Direct involvement of community pharmacists in the sale of OTC medicines is expected to help prevent adverse drug reactions (ADRs) and enhance treatment efficacy. However, the extent of their actual involvement in OTC medicine sales remains insufficiently investigated. To address this, we retrospectively analyzed OTC medicine sales survey forms to assess the involvement of community pharmacists in OTC medicine sales, and identify drug-related problems (DRPs) requiring pharmaceutical decisions. All customers who visited the Yokohama Nishiguchi branch of WinPharma Co., Ltd. to purchase OTC medicines were included in the study. Community pharmacists were involved in all OTC medicine sales. Among the 821 customers who sought specific OTC medicines, product choice was changed based on pharmacist recommendation in 124 cases (15.1%), including cases recommended to visit a doctor. Frequency of product change was highest for second-class OTC medicine sales. In addition, contraindications (21.0%) were the most common DRPs, with second-class OTC medicines accounting for 80.8% of all these cases. Furthermore, when including the 666 cases in which community pharmacists were consulted directly about purchasing OTC medicines, 790 of the 1487 cases (53.1%) required pharmacist involvement. These findings highlight the crucial role of community pharmacists preventing ADRs and enhancing treatment efficacy based on OTC medicines characteristics and conditions and lifestyles of users regardless of the risk classification of OTC medicines. Proactive involvement by community pharmacists can improve self-medication safety and efficacy by ensuring the proper use of OTC medicines.

Since pharmacy is a discipline based on natural and life sciences, learning about pharmacy is considered useful for science students outside this field. In this survey, we investigated whether pharmacy lectures delivered to students majoring in life sciences were useful for their studies within their respective fields. A questionnaire was sent to the students enrolled in the course, asking them to evaluate, on a five-point scale, whether the lectures were helpful in deepening their learning in their field of study, both overall and for each lecture theme. Additionally, we conducted a Customer Satisfaction (CS) analysis, using the overall evaluation of the lectures as the objective variable and the evaluation of each lecture theme as the explanatory variable. The response rate was 75.0% (72/96). Overall, 98.6% of the respondents found the lectures helpful in deepening their learning in their field of study. The satisfaction rate for each lecture topic exceeded 80%. When the CS graph was created, the lecture themes categorized as “priority maintenance field” were “Pain, psychology, analgesics, psychotic drugs” and “Adverse event.” In contrast, the themes identified as “priority improvement field” were “Hypertension and the therapeutic agent” and “Drug interactions.” These findings suggest that pharmacy lectures might be useful for deepening the learning of students majoring in life sciences.

The primary aim of this study is to examine whether the appearance of pharmacists in Japan is an issue worthy of discussion. A web-based survey was conducted in June 2023 among 500 men and women aged 25–74 (male/female ratio=1 : 1, equally assigned to five age categories). The respondents were asked about their trust in eight pictures of male pharmacists with different appearance factors (trust scale: seven questions, 6-point response). The pictures were combined using an orthogonal table for five factors (hair color (black and brown), hair length (normal and long), accessories, white coat condition (clean and dirty), and clothing under white coat (Y shirt+tie, Y shirt+T-shirt)). The data were analyzed through conjoint analysis. The median age of the 500 respondents was 50.5 (38–62) years. The highest mean confidence score for each of the eight images was 28.8(SD6.4) and the lowest was 16.1 (SD7.1). Conjoint analysis indicated that the relative importance of clothing and hair to trustworthiness was 50.9% and 33.8%, respectively. The condition of the white coat was high at 29.1%. The level utilities scores were 0.341 for “Y-shirt” and −0.008 for “Y-shirt+tie” for clothing under the white coat. Notably, cleanliness of the white coat had a greater impact than hair color or length. The results indicate that the appearance of male pharmacists significantly affects initial trust. Thus, appearance standards for pharmacists, including females, should be actively discussed.

Community pharmacists play a vital role in delivering person-oriented services, such as addressing prescription inquiries, providing home care services, and conducting medication follow-ups. Despite their significance, no nationwide surveys have assessed the efficacy of these pharmaceutical activities. Therefore, this study aimed to collect information on these three pharmacist tasks and investigate their effectiveness in preventing serious adverse drug reactions and reducing medical costs. Ten percent of insurance pharmacies in each prefecture were randomly selected to participate in the survey. Data were collected on basic pharmacy information, prescription inquiries, home care services, and medication follow-up, which spanned from 12 June to 18 June 2023. Of the 561 pharmacies pre-registered for the study, valid responses were obtained from 433 pharmacies (77.2%). The reported cases included 3064 prescription inquiries, 765 home care services, and 326 medication follow-ups. Prescription inquiries prevented serious adverse drug reactions in 122 cases, home care services in 209 cases, and medication follow-ups in 13 cases. The cost reductions associated with these activities were ¥28291790, ¥58285600, and ¥2544950, respectively, resulting in a total cost reduction of ¥89122340. The annual cost reduction was ¥33229078321.7, assuming a severity rate of 6.7%. The estimated annual reduction in medical costs specifically attributed to prescription inquiries was ¥8732177830. This study indicates that pharmacists prevent adverse drug reactions and contribute to the safety of drug treatment through prescription inquiries, home care services, and medication follow-up. These tasks reduced annual medical costs by approximately ¥42 billion, highlighting the economic and healthcare benefits of community pharmacy services.

Lemborexant, an orexin receptor antagonist (ORA), was introduced as a safer sleep medication at our hospital, but its prescription rate remained low. To address this issue, promotion of ORAs began in August 2022. This study aimed to evaluate the impact of these activities on the number of patients prescribed lemborexant. And it aimed to evaluate prescription conditions non-benzodiazepine drugs (NBDs) and delirium treatment antipsychotics (DTAs). The study spanned from August 2021 to March 2024, with August 2022 serving as the intervention point. The drugs analyzed included lemborexant, zolpidem and eszopiclone (NBDs), and risperidone and quetiapine (DTAs). Analyzed using interrupted time-series analysis, and assess changes in the number of patients prescribed these medications and the number of patients with abnormal indications. The promotion of ORAs significantly increased lemborexant prescriptions [level change 18 (95% confidence interval 0.07 to 35: p=0.049), slope change 2.7 (0.57 to 4.9: p=0.015)]. Concurrently, prescriptions for NBDs decreased [level change −56 (−86 to −25: p<0.001), slope change −30 (−54 to −5.7: p=0.017)], and the slope change for DTAs with abnormal instructions also decreased [−1.2 (−2.3 to −0.11: p=0.032)]. No significant differences were found for the other items. Promoting ORAs increased its use, and led to a reduction in the prescriptions of NBDs and DTAs with abnormal indications. Although there was no change in patient conditions, given the adverse effects associated with NBDs and DTAs these changes suggest a shift toward safer drug treatment practices.

LM1010, a high-performance liquid chromatography system for therapeutic drug monitoring (TDM) of various agents in clinical practice, is currently approved in Japan. Unlike conventional systems, LM1010 can rapidly measure clinical samples, and data analysis is based on the absolute calibration curve method and fully automated. However, the analytical performance of the LM1010 for the measurement of serum concentrations of linezolid (LZD) has not yet been evaluated. In this study, we aimed to evaluate the analytical performance of LM1010 and confirm the long-term stability of LZD at −30°C. One hundred forty-eight serum samples were collected from 25 patients (17 men and 8 women) who received LZD. Serum concentrations of LZD were measured using LM1010 and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three LM1010 instruments were used to confirm the differences in the measured values. A Passing–Bablok regression analysis demonstrated a strong correlation between LM1010 and LC-MS/MS (r=0.991), and comparable results were observed among the three LM1010 instruments (r=0.982–0.998). Bland–Altman analyses revealed that the average difference between LM1010 and LC-MS/MS methods was 1.7%, and similar results were observed among the three LM1010 instruments. The long-term stability of serum LZD in samples stored at −30°C for 48 weeks was also confirmed. These results suggest that LM1010 can be used for TDM of LZD in clinical practice.

Durotep^®MT Patch (DMTP) (Janssen Pharmaceutical K.K., Tokyo) is a systemically acting narcotic patch containing fentanyl. It is applied transdermally and removed 72 h after applying. The range of effective serum fentanyl concentrations is very narrow (0.3–3 ng/mL). Therefore, analysis of the absorption kinetics (ABK) is especially important. We studied ABK for fentanyl from DMTP 16.8 mg. There are 5 analytical methods to obtain ABK: The estimated mean absorbed rate at steady state (EMARSS) obtained using the residual method (standard value), absolute bioavailability method, Wagner–Nelson method, 3-compartment model Loo–Riegelman method (3LR), and SPLINE–Deconvolution method (SDecon), yielding results of 0.104, 0.119, 0.114, 0.109, and 0.103 mg/h respectively. EMARSS for 3LR and SDecon were nearly equal to the standard value. The absorbed rate for fentanyl with elapsed time by SDecon indicated an amplitude of 3 times with about a 20 h period at 10.7–72 h and the increase in the absorption rate began before the increase in the serum concentration when DMTP was applied transdermally. This phenomenon indicates that the mean absorption rate was constant; thus, an absorption steady state was reached. The actual mean absorption rate during this period was 0.0924 mg/h (range: 0.0594–0.131). The cumulative absorption ratio increased gradually with only a small amplitude, and bioavailability was 44.2%. From our results, SPLINE–Deconvolution is the most suitable method to assess fentanyl absorption kinetics of DMTP.

Active vitamin D₃ (VDRAs) can cause drug-induced hypercalcemia and acute renal failure. Eldecalcitol (ELD), a VDRA, promotes bone formation more strongly than other VDRAs, such as alfacalcidol (ALF), but whether or not ELD affects serum calcium (Ca) levels and renal function more significantly than other VDRAs is unclear. In Japan, the supply of ALF was temporarily stopped in 2021, and patients at Fukuoka University Hospital who were taking ALF were either switched to ELD or discontinued ALF. We retrospectively investigated how these prescription changes affected serum Ca levels and renal function. Sixty-seven adult patients who were admitted to our hospital for at least 5 d between September 2021 and March 2022 and were taking ALF at the time of admission were divided into 3 groups: 36 patients who continued ALF (ALF-C), 12 who were switched to ELD (ELD-S), and 19 who discontinued VDRAs (DC). The changes in weekly serum Ca levels and renal function during hospitalization were compared between the groups. At the second week of observation, the change in the serum Ca level was 0.01 mg/dL in the ALF-C group, +0.45 mg/dL in the ELD-S group, and −0.37 mg/dL in the DC group, showing a significant difference among these groups. In addition, serum Ca levels were increased in all patients in the ELD-S group at Week 2. The estimated glomerular filtration rate didn’t change significantly in any group during hospitalization. These results suggest that serum Ca levels should be measured by Week 2 when ELD is newly started or changed.

In this study, we assessed the information sharing practices between pharmacists and multidisciplinary healthcare professionals such as doctors, care managers, and nurses, and others. We evaluated the effectiveness of “home medical care management guidance reports” and “home-visit drug management guidance reports” prepared by pharmacists. We also identified factors that could enhance collaborative practices. To improve the reports, we introduced a new report form with an overview column and a reply column. We used the SOAP format in the new reports. We found that the response rate for reports from X pharmacy was significantly higher than that of Y pharmacies. A survey revealed that X’s reports contained more categories (median of 3 versus 1 in Y’s reports). Pharmacy X’s reports had a smaller proportion of pharmacotherapy details, and a larger proportion of information regarding patients’ living and health conditions, as well as environmental factors. We also found that the character count in X’s assessment column was significantly greater (168.5 versus 60), and notably less in the overview sections (12 versus 22) when compared to Y’s reports. Suggestions and guidance constituted a significantly larger portion of X’s reports (29.8% compared to 10.8% in Y’s). Questionnaire feedback from other healthcare professionals to whom the subject pharmacies send reports highlighted the importance of pharmacist-provided information on health and living conditions, based on pharmacological knowledge. Based on these results, to enhance health information sharing, pharmacists should integrate assessments of pharmacotherapy with health and living conditions and effectively communicate this information to other professionals.

Introduction: This study examines current OTC pharmaceuticals in Japan categorized as potential substances for abuse and discusses future initiatives for drug abuse prevention. Methods: The Pharmaceuticals and Medical Devices Agency package inserts search function was used to identify OTC pharmaceuticals containing substances prone to abuse. Subsequently, the corresponding OTC pharmaceuticals containing the designated ingredients were investigated, analyzing their therapeutic and risk categories. Results: In total, 1427 (13.9%) OTC pharmaceuticals contained the designated ingredients, with those containing methylephedrine and dihydrocodeine accounting for the majority (1245/1427, 87.2%). Among the therapeutic categories, oral cold medicines were predominant at 564, followed by antitussives and expectorants at 213, and oral rhinitis medicines at 100. Regarding risk categories, designated schedule II pharmaceuticals predominated in 9 out of 11 therapeutic category classifications. Conclusion: Designated schedule II pharmaceuticals, such as oral cold medicines, antitussives and expectorants, and oral rhinitis medicines, pose a high risk of drug abuse. Addressing this challenge necessitates collaboration between pharmacists and registered sales clerks to implement preventive measures aligned with current trends in drug abuse.

Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC). Prophylactic supplementation with vitamin B₁₂ and folic acid reduces hematotoxicity associated with pemetrexed. Metformin, the antidiabetic agent, has been associated with the potential side effect of vitamin B₁₂ deficiency. This retrospective observational study aimed to evaluate the effect of concomitant metformin use on hematologic adverse events in patients with NSCLC undergoing pemetrexed-based chemotherapy using the Medical Data Vision Database. Patients with stage III or higher NSCLC who received pemetrexed from April 2008 to May 2021 were categorized into metformin-treated (MTF) and non-metformin-treated (non-MTF) groups. The primary outcome was the proportion of granulocyte colony-stimulating factor (G-CSF) administration during cycle (C) 1 to C2 or C2 to C3 of pemetrexed therapy. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. A total of 1174 patients met the inclusion criteria (54 in MTF and 1120 in non-MTF). After PSM, 52 patients were included in each group. The median metformin dosage in the MTF group was 500 mg/d before and 625 mg/d after PSM. There were no significant differences between the MTF and non-MTF groups in G-CSF administration (15.4 vs. 21.2%, p=0.446). Multivariate logistic regression analysis also showed that metformin use did not significantly affect hematologic toxicity (odds ratio: 1.208, 95% CI: 0.554–2.634). This suggests that the concomitant use of a relatively low dose of metformin is unlikely to significantly increase the risk of hematotoxicity in Japanese patients with NSCLC receiving pemetrexed-based chemotherapy.

Intentional overdose (OD) of over-the-counter (OTC) and prescription drugs is becoming a significant social issue all over the world. While previous research has focused on drug misuse, there has been limited analysis using social networking service data. This study aims to analyze posts related to a drug overdose on Twitter^® (X^®) to understand the characteristics and trends of drug misuse, and to examine the applicability of social media in understanding the current situation of OD through natural language processing techniques. We collected posts in Japanese containing the term “OD” from January 10 to February 8, 2023, and analyzed 30203 posts. Using a pre-trained, fine-tuned bidirectional encoder representations from transformers (BERT) model, we classified the posts into categories, including direct mentions of OD. We examined the content for drug types and emotional context. Among the 5283 posts categorized as “Posts describing ODing,” about one-third included specific drug names or related terms. The most frequently mentioned OTC drugs included active ingredients such as codeine, dextromethorphan, ephedrine, and diphenhydramine. Prescription drugs, particularly benzodiazepines and pregabalin, were also common. Tweets peaked at midnight, suggesting a link between negative emotions and potential OD incidents. Our classifier showed high accuracy in distinguishing OD-related posts. Analyzing Twitter^® posts provides valuable insights into the patterns and emotional contexts of drug misuse. Monitoring social networking services for OD-related content could help identify high-risk individuals and inform prevention strategies. Enhanced monitoring and public awareness are crucial to reducing the risks associated with both OTC and prescription drug misuse.

In recent years, virtual reality (VR) technology has garnered attention as an educational tool. It is believed to be beneficial to utilize VR technology for the acquisition of pharmacist skills. Therefore, we developed a VR training tool aimed at acquiring skills in the preparation of pharmaceuticals in preparatory clinical education for pharmacy students. Additionally, we evaluated the effectiveness of the VR training tool by having beginners learn about the preparation of liquid medications through VR materials or existing texts (Tx) and assessing their learning outcomes in subsequent practical exams. The study included 12 participants in the VR group and 10 in the Tx group. For the items “smoothly and rhythmically performing a series of actions or operations,” “aligning the meniscus with eye level during scale confirmation,” “marking lines on the dispensing bottle,” and “placing lines at the appropriate scale on the dispensing bottle,” students in the VR group were significantly more capable in practical application. The time required to prepare the liquid medication was significantly shorter for students in the VR group, with over half of the Tx group students exceeding 10 min and terminating the task. According to the survey results, many students cited VR as a method for acquiring dispensing skills. Based on these results, our developed VR training tool for liquid formulation showed usefulness in teaching practical skills to beginners.

This survey aimed to reveal the actual preventing exposure for handling of clothing and sweat of patients treated with anticancer drugs, following the publication of “Guideline for Preventing Occupational Exposure in Cancer Chemotherapy Drugs, 2019 Edition” (Guideline 2019). A survey was conducted among nurses working at 95 hematopoietic stem cell transplantation promotion base hospitals from September 1, 2023 to October 31, 2023. The response rate was 84.2% (80 facilities). Of the respondents, 45% wore gloves when touching patients’ skin to administer anticancer drugs. Almost the nurses identified “urine” and “feces” as fluids on contaminated linen, while 14.1% also identified “sweat.” For new staff, the results for preventing exposure education on “if touching the patients’ skin” and “if handling clothing and linen” were 23.8% and 34.9%, respectively. This survey shows that nurses may not be following the Guideline 2019 for use of personal protective equipment and handling of clothes. Medical institutions handling anticancer drugs need to educate their staff for preventing occupational exposure.

Burow’s solution is a 13% aluminum acetate solution used for treating chronic suppurative otitis media. However, multiple formulations for Burow’s and neo-Burow’s solutions are used as in-hospital preparations. Each formulation uses different types and amounts of reagents, and takes a different time to prepare. Thus, the ions, including aluminum ion (Al³⁺), and other molecules in the prepared Burow’s and neo-Burow’s solutions are not identical, and the pH also differs. Furthermore, details about the antibacterial activity of these preparations are unknown. This study evaluated the stability and antibacterial activity of four Burow’s and two neo-Burow’s solutions prepared using different methods. Preparation times ranged from 20 min to 3 d, and the pH ranged from 2.2 to 4, meaning some solutions were more acidic or more basic than the pH 3 devised by Burow. In addition, the Al³⁺ concentrations ranged from 0.05 to 1.51 mol/L, meaning some solutions were more concentrated or diluted than 13% aluminum acetate (0.64 mol/L). One of the Burow’s solutions we prepared produced a white residue after 14 d, making it difficult to ensure stability. In addition, confirming the antibacterial activity of another Burow’s solution against the test bacteria was problematic. Despite the differences in pH and Al³⁺ concentrations between the various Burow’s and neo-Burow’s solutions, the antibacterial activity was equivalent. It was considered necessary to use the basic data obtained in this study to select a formulation for each hospital. Evaluation of the antibacterial activity of each formulation in clinical settings will be a subject for future study.

In Japan, the Pharmaceutical and Medical Device Act was amended in December 2019, and now requires pharmacists to follow-up on patients during treatment. Although there have been some studies on the effectiveness of follow-ups by pharmacists, there are no reports on the status of implementation in clinical practice. We conducted a nationwide survey on follow-up care to investigate the actual situation. We randomly selected 10% of community pharmacies in each prefecture and conducted a survey. We built a web-based system for the collection of basic information on the pharmacies and follow-up cases. A total of 561 pharmacies were pre-entered. Of these, 110 pharmacies (19.6%) reported 326 follow-up cases. Information was provided to doctors in 129 cases (39.6%), of which prescription proposals were made in 10 (7.8%) instances. The follow-up implementation rate based on the number of prescriptions dispensed was estimated to be 0.84% (95% confidence interval: 0.76–0.94%). This study revealed the status of follow-ups in clinical practice. Pharmacists can contribute to the optimization of drug treatment by providing follow-up information to doctors and making prescription proposals.

In Japan, influenza vaccination is offered to children and pregnant women at clinics or hospitals as an elective, self-funded treatment, as the vaccination is not included in the national vaccination subsidy program. However, some Japanese municipalities offer a discretionary subsidy for seasonal influenza vaccination of children and pregnant women as a local policy. We identified these local subsidy programs during 2019/2020 seasonal influenza season by conducting a cross-sectional survey across Japan. Out of a total of 1741 municipalities, responses were received from 1732; therefore, the response rate was 99.5%. The local influenza vaccine subsidy programs for children were offered in 45.7%, and for pregnant women in 10.2%, of Japanese municipalities. This is the first survey of subsidy programs for pregnant women. While policy diffusion of subsidy programs for children was observed during the 9 years since a previous study, such programs for pregnant women remain limited. Despite many municipalities having subsidy programs, we found that their provision still remains limited when viewed as a whole.

Recently, feeding damage by the olive weevil Pimelocerus (Dyscerus) perforatus Roelofs, which utilizes olive trees (Olea europaea Linne) as a host plant, has become the biggest obstacle to olive cultivation in Japan. We previously identified several volatile plant-derived natural products that exhibit repellent activity against olive weevils. In this study, we conducted a pilot test of repellents in an olive orchard along with the use of insecticide. During three consecutive years from 2021 to 2023, the first year was the observation period, and the second and third years were set aside for a trial period for o-vanillin and geraniol as repellents, respectively. Using o-vanillin, the number of adult olive weevil outbreaks decreased to almost half a year in the experimental area, the use of geraniol then resulted in a drastic reduction of the number of individual olive weevils in the experimental area. In contrast, adults and larvae outbreaks increased in the control area without a repellent, despite the use of insecticide. These results indicate that the volatile repellents drove the olive weevils away and kept them at bay in the field. Based on the observations, we will be able to provide a new approach for the control of olive cultivation, including fruit and leaves used for commercial purposes, following integrated pest management (IPM) practices, such as reducing environmental poisoning from intense insecticides, and returning olive weevils to their original habitat outside of olive orchards.

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan–Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

Excessive production of reactive oxygen species (ROS) causes oxidative stress and is involved in the development and progression of a wide variety of diseases. Therefore, techniques for measuring oxidative stress are indispensable for analysis of the mechanisms of various diseases. The method involving ESR and the durable nitroxyl radical (ESR/spin probe method) is useful for this purpose, because the ESR signal intensity of the spin probe changes on reacting with ROS and other unstable radicals. In this review, the author’s research applying the ESR/spin probe method to clarify disease mechanisms in vivo and in vitro is presented. The ESR signal of the probe injected into animals may decay through a few mechanisms besides reaction with ROS; thus, interpretation of the results is complicated. As the first approach to solving this problem, a probe resistant to enzymatic reduction by introducing a bulky group adjacent to the nitroxy group was created. The second approach was the use of a hydroxylamine probe which dominantly oxidized to nitroxyl radicals by reacting with superoxide anion radicals and oxidants. Using acyl-protected hydroxyl amine, it was demonstrated that sepsis model mice are under oxidative stress due to ROS production by activated phagocytes. On the other hand, it was shown in vitro that the UV-induced radical reaction of ketoprofen also occurs in lipid membranes, and that the reaction is related to ROS generation and membrane disruption. We believe that use of the ESR/spin probe method with ingenuity will clarify the mechanisms of various diseases.