Journal of Clinical Psychiatry最新文献

{"title":"Reproductive Pharmacovigilance and Best Practices.","authors":"Marlene P Freeman","doi":"10.4088/JCP.24com15473","DOIUrl":"https://doi.org/10.4088/JCP.24com15473","url":null,"abstract":"","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Economic Impact of Cognitive Impairment and Negative Symptoms in Schizophrenia: A Targeted Literature Review With a Focus on Outcomes Relevant to Health Care Decision-Makers in the United States.","authors":"Christoph U Correll, Pin Xiang, Kaushik Sarikonda, Nikhil Bhagvandas, Matthew Gitlin","doi":"10.4088/JCP.24r15316","DOIUrl":"10.4088/JCP.24r15316","url":null,"abstract":"<p><p><b>Abstract</b>.</p><p><p><b>Objective:</b> To conduct a targeted literature review to examine the impact of cognitive impairment and negative symptoms among patients with schizophrenia treated in the United States across a range of outcomes pertinent to the US health care system decision-makers, such as payers and policy-makers.</p><p><p><b>Data Sources:</b> The authors searched EMBASE and PubMed from January 2012 to January 2024. Search terms included schizophrenia, cognitive impairment and negative symptoms, and direct medical and nonmedical, indirect, and societal outcomes.</p><p><p><b>Study Selection:</b> Considered for inclusion were US-based studies reporting on the relationship between cognitive impairment or negative symptoms and direct medical and nonmedical, indirect, and societal outcomes in patients with schizophrenia. A total of 4,212 articles were initially identified for screening.</p><p><p><b>Data Extraction:</b> One reviewer extracted data and another reviewer ensured studies met Population, Intervention, Comparison, Outcomes, Study Design-Time Period (PICOS-T) criteria for inclusion and exclusion.</p><p><p><b>Results:</b> Eight studies (n = 262,683) were included that reported specifically on associations between cognitive impairment or negative symptoms and targeted outcomes. Patients with schizophrenia and moderate/severe cognitive impairment had a 100% increase in relapse-related hospitalizations (0.6 vs 0.3, adjusted incidence rate ratio = 1.85, <i>P</i> < .05) and ER visits (0.4 vs 0.2, adjusted odds ratio = 1.77, <i>P</i> < .05) vs patients with no/mild cognitive impairment. Additionally, there was an almost 50% increase in outpatient visits (8.4 vs 5.5, <i>P</i> < .001) and inpatient admissions (6.8 vs 4.5, <i>P</i> < .001) over the study period (2014 Q1-2017 Q4) for patients with negative symptoms vs without negative symptoms. Direct nonmedical, indirect, and societal outcomes are described.</p><p><p><b>Conclusions:</b> This review highlights the economic burden of cognitive impairment and negative symptoms by focusing on outcomes relevant to health care decision-makers in the United States.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Unblinding in Pivotal Studies and the Future of Psychedelic Medicine.","authors":"Jerrold F Rosenbaum","doi":"10.4088/JCP.24com15504","DOIUrl":"https://doi.org/10.4088/JCP.24com15504","url":null,"abstract":"","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Effects, Side Effects, and Adverse Effects of Neuropsychiatric Drugs in the Context of Treating Cancer-Related Anorexia With Olanzapine and Mirtazapine.","authors":"Chittaranjan Andrade","doi":"10.4088/JCP.24f15532","DOIUrl":"https://doi.org/10.4088/JCP.24f15532","url":null,"abstract":"<p><p>Drugs have actions that may be classified as therapeutic effects and side effects; side effects are actions that do not contribute to therapeutic benefit. Some side effects are neutral; others, experienced as undesirable or unpleasant, are recorded as adverse effects. Some drug actions are therapeutic for some disorders and adverse for others; or therapeutic during acute illness and adverse during maintenance treatment. As an example, anticholinergic action may be adverse when a tricyclic antidepressant is used to treat depression but therapeutic when the drug is used to treat irritable bowel syndrome with diarrhea. In clinical practice, side or adverse effects of a drug may be leveraged to manage troublesome symptoms. As an example, the sedative effect of a low dose of trazodone may be useful for some patients with insomnia. With this background, studies have examined whether the increase in appetite and weight associated with olanzapine and mirtazapine may be effective against anorexia and cachexia associated with cancer and cancer chemotherapy. The subject is important because cachexia may be present in 30%-50% of patients with cancer (with higher prevalence in patients with more advanced cancer) and because the presence of cachexia is associated with a higher risk of disease progression and mortality. Many randomized controlled trials (RCTs) have examined pharmacologic interventions such as progestins, corticosteroids, anamorelin, and medical cannabis for cancer related cachexia; most results have been disappointing. A recent RCT found that olanzapine (2.5 mg/d for 12 weeks) improved appetite, weight, other nutritional parameters, and quality of life in patients with locally advanced or metastatic cancer treated with chemotherapy. Another RCT, however, found that mirtazapine (30 mg/d for 8 weeks) brought no nutritional or anthropometric gain in patients with cancer and anorexia. It is concluded that olanzapine but not mirtazapine merits further investigation in patients with cancer who have anorexia and cachexia.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia.","authors":"Bruce J Kinon, Stefan Leucht, Carol Tamminga, Alan Breier, Ronald Marcus, Steven M Paul","doi":"10.4088/JCP.23nr15240","DOIUrl":"https://doi.org/10.4088/JCP.23nr15240","url":null,"abstract":"<p><p><b>Importance:</b> Schizophrenia is a complex syndrome with taxing symptoms and for which treatment challenges remain. Current dopamine D₂receptor-blocking antipsychotics have well-known limitations, including ineffectively treating across all symptom domains and generating common side effects such as motor disturbances, weight gain, and metabolic dysfunction. New approaches are sorely needed to address the continued unmet treatment needs for individuals living with schizophrenia.</p><p><p><b>Observations:</b> Although current antipsychotic drugs indicated for the treatment of schizophrenia interact with various neurotransmitter receptors, they all commonly act as dopamine D₂receptor antagonists or partial agonists. While antipsychotics primarily relieve positive symptoms, residual positive symptoms are still common, and management of negative symptoms and cognitive impairment remains an unmet need. Problematic side effects are common with current agents and can contribute to nonadherence. In addition to alterations in dopaminergic pathways, increasing evidence indicates that the pathophysiology of schizophrenia also includes dysfunction in other neurotransmitter systems including glutamate, acetylcholine, serotonin, and γ-aminobutyric acid. While the pathophysiology of schizophrenia is complex, treatments with novel pharmacologic actions that target these systems are of interest as adjunctive treatment for individuals with schizophrenia.</p><p><p><b>Conclusion and Relevance:</b> An unmet need exists for effective treatment of all the core symptoms of schizophrenia. Novel antipsychotics with a nondopaminergic mechanism of action may be useful candidates for antipsychotic adjunctive treatment in people with schizophrenia who are showing inadequate responses, treatment resistance, or low tolerance to dopamine D₂receptor-blocking antipsychotics.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation Across Bipolar Disorder and Major Depressive Disorder by Whole-Night Polysomnographic Findings.","authors":"Meihong Xiu, Wenxin Li, Yu Lan, Kaiwen Li, Xiaoe Lang","doi":"10.4088/JCP.23m15210","DOIUrl":"https://doi.org/10.4088/JCP.23m15210","url":null,"abstract":"<p><p><b>Abstract</b>.</p><p><p><b>Background:</b> There is growing evidence that understanding the role of sleep disturbance in bipolar disorder (BD) and major depressive disorder (MDD) is helpful when studying the high heterogeneity of patients across psychiatric disorders.</p><p><p><b>Objective:</b> The present study was designed to investigate the transdiagnostic role of sleep disturbance measured by polysomnography (PSG) in differentiating from MDD with BD.</p><p><p><b>Methods:</b> A total of 256 patients with MDD and 107 first-episode and never medicated patients with BD using the <i>Diagnostic and Statistical Manual of Mental Disorders,</i> Fourth Edition, criteria were recruited. All patients completed 1 night of PSG recording, and the changes in objective sleep structure parameters were determined by PSG analysis.</p><p><p><b>Results:</b> We showed that patients with MDD had statistically longer rapid eye movement (REM) latency, a higher percentage of stage N2 sleep, and lower percentages of stage N3 sleep and REM sleep than those with BD after controlling for confounding factors (all <i>P</i> < .05). Moreover, using the logistic regression analysis, we identified that REM latency was associated with BD diagnosis among the PSG sleep features. The cutoff value for PSG characteristics to differentiate BD from MDD was 261 in REM latency (sensitivity: 41.4% and specificity: 84.1%).</p><p><p><b>Conclusions:</b> Our findings suggest that PSG-measured sleep abnormalities, such as reduced REM latency, may be a diagnostic differentiating factor between MDD and BD, indicating their roles in identifying homogeneous transdiagnostic subtypes across psychiatric disorders.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and Course of Unwanted, Intrusive Thoughts of Infant-Related Harm.","authors":"Fanie Collardeau, Olivia L U, Arianne Y K, Jazlyn G Mayhue, Nichole Fairbrother","doi":"10.4088/JCP.23m15145","DOIUrl":"https://doi.org/10.4088/JCP.23m15145","url":null,"abstract":"<p><p></p><p><p><b>Objective:</b> Unwanted, intrusive thoughts (UITs) of infant-related harm are a common postpartum phenomenon and can be classified into thoughts of accidental harm (TAHs) and thoughts of intentional harm (TIHs). Our study's objective was to complete a comprehensive, comparative analysis of TAHs and TIHs by commenting on their prevalence, course, characteristics (time, distress, and impairment) and most intense period.</p><p><p><b>Methods:</b> A total of 763 English-speaking pregnant women across British Columbia were recruited to participate in a prospective cohort study. Study data were collected between February 2014 and February 2017. UITs were assessed by semistructured interviews twice during the postpartum period.</p><p><p><b>Results:</b> The prevalence of TAHs and TIHs in the postpartum period was 95.8% and 53.9%, respectively. The most common TAHs included thoughts of the baby suffocating or dying from sudden infant death syndrome; the most common TIHs included thoughts of neglect. On average, TAHs are more prevalent, time-consuming, and result in greater interference compared to TIHs. The most intense period for TAHs (5.74 weeks postpartum) and TIHs (within first 8 weeks postpartum) was identified. During this period, over 40% of participants reported moderate or extreme distress related to UITs. For most, UITs decreased in frequency or completely resolved by 6 months postpartum, and most participants did not report clinically significant symptoms.</p><p><p><b>Conclusion:</b> UITs are a normative and typically self-resolving occurrence in the postpartum period. UITs' most intense period signifies a time of heightened vulnerability. Increased education is necessary to normalize and reduce distress associated with UITs.</p><p><p><i>J Clin Psychiatry 2024;85(3):23m15145</i>.</p><p><p>\u0000 <i>Author affiliations are listed at the end of this article.</i>\u0000 </p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initiating Aripiprazole Lauroxil: Post Hoc Analysis of Safety and Tolerability of 1-Day and 21-Day Regimens.","authors":"Roger W Sommi, Stephen R Saklad, Peter J Weiden, Daniel Still, Meihua Wang, Sergey Yagoda","doi":"10.4088/JCP.23m15132","DOIUrl":"https://doi.org/10.4088/JCP.23m15132","url":null,"abstract":"<p><p><b>Objective:</b> Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic, has 2 initiation options: 1-day (AL NanoCrystal Dispersion [AL_NCD] injection plus 30 mg oral aripiprazole on day 1 only) and 21-day (15 mg oral aripiprazole for 21 days). This post hoc analysis assessed the safety and tolerability of both initiation approaches.</p><p><p><b>Methods:</b> We analyzed data from the first 4 weeks of 2 AL studies, one using the 1-day initiation regimen (conducted between November 2017 and March 2019) and the other using the 21-day initiation regimen (conducted between December 2011 and March 2014). Outcomes of interest during the matched 4-week period included the likelihood of adverse events (AEs), including those associated with discontinuation, rated as serious, or of special interest (injection site reactions [ISRs] and akathisia).</p><p><p><b>Results:</b> The 1-day (n = 99) and 21-day (n = 415) initiation regimens had comparable rates of AEs (57.6% and 52.0%, respectively; most were mild), serious AEs (2.0% and 1.4%), and AEs leading to discontinuation (4.0% and 3.1%). The incidence of ISRs was 11.1% after the AL_NCDinjection (day 1) in the 1-day initiation regimen. ISR rates for the AL starting doses were 9.2% for the 1-day regimen (AL 1064 mg on day 8) and 3.9% for the 21-day regimen (AL 441 mg/882 mg on day 1). Rates of akathisia were 9.1% and 11.1% for the 1-day and 21-day regimens, respectively. One patient discontinued because of an ISR in the 21-day study, and 2 patients in the 21-day study discontinued because of akathisia. Mean changes from baseline in week 4 Positive and Negative Syndrome Scale total scores were -17.4 (1-day) and -19.5 (21-day).</p><p><p><b>Conclusions:</b> Four-week safety and tolerability were similar following the initiation of AL with either the 1-day or 21-day regimen, supporting the utility of both initiation regimens. Engaging patients in discussions regarding options for initiating AL may help facilitate shared decision-making and personalization of treatment for patients with schizophrenia.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifiers: NCT03345979 and NCT01469039.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 24-Year Course of Symptomatic Disorders in Patients With Borderline Personality Disorder and Personality-Disordered Comparison Subjects: Description and Prediction of Recovery From BPD.","authors":"Mary C Zanarini, Frances R Frankenburg, Isabel V Glass, Garrett M Fitzmaurice","doi":"10.4088/JCP.24m15370","DOIUrl":"https://doi.org/10.4088/JCP.24m15370","url":null,"abstract":"<p><p><b>Objectives:</b> Our first objective was to compare the prevalence of symptomatic disorders (formerly Axis I disorders) over 24 years of prospective follow-up among patients with borderline personality disorder (BPD) and other personality disordered comparison subjects as well as recovered vs nonrecovered borderline patients. Our second objective was to assess the relationship between the absence of 5 major classes of symptomatic disorders over time and the likelihood of concurrent recovery among borderline patients.</p><p><p><b>Methods:</b> The McLean Study of Adult Development (MSAD) is a naturalistic prospective follow-up study of 362 inpatients assessed at 12 contiguous 2-year follow-up waves. Symptomatic disorders were assessed at each follow-up using the Structured Clinical Interview for <i>DSM-III-R</i> Axis I Disorders. Generalized estimating equations were used to assess all outcomes. Data were collected from June 1992 to December 2018.</p><p><p><b>Results:</b> Patients with BPD had significantly higher rates of all 5 types of disorders studied than comparison subjects. However, the prevalence of these disorders declined significantly over time at similar rates for both study groups. This finding was similar for recovered and nonrecovered borderline patients. When the absence of these types of comorbid disorders was used to predict recovery status, substance use disorders were a substantially stronger predictor of recovery than the other 4 classes of disorders (relative risk ratio: 2.53, <i>P</i> < .001).</p><p><p><b>Conclusions:</b> The results of this study suggest that symptomatic disorders co occur less commonly with BPD over time, particularly for recovered borderline patients. They also suggest that the absence of substance use disorders is the strongest predictor of achieving recovery from BPD.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the Predictive Validity of Early Post-injury CAPS-5 for Later Posttraumatic Stress Disorder Diagnosis.","authors":"Jae-Min Kim, Ju-Wan Kim, Hee-Ju Kang, Ju-Yeon Lee, Hyunseok Jang, Inseok Jeong, Jung-Chul Kim, Sung-Wan Kim, Il-Seon Shin","doi":"10.4088/JCP.24m15267","DOIUrl":"https://doi.org/10.4088/JCP.24m15267","url":null,"abstract":"<p><p><b>Abstract</b>.</p><p><p><b>Objective:</b> The Clinician-Administered PTSD Scale for <i>DSM-5</i> (CAPS-5) is a widely recognized tool with exceptional reliability and validity in evaluating and diagnosing PTSD. This study aimed to determine the predictive values of CAPS-5 assessed early postinjury for subsequent development of PTSD during a 2-year follow-up period.</p><p><p><b>Methods:</b> Patients with moderate to severe physical injuries were recruited from a trauma center at a university hospital in South Korea between June 2015 and January 2021. At baseline, 1,142 patients underwent evaluations using CAPS-5 for the diagnosis of acute stress disorder (ASD) along with total scores. They were followed up for PTSD using the CAPS-5 evaluations at 3, 6, 12, and 24 months post-baseline. Area under receiver operating curve (AUROC) analyses were conducted to identify predictive values of the CAPS-5 for later PTSD development.</p><p><p><b>Results:</b> CAPS-5 diagnosis of ASD at baseline displayed fair to failed performance (AUROCs: 0.555-0.722) for predicting follow-up PTSD. However, CAPS-5 scores of ≥15 exhibited good to fair predictive accuracy (AUROCs: 0.767-0.854) for later PTSD development. Notably, for patients with intentional injuries or a history of previous trauma, a higher CAPS-5 score of ≥16 showed improved predictive accuracy.</p><p><p><b>Conclusion:</b> A CAPS-5 score of ≥15 would be an effective and practical cutoff for early prediction of PTSD following physical injuries. In cases of intentional injuries or a documented trauma history, a cutoff of ≥16 may offer enhanced predictive precision. Future research in diverse settings and populations is needed to confirm the generalizability of our findings.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}