 μg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT)., Results: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUC follow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUC follow-up of 400-600 μg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m 2 or higher; the accuracy was adequate (92 %, R 2  0.52)., Conclusion: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated., Competing Interests: Declaration of competing interest KM received grant support funding from Meiji Seika Pharma Co., Ltd., Sumitomo Pharma Co., Ltd., and Shionogi & Co., Ltd., and speaker honoraria from Meiji Seika Pharma Co., Ltd. The other authors have no conflicts of interest to declare., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: The latest therapeutic drug monitoring guidelines for vancomycin (VCM) recommend that area under the concentration-time curve is estimated based on model-informed precision dosing and used to evaluate efficacy and safety. Therefore, we predicted VCM concentrations in individual methicillin-resistant Staphylococcus aureus-infected patients using existing a physiologically based pharmacokinetic (PBPK) model and 1- and 2-compartment population pharmacokinetic (PPK) models and confirmed and verified the accuracy of the PBPK model in estimating VCM concentrations with the PPK model., Methods: The subjects of the study are 20 patients, and the predicted concentrations were evaluated by comparing the observed and predicted trough and peak values of VCM concentrations for individual patients., Results: The results showed good correlation between the observed and predicted trough and peak concentrations of VCM was observed generally in the PBPK model, R 2 values of 0.72, 0.62, and 0.40 with trough values of 0.49, 0.40, and 0.34 with peak values for PBPK model, 1-compartment, and 2-compartment model, respectively., Conclusions: Although the performance of the PBPK model is not as predictive as the PPK model, generally similar predictive trends were obtained, suggesting that it may be a valuable tool for rapid and accurate prediction of AUC for VCM., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs., Methods: Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (O 2 ) requirement ≥5 L, and neutralizing antibody levels were compared in TRs with COVID-19 without/with casirivimab/imdevimab., Results: Casirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of O 2  ≥ 5 L in TRs with COVID-19 [mean: without/with: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763-0.6301; 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878-0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511-0.8980]. Casirivimab/imdevimab was associated with early defervescence after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205-0.826). The antibody levels between patients without/with casirivimab/imdevimab on the day of hospitalization were not significantly different (P = 0.1055), including 13 TRs with vaccination. Antibody levels were higher in patients with casirivimab/imdevimab at 3-5 days after hospitalization than in those without, at 7-9 days after hospitalization (P < 0.0001, mean, without/with: 414.9/40000 AU/mL)., Conclusion: Casirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Under the Japanese health insurance system, medicines undergoing therapeutic drug monitoring (TDM) can be billed for medical fees if they meet the specified requirements. In Japan, TDM of vancomycin, teicoplanin, aminoglycosides, and voriconazole, which are used for the treatment of infectious diseases, is common practice. This means the levels of antibiotics are measured in-house using chromatography or other methods. In some facilities, the blood and/or tissue concentrations of other non-TDM drugs are measured by HPLC and are applied to treatment, which is necessary for personalized medicine. This review describes personalized medicine based on the use of chromatography as a result of the current situation in Japan.

Similar to antimicrobial stewardship, the concept of antifungal stewardship (AFS) has also received attention. AFS outcomes include reduced healthcare costs, avoidance of adverse events, and increased implementation of therapeutic drug monitoring (TDM). Several processes and outcome measures have recently been reported for implementing AFS and evaluating its effectiveness in healthcare institutions. This review focuses on our AFS efforts to standardize treatment using a template for pharmacist-led patient intervention for candidemia and to evaluate TDM dosage adequacy rates for voriconazole. The importance of "task shifting", in which the physician's work is transferred or shared with pharmacists and other co-medical staff to alleviate concentration of physician workload, has also been advocated. This review focuses on how pharmacists are involved in AFS.

In Japan, there is concern regarding the relation between the inappropriate use of antibiotics and antibiotic resistance (AMR). Increased bacterial resistance is due in part to the inappropriate use of antimicrobial agents. The support of the pharmacist becomes important, and there is growing interest in antimicrobial stewardship to promote the appropriate and safe use of antimicrobials needed for the optimal selection of drugs, doses, durations of therapy, therapeutic drug monitoring (TDM), and implementations of cost containment strategies in Japan. Pharmacists should strive to disseminate the concept of "choosing wisely" in relation to all medicines, implement further interventions, and put them into practice. In this article, we present data for antimicrobial stewardship and Japan's AMR action plan, focusing on how pharmacists should be involved in enabling physicians to choose antimicrobials wisely.

Background: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy., Objective: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy., Methods: The target voriconazole trough concentration (C min ) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine C min cut-offs for AEs., Results: A total of 401 patients were included. Among 108 patients with high initial C min , voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial C min , voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial C min was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with C min at the onset of AEs, and the C min cut-offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms., Conclusions: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy., (© 2020 The Authors. Mycoses published by Blackwell Verlag GmbH.)

Somatic angiotensin-I converting enzyme (sACE) is a broadly distributed peptidase which plays a role in blood pressure and electrolyte homeostasis by the conversion of angiotensin I into angiotensin II. N-domain isoforms (nACE) with 65 and 90 kDa have been described in body fluids, tissues and mesangial cells (MC), and a 90 kDa nACE has been described only in spontaneously hypertensive rats. The aim of this study was to investigate the existence of proteolytic enzymes that may act in the hydrolysis of sACE generating nACEs in MC. After the confirmation of the presence of ACE sheddases in Immortalized MC (IMC), we purified and characterized these enzymes using fluorogenic substrates specifically designed for ACE sheddases. Purified enzyme identified as a serine protease by N-terminal sequence was able to generate nACE. In the present study, we described for the first time the presence of ACE sheddases in IMC, identified as serine proteases able to hydrolyze sACE in vitro. Further investigations are necessary to elucidate the mechanisms responsible for the expression and regulation of ACE sheddases in MC and their roles in the generation of nACEs, especially the 90 kDa form possibly related to hypertension., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Renin-angiotensin system activation is recognized to play an important role in atherosclerosis. This study aimed to verify the antiatherosclerotic effects of ACE inhibition on an experimental model of diabetes and hypercholesterolemia. Diabetes was induced in New Zealand male rabbits with a single dose of alloxan (100 mg/kg, i.v.), and, according to plasma glucose levels obtained after 1 week, the animals were divided into 2 groups (> or =250 mg/dL or <250 mg/dL). Each group was randomly assigned to receive or not quinapril (30 mg/d) added to a 0.5% cholesterol-enriched diet. Animals with high glucose levels at 1 week and that remained high after 12 weeks presented higher triglyceride levels (P < 0.02 versus basal). Those initially hyperglycemic but presenting <250 mg/dL glucose at the end of study formed an additional group. Plasma ACE activity was lower in quinapril-treated animals (P < 0.01 versus untreated groups). However, aorta intima/media ratio and intima area were lower only in the subgroups of quinapril-treated animals with low glucose levels (P < 0.05). Our results support the hypothesis that high plasma glucose may abolish the antiatherosclerotic effect of ACE inhibitors.

In the kidney, neutral endopeptidase (NEP) is implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as the atrial natriuretic peptide, bradykinin and angiotensin I. Due to its physiological importance in the modulation of pressor responses, the presence of NEP in mouse mesangial cells has been investigated, since these cells control glomerular function and are able to synthesise components of the renin-angiotensin system. A NEP-like activity (NEP-like) that cleaves the fluorogenic substrates Abz-BKQ-EDDnp and Abz-DRRL-EDDnp was purified from mesangial cell lysate by ion-exchange, followed by gel filtration chromatography. The enzyme was able to hydrolyse bradykinin at the G4-F5 peptide bond and was inhibited by thiorphan. A pH study established that enzyme activity was maximal at pH 7.5 and the determined K(m) was 4.86 M using Abz-DRRL-EDDnp as substrate. NEP-like was recognised by monoclonal anti-NEP and had a molecular mass of 95 kDa. The purified enzyme was sequenced and showed similarity with human, rat, mouse and rabbit NEPs. We isolated, for the first time, NEP-like from mesangial cells. This enzyme could have an important role in the renal physiology by its action upon different peptides that are able to alter renal haemodynamics.

This paper discusses a process for making a novel granular detergent with an interspersion particle comprising an anionic surfactant and a polymeric polycarboxalate. This process contains three steps to develop the interspersion particles with anionic surfactant and polymeric ploycarboxalate. The first step was to form a detergent particle by spray drying of an aqueous detergent slurry comprising anionic surfactant (liner alkyl benzene sulfonate) with the different levels of polymeric polycarboxalate. In the second step, the spray-dried granules were densified and ground by a roll compacter and a grinder. The ground particles were coated by nonionic and zeolite in a vertical batch type high shear mixer (third step). In this study, the feasibility to make better performance of granular detergent was discussed.