Ami Nakazawa, Yuki Matsuda, Ryuichi Yamazaki, Nanase Taruishi, Shinsuke Kito
{"title":"Effects of repetitive transcranial magnetic stimulation therapy on weight and lipid metabolism in patients with treatment-resistant depression: A preliminary single-center retrospective cohort study.","authors":"Ami Nakazawa, Yuki Matsuda, Ryuichi Yamazaki, Nanase Taruishi, Shinsuke Kito","doi":"10.1002/npr2.12494","DOIUrl":"10.1002/npr2.12494","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to elucidate the effects of repetitive transcranial magnetic stimulation (rTMS) on weight, body mass index (BMI), and lipid metabolism in patients with treatment-resistant depression (TRD).</p><p><strong>Methods: </strong>This retrospective observational study included patients with TRD who received rTMS treatment at the Jikei University Hospital from September 2018 to August 2021. The patients were diagnosed based on the DSM-5 and ICD-10 criteria and treated using the NeuroStar TMS System. For 3-6 weeks, 10-Hz rTMS was administered to the left dorsolateral prefrontal cortex at 120% motor threshold. The primary outcomes were changes in weight and BMI, whereas the secondary outcomes included changes in total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels, thyroid function indicators, as well as HAMD-17, HAMD-24, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Statistical analysis was conducted using paired t-tests and repeated measures ANOVA.</p><p><strong>Results: </strong>Among the 34 patients (20 men and 14 women) included, no significant changes were observed in weight or BMI after rTMS treatment (average weight reduction: -0.50 kg, 95% CI: -0.14 to 0.56, p = 0.24; average BMI reduction: -0.21, 95% CI: -0.10 to 0.61, p = 0.15). However, significant reductions in total, HDL, and LDL cholesterol levels and FT4 were observed. Furthermore, the HAMD-17, HAMD-24, and MADRS scores significantly increased post-treatment.</p><p><strong>Conclusion: </strong>rTMS treatment did not affect weight or BMI in patients with TRD but is believed to improve lipid metabolism.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"e12494"},"PeriodicalIF":2.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Initial psychotropic prescriptions and symptom associations in first-visit patients with major depressive disorder: A single-center cross-sectional study.","authors":"Yugo Ishihara, Norio Sugawara, Yasushi Kawamata, Norio Yasui-Furukori","doi":"10.1002/npr2.12507","DOIUrl":"10.1002/npr2.12507","url":null,"abstract":"<p><strong>Aim: </strong>There are limited reports regarding psychotropic prescriptions in first-visit patients with major depressive disorder (MDD). The objective of this study is to clarify the prescription patterns of psychotropics and their association with symptoms among first-visit patients with MDD in Japan.</p><p><strong>Methods: </strong>In this cross-sectional analysis, we examined 376 first-visit patients diagnosed with MDD. Depressive symptoms were evaluated using the Quick Inventory of Depressive Symptomatology Japanese version (QIDS-J). To assess personality traits, we administered the Japanese version of the Ten Item Personality Inventory (TIPI-J), and psychotic symptoms were evaluated using the PRIME Screen-Revised (PS-J).</p><p><strong>Results: </strong>Among the first-visit patients with MDD, 31.4% (118/376) were prescribed antidepressants, and 18.1% (68/376) received benzodiazepines. Overall, 40.2% (151/376) of the patients were prescribed at least one psychotropic medication. In a multivariate logistic regression model using the forced entry method, missing data on educational attainment and the view of myself domain of the QIDS-J were negatively associated, while the concentration/decision-making domain of the QIDS-J was positively associated with antidepressant prescription.</p><p><strong>Conclusion: </strong>More than half of the first-visit patients did not receive any psychotropic medication. Psychiatrists appear to consider specific symptoms and personality traits when deciding whether to prescribe medications, which may also be influenced by patient preferences. Further studies, including longitudinal analyses, are needed to explore these associations in more detail.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"e12507"},"PeriodicalIF":2.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibitory effects of the selective μ-opioid receptor antagonist UD-030 on methamphetamine-induced conditioned place preference.","authors":"Soichiro Ide, Noriaki Iwase, Kenichi Arai, Masahiro Kojima, Shigeru Ushiyama, Kazutaka Ikeda","doi":"10.1002/npr2.12503","DOIUrl":"10.1002/npr2.12503","url":null,"abstract":"<p><p>Although methamphetamine (METH) and other addictive substance use disorders are a major social problem worldwide, appropriate pharmacotherapies have not yet been discovered. Subtype-nonselective opioid receptor antagonists, such as naltrexone (NTX), have been reported to suppress METH addiction, but unclear are the opioid receptor subtypes that are involved in this beneficial effect. To clarify the role of μ-opioid receptors (MOPs), we examined effects of the novel nonpeptidic MOP-selective antagonist UD-030 on the acquisition and expression of METH-induced conditioned place preference (CPP) using behavioral tests in C57BL/6J mice. UD-030 was found to inhibit both the acquisition and expression of METH-induced CPP in a dose-dependent manner, with effects comparable to those observed with NTX. These findings suggest that UD-030 has the potential to mitigate METH-related reward mechanisms and may serve as a promising candidate for MOP-selective pharmacotherapy targeting METH addiction.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"e12503"},"PeriodicalIF":2.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Development of cefepime-induced encephalopathy in a patient with depression and rectal cancer: A case report.","authors":"Junji Yamaguchi, Ryoichi Sadahiro, Saho Wada, Eri Nishikawa, Tatsuto Terada, Rika Nakahara, Hiromichi Matsuoka","doi":"10.1002/npr2.12502","DOIUrl":"10.1002/npr2.12502","url":null,"abstract":"<p><strong>Background: </strong>Cefepime, a fourth-generation cephalosporin, has neurotoxic side effects such as encephalopathy. Baseline conditions, including blood-brain barrier (BBB) impairment and renal dysfunction, are known to associate with elevated central nervous concentration of cefepime. Although BBB dysfunction occurs with depression or cancer, currently, neither is regarded as a risk factor for cefepime-induced encephalopathy.</p><p><strong>Case presentation: </strong>A 79-year-old woman with a history of depression and rectal cancer was hospitalized for a bacterial liver abscess. Brain metastasis and other causes for delirium were excluded, and no renal dysfunction was observed. However, 11 days after cefepime and metronidazole administration, the patient suddenly developed confusion, disorientation, and myoclonus, with no apparent changes on brain magnetic resonance imaging. Electroencephalography revealed a consistent tri-phasic wave pattern. Clinical symptoms were well consistent with cefepime-induced encephalopathy; hence, cefepime and metronidazole were discontinued, followed by rapid physical and mental recovery, with no aftereffects.</p><p><strong>Conclusions: </strong>In terms of BBB dysfunction, depression and cancer might be possible occult risk factors for cefepime-induced encephalopathy. Doctors need to pay attention to encephalopathy risk when administering cefepime in patients with depression or cancer because the psychiatric symptoms of encephalopathy, depression, and delirium from other causes are often confusing, leading to misdiagnosis and a poor prognosis.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"e12502"},"PeriodicalIF":2.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Association between psychological distress and schizotypy in adults: A cross-sectional study.","authors":"Hiroyuki Uchida, Sae Ohki, Chiaki Kuroiwa, Kenji Tsuchiya, Senichiro Kikuchi, Kazuki Hirao","doi":"10.1002/npr2.12511","DOIUrl":"https://doi.org/10.1002/npr2.12511","url":null,"abstract":"<p><strong>Background: </strong>Schizotypy refers to a personality type characterized by behavioral and cognitive abnormalities similar in nature but less severe than those of schizophrenia. Schizotypy often progresses to schizophrenia, so identifying risk factors may facilitate early schizophrenia diagnosis and improve treatment. Psychological distress may be associated with schizotypy, highlighting its importance. However, the link between psychological distress and schizotypy remains unclear.</p><p><strong>Methods: </strong>This cross-sectional study examined the relationship between schizotypy and psychological distress in a Japanese adult population using internet-based questionnaires. Schizotypy was assessed using the Schizotypal Personality Questionnaire-Brief and psychological distress was measured using the Kessler Screening Scale for Psychological Distress. Multivariate logistic regression analysis was used to assess the relationship between psychological distress and schizotypy after adjusting for numerous potential confounding variables.</p><p><strong>Results: </strong>Among 6632 participants, 225 were classified with schizotypy (3.39%, 89 females [39.6%]). Multivariate logistic regression analysis adjusting for confounding factors revealed that participants with psychological distress were significantly more likely to exhibit signs of schizotypy than those without psychological distress (adjusted odd ratio, 2.91; 95% confidence interval, 1.85-4.59).</p><p><strong>Conclusions: </strong>The emergence of schizotypy in adults is strongly associated with psychological distress. This finding emphasizes the need for physicians to carefully, thoroughly, and routinely assess psychological distress in adults. Longitudinal studies are warranted to investigate the causal relationship between schizotypy and psychological distress.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effects of short-term exposure to moderate amounts of alcohol on brain volume.","authors":"Sakiko Tsugawa, Fumihiko Ueno, Mutsuki Sakuma, Hideaki Tani, Ryo Ochi, Ariel Graff-Guerrero, Yoshihiro Noda, Hiroyuki Uchida, Masaru Mimura, Shunji Oshima, Sachio Matsushita, Shinichiro Nakajima","doi":"10.1002/npr2.12500","DOIUrl":"https://doi.org/10.1002/npr2.12500","url":null,"abstract":"<p><strong>Aim: </strong>Although numerous studies have reported that chronic alcohol consumption causes brain volume reduction and cerebrospinal fluid volume increase, few studies have examined the acute effects of alcohol on brain structure. This study aims to investigate the short-term brain volume changes following alcohol administration.</p><p><strong>Methods: </strong>Moderate doses of alcohol were administered intravenously to 18 healthy volunteers for a total of 90 min to achieve a blood alcohol concentration of 0.5 mg/mL. An alcohol clamp method combined with physiologically based pharmacokinetic modeling was used to achieve fine control over blood alcohol concentration. T1 images with 3T MRI were scanned at three time points: baseline, 0 min, and 90 min after the end of alcohol administration. Cortical, subcortical, and ventricular volumes were computed after segmentation with FreeSurfer. Repeated measures analysis of variance was used to evaluate longitudinal changes in brain volume at 96 regions.</p><p><strong>Results: </strong>Acute alcohol administration increased bilateral lateral ventricular volumes, which lasted until 90 min after the end of alcohol injection. On the other hand, the volumes of total gray matter, left precentral cortex, left caudal middle frontal cortex, and left superior frontal cortex decreased after alcohol administration, but these changes disappeared 90 min after the end of alcohol administration.</p><p><strong>Conclusion: </strong>Acute injection of moderate doses of alcohol may enlarge ventricle volumes and reduce gray matter volumes. The transient volume changes caused by acute administration of alcohol may be related to changes in CSF flow and water content of brain tissue, which warrants further study.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Real-world predictors of severe psychological distress during the COVID-19 pandemic in Japan: Insights from a large-scale internet-based cohort study.","authors":"Keita Tokumitsu, Norio Sugawara, Takahiro Tabuchi, Norio Yasui-Furukori","doi":"10.1002/npr2.12495","DOIUrl":"10.1002/npr2.12495","url":null,"abstract":"<p><strong>Aim: </strong>The COVID-19 pandemic has had negative physical and psychological impacts worldwide. However, there has been a lack of real-world evidence concerning the predictors of severe psychological distress (SPD) among the general population in Japan during the COVID-19 pandemic. The aim of this study was to examine predictors of SPD during the COVID-19 pandemic.</p><p><strong>Methods: </strong>We investigated the predictors of new-onset SPD in the general Japanese population using data from a large-scale internet-based cohort study.</p><p><strong>Results: </strong>We included 16 489 study participants (age range = 16-81, mean age = 52.7, percentage of male = 50%) in the analysis. Over the course of 1 year from baseline, the estimated proportion of participants who experienced SPD was 5.2% with inverse probability weighting. The predictors of SPD included younger age, being never married, being unemployed, having a higher education background, scoring higher on the Fear of Coronavirus-19 Scale, experiencing more adverse childhood experiences, reporting poorer subjective health status, and COVID-19 with oxygen therapy. Our internet-based survey of the Japanese population may have selection bias, limiting the generalizability to other countries and cultures.</p><p><strong>Conclusion: </strong>This study revealed that being afflicted with COVID-19 requiring oxygen therapy is the most significant predictor of SPD. In addition, we found that vulnerability to social isolation, such as never being unmarried, anxiety toward COVID-19, and susceptibility to stress, are predictors of the emergence of SPD. Therefore, the implementation of online support systems and ensuring access to accurate information may protect against SPD during the COVID-19 pandemic in Japan.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"798-808"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Masato Masuda, Brian Waters, Leo Gotoh, Yoshihiko Nakamura, Yoshifumi Kato, Shigeki Nabeshima, Shin-Ichi Kubo, Nobuaki Eto, Hiroaki Kawasaki
{"title":"Qualitative analysis of blood from patients engaging in deliberate self-harm: Differences between prescribed and detected drugs.","authors":"Masato Masuda, Brian Waters, Leo Gotoh, Yoshihiko Nakamura, Yoshifumi Kato, Shigeki Nabeshima, Shin-Ichi Kubo, Nobuaki Eto, Hiroaki Kawasaki","doi":"10.1002/npr2.12492","DOIUrl":"10.1002/npr2.12492","url":null,"abstract":"<p><strong>Background: </strong>While drugs are sometimes taken during deliberate self-harm (DSH), no study has attempted to analyze drugs in the blood of DSH patients and compare them with prescribed medications or other drugs. In this study, drugs were analyzed from the blood of DSH patients, and the detected, prescribed, and suspected drugs were documented.</p><p><strong>Methods: </strong>Patients who practiced DSH and were transferred to the emergency sites of Fukuoka University Hospital between April 2021 and September 2022 participated in the study. Psychiatrists assessed information such as the history of psychiatric treatment and recent methods of DSH, as well as prescribed drugs within 1 month of presenting to the hospital. Blood samples were analyzed using LC-MS/MS. Participants were divided into groups according to whether or not they were prescribed psychotropics within 1 month.</p><p><strong>Results: </strong>Fifty-five patients were enrolled in the study. Forty had been prescribed psychotropics within 1 month of hospital admission. However, non-prescribed drugs (NPD) were detected in 42 of the 55 participants (76%). The detection of NPD was significantly high among patients with overdose of medications and OTC drugs (p = 0.036), but NPD were also detected in patients who engaged in other methods (n = 14), and in patients without prescribed medication (n = 10).</p><p><strong>Discussion: </strong>This is the first study focused on the drug analysis of blood from patients engaging in DSH. Approximately 80% of the DSH patients in this study had taken NPD, revealing a large discrepancy between prescribed medications and those detected in the blood.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"809-820"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effects of frequently prescribed antiseizure medications on motor vehicle driving performance: Narrative review based on a tiered approach for the assessment of clinically meaningful driving impairment in the Ministry of Health, Labour, and Welfare guideline.","authors":"Kunihiro Iwamoto, Tetsuo Nakabayashi, Akiko Yamaguchi, Yuki Konishi, Momoe Saji, Reiji Yoshimura, Kousuke Kanemoto, Hirofumi Aoki, Masahiko Ando, Norio Ozaki","doi":"10.1002/npr2.12469","DOIUrl":"10.1002/npr2.12469","url":null,"abstract":"<p><p>Patients with epilepsy often require long-term treatment with antiseizure medications, and their impact on daily activities, particularly driving, is of significant concern. The recently published \"Guideline for Evaluating Effects of Psychotropic Drugs on the Performance to Drive a Motor Vehicle\" in Japan provides a framework that can be referred to for not only the evaluation of new drugs but also the reevaluation of approved drugs. This study conducted a literature review regarding the effects of carbamazepine, valproate, lamotrigine, lacosamide, and levetiracetam, which are frequently prescribed for epilepsy, on driving performance following the guideline's tiered evaluation approach. Analyses of pharmacological, pharmacodynamic, and adverse events suggested that these drugs primarily affect arousal function. Driving studies showed that acute administration of carbamazepine, but not chronic monotherapy with carbamazepine, valproate, lamotrigine, and levetiracetam, significantly impairs driving performance. Epidemiological studies have not identified a definitive association between these drugs and traffic accidents. Initial administration of these five antiseizure medications may affect driving performance, warranting special attention, but the influence appears to diminish with continued use. Nevertheless, while long-term administration of these five drugs may not have a clinically meaningful effect on driving performance, safe driving is not guaranteed for each individual patient, and appropriate individualized guidance is important in clinical practice.</p>","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"682-687"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to \"Brexpiprazole: A new option in treating agitation in Alzheimer's dementia-Insights from transgenic mouse models\".","authors":"","doi":"10.1002/npr2.12496","DOIUrl":"10.1002/npr2.12496","url":null,"abstract":"","PeriodicalId":19137,"journal":{"name":"Neuropsychopharmacology Reports","volume":" ","pages":"868"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}