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The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia
- Roger S. McIntyre, David G. Daniel, Eduard Vieta, István Laszlovszky, Pascal J. Goetghebeur, Willie R. Earley, Mehul D. Patel
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- Journal:
- CNS Spectrums / Volume 28 / Issue 3 / June 2023
- Published online by Cambridge University Press:
- 23 February 2022, pp. 319-330
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Objective
To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia.
MethodsPost hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance.
ResultsIn patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=−0.5 [P<.001]; 3 mg/d=−0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=−1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; −2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073).
ConclusionThese post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.
Effects of Cariprazine on Cognition in Patients With Bipolar Mania or Mixed States: Post Hoc Analysis From 3 Randomized, Controlled Phase III Studies
- Roger S. Mcintyre, Eduard Vieta, Willie Earley, Mehul Patel
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 182
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Introduction
Cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, is approved for the treatment of schizophrenia and for depressive, manic, or mixed episodes associated with bipolar I disorder. Previous post hoc analyses have demonstrated that cariprazine was effective versus placebo for improving cognitive symptoms in patients with schizophrenia or bipolar depression. This post hoc analysis evaluated the effects of cariprazine on cognitive symptoms in patients with acute manic or mixed bipolar episodes.
MethodsData from 3 phase II/III, randomized, double-blind, placebo-controlled studies in patients with manic or mixed episodes associated with bipolar I disorder (NCT00488618, NCT01058096, NCT01058668) were pooled and analyzed. Patients were randomized to placebo or flexibly dosed cariprazine (3-12 mg/d, 3-6 mg/d, or 6-12 mg/d [1 study only]) for 3 weeks of double-blind treatment; all dose groups were combined for the pooled analysis. Cognitive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) Cognitive subscale (sum of PANSS items P2, N5, N7, G10, G11); a score of 15 or greater at baseline indicated the presence of cognitive symptoms. Mean changes from baseline to week 3 in PANSS cognitive subscale/item scores and Young Mania Rating Scale (YMRS) total score were evaluated in the overall intent-to-treat (ITT) population and in the subgroup of patients with baseline cognitive symptoms. A mixed-effects model for repeated measures (MMRM) was used to impute missing values.
ResultsOf the 1012 patients in the ITT population, 174 (placebo=71; cariprazine=103) had a PANSS Cognitive subscale score of 15 or greater at baseline. At week 3, the cariprazine group demonstrated significantly greater mean improvement than the placebo group on PANSS cognitive subscale scores in both the ITT population (−2.2 vs −1.3; P<.0001) and the subgroup with baseline cognitive symptoms (−4.0 vs −1.9; P=.0002). In patients with baseline cognitive symptoms, improvement was significantly greater for cariprazine- versus placebo-treated patients on YMRS total score (−16.7 vs −8.2; P<.0001) and the individual PANSS cognitive subscale items of conceptual disorganization (−1.1 vs −0.5; P=.0004), difficulty in abstract thinking (−0.8 vs −0.3; P=.0044), stereotyped thinking (−0.3 vs −0.1; P=.0350), and poor attention (−1.1 vs −0.6; P=.0043).
ConclusionIn patients with manic or mixed episodes associated with bipolar I disorder, cariprazine versus placebo was effective in improving cognitive symptoms in the overall patient population as well as in patients with baseline cognitive symptoms. In addition, cariprazine versus placebo also demonstrated efficacy in improving manic symptoms in patients with baseline cognitive symptoms. These results suggest that cariprazine may provide benefits for the treatment of cognitive symptoms in patients with bipolar I mania.
FundingAbbVie Inc.
Evaluation of MADRS Severity Thresholds in Patients With Bipolar Depression
- Michael E. Thase, Amanda Harrington, Joseph Calabrese, Stuart Montgomery, Xiaomeng Niu, Mehul Patel
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 182-183
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Introduction
The Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or bipolar depression. Categories of depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of depression severity in patients with bipolar I depression.
MethodsData were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with bipolar I depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level.
ResultsThe pooled dataset included 1523 patients with bipolar depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P<.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity.
ConclusionsUtilizing data from 3 recent clinical trials of subjects with bipolar depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from bipolar clinical research and apply to their patients in practice.
FundingAbbVie Inc.
The Rapid Mood Screener: A Novel and Pragmatic Screener Tool for Bipolar I Disorder
- C. Brendan Montano, Mehul Patel, Rakesh Jain, Prakash S. Masand, Amanda Harrington, Patrick Gillard, Kate Sullivan, Susan L. McElroy, T. Michelle Brown, Lauren Nelson, Roger S. McIntyre
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 167-168
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Introduction
Approximately 70% of patients with bipolar disorder (BPD) are initially misdiagnosed, resulting in significantly delayed diagnosis of 7–10 years on average. Misdiagnosis and diagnostic delay adversely affect health outcomes and lead to the use of inappropriate treatments. As depressive episodes and symptoms are the predominant symptom presentation in BPD, misdiagnosis as major depressive disorder (MDD) is common. Self-rated screening instruments for BPD exist but their length and reliance on past manic symptoms are barriers to implementation, especially in primary care settings where many of these patients initially present. We developed a brief, pragmatic bipolar I disorder (BPD-I) screening tool that not only screens for manic symptoms but also includes risk factors for BPD-I (eg, age of depression onset) to help clinicians reduce the misdiagnosis of BPD-I as MDD.
MethodsExisting questionnaires and risk factors were identified through a targeted literature search; a multidisciplinary panel of experts participated in 2 modified Delphi panels to select concepts thought to differentiate BPD-I from MDD. Individuals with self-reported BPD-I or MDD participated in cognitive debriefing interviews (N=12) to test and refine item wording. A multisite, cross-sectional, observational study was conducted to evaluate the screening tool’s predictive validity. Participants with clinical interview-confirmed diagnoses of BPD-I or MDD completed a draft 10-item screening tool and additional questionnaires/questions. Different combinations of item sets with various item permutations (eg, number of depressive episodes, age of onset) were simultaneously tested. The final combination of items and thresholds was selected based on multiple considerations including clinical validity, optimization of sensitivity and specificity, and pragmatism.
ResultsA total of 160 clinical interviews were conducted; 139 patients had clinical interview-confirmed BPD-I (n=67) or MDD (n=72). The screening tool was reduced from 10 to 6 items based on item-level analysis. When 4 items or more were endorsed (yes) in this analysis sample, the sensitivity of this tool for identifying patients with BPD-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties represent an improvement over the Mood Disorder Questionnaire, while using >50% fewer items.
ConclusionThis new 6-item BPD-I screening tool serves to differentiate BPD-I from MDD in patients with depressive symptoms. Use of this tool can provide real-world guidance to primary care practitioners on whether more comprehensive assessment for BPD-I is warranted. Use of a brief and valid tool provides an opportunity to reduce misdiagnosis, improve treatment selection, and enhance health outcomes in busy clinical practices.
FundingAbbVie Inc.
Healthcare Provider Perspectives on Bipolar I Disorder Screening and the Rapid Mood Screener (RMS), a Pragmatic, New Tool
- Michael E. Thase, Stephen M. Stahl, Roger S. McIntyre, Tina Matthews-Hayes, Mehul Patel, Amanda Harrington, Vladimir Maletic, William clay Jackson, Eduard Vieta
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- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 30 April 2021, p. 181
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Introduction
Although mania is the hallmark symptom of bipolar I disorder (BD-I), most patients initially present for treatment with depressive symptoms. Misdiagnosis of BD-I as major depressive disorder (MDD) is common, potentially resulting in poor outcomes and inappropriate antidepressant monotherapy treatment. Screening patients with depressive symptoms is a practical strategy to help healthcare providers (HCPs) identify when additional assessment for BD-I is warranted. The new 6-item Rapid Mood Screener (RMS) is a pragmatic patient-reported BD-I screening tool that relies on easily understood terminology to screen for manic symptoms and other BD-I features in <2 minutes. The RMS was validated in an observational study in patients with clinically confirmed BD-I (n=67) or MDD (n=72). When 4 or more items were endorsed (“yes”), the sensitivity of the RMS for identifying patients with BP-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. To more thoroughly understand screening tool use among HCPs, a 10-minute survey was conducted.
MethodsA nationwide sample of HCPs (N=200) was selected using multiple HCP panels; HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the widely recognized Mood Disorder Questionnaire (MDQ). Results were reported by grouped specialties (primary care physicians, general nurse practitioners [NPs]/physician assistants [PAs], psychiatrists, and psychiatric NPs/PAs). Included HCPs were in practice <30 years, spent at least 75% of their time in clinical practice, saw at least 10 patients with depression per month, and diagnosed MDD or BD in at least 1 patient per month. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence interval.
ResultsAmong HCPs, 82% used a tool to screen for MDD, while 32% used a tool for BD. Screening tool attributes considered to be of the greatest value included sensitivity (68%), easy to answer questions (66%), specificity (65%), confidence in results (64%), and practicality (62%). Of HCPs familiar with screening tools, 70% thought the RMS was at least somewhat better than other screening tools. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. Most HCPs (81%) preferred the RMS to the MDQ, and the RMS significantly outperformed the MDQ across valued attributes; 76% reported that they were likely to use the RMS to screen new patients with depressive symptoms. A total of 84% said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.
DiscussionThe RMS was viewed positively by HCPs who participated in a brief survey. A large percentage of respondents preferred the RMS over the MDQ and indicated that they would use it in their practice. Collectively, responses indicated that the RMS is likely to have a positive impact on screening behavior.
FundingAbbVie Inc.
156 The Broad Efficacy of Cariprazine Across Symptoms in Patients with Bipolar I Disorder: Post Hoc Analysis of Randomized, Placebo-Controlled Trials
- Lakshmi N. Yatham, Eduard Vieta, Roger S. McIntyre, Rakesh Jain, Willie R. Earley, Mehul Patel
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 300
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Study Objective:
Patients with bipolar disorder experience a wide range of depressive and manic symptoms. Only 2 drugs are FDA-approved to treat episodes of both mania and depression in patients with bipolar disorder, highlighting the need for treatments with proven efficacy at opposite poles of the bipolar spectrum. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, is approved in the US for the treatment of both bipolar depression and manic and mixed episodes associated with bipolar I disorder. Cariprazine has previously demonstrated broad efficacy in patients with bipolar mania, with significantly greater improvement in favor of cariprazine vs placebo (PBO) across all individual symptom domains (P<.001) measured by the Young Mania Rating Scale (YMRS). Additionally, cariprazine has demonstrated efficacy vs PBO in 3 phase II/III clinical studies in patients with depressive episodes associated with bipolar I disorder (NCT01396447, NCT02670538, NCT02670551). To further assess the broad efficacy of cariprazine in patients with bipolar I disorder, we performed post hoc analyses to evaluate the range of depressive symptoms comprising the individual items of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients from the bipolar depression studies.
Methods:Data from the 3 randomized, double-blind, PBO-controlled trials in patients with bipolar depression were pooled. Least squares (LS) mean change from baseline to week 6 in MADRS individual items was assessed in the pooled cariprazine 1.5 and 3 mg/d groups vs PBO using a mixed-effects model for repeated measures in the intent-to-treat (ITT) population.
Results:There were 1383 patients in the ITT population (placebo=460; cariprazine 1.5-3 mg/d=923). At week 6, LS mean change from baseline was significantly greater for cariprazine 1.5-3 mg/d vs PBO on 9 of 10 individual MADRS items: Apparent Sadness (-2.0 vs -1.6, P<.0001); Reported Sadness (-2.0 vs -1.6, P<.0001); Reduced Sleep (-1.6 vs -1.4, P=.0357); Reduced Appetite (-1.2 vs -1.0, P=.0001); Concentration Difficulties (-1.5 vs -1.2, P=.0002); Lassitude (-1.7 vs -1.4, P=.0003); Inability To Feel (-1.7 vs -1.5, P=.0009); Pessimistic Thoughts (-1.4 vs -1.2, P=.0054) and Suicidal Thoughts (-0.3 vs -0.2, P=.0383); differences between cariprazine and PBO on the Inner Tension item were not significant.
Conclusions:Significant improvement in most MADRS single items suggests broad efficacy in depressive symptoms for cariprazine 1.5-3 mg/d vs PBO in patients with bipolar depression. Coupled with broad efficacy in manic symptoms as demonstrated by significant improvement in all YMRS individual items in patients with bipolar mania or mixed episodes, cariprazine appears be effective across the range of symptoms that affect patients with bipolar disorder.
Funding Acknowledgements:Supported by Allergan plc.
145 Incidence and Characteristics of Akathisia and Restlessness During Cariprazine Treatment for Bipolar I Disorder
- Leslie Citrome, Lakshmi N. Yatham, Mehul Patel, Willie R. Earley
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- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 292
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Study Objective:
Akathisia and restlessness are common adverse events associated with atypical antipsychotic use; in severe cases, symptoms may lead to treatment discontinuation. Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is approved for the treatment of schizophrenia (1.5–6 mg/d), and manic or mixed (3–6 mg/d) and depressive episodes (1.5–3 mg/d) associated with bipolar I disorder. Pooled post hoc analyses were conducted to characterize the incidence and severity of cariprazine-related akathisia and restlessness in patients who participated in bipolar disorder studies.
Method:All studies were Phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in patients with bipolar I disorder who were currently experiencing a manic/mixed (NCT00488618, NCT01058096, NCT01058668) or depressive (NCT01396447, NCT02670538, NCT02670551) mood episode. Patients received flexibly dosed cariprazine 3-12 mg/d (day 1: 1.5 mg; day 2: 3 mg; subsequent up-titration in 3-mg increments if needed) or placebo in the bipolar mania studies and fixed-dose cariprazine 1.5 mg/d, 3 mg/d (slow titration to 1.5 mg [day 8] and 3 mg [day 15] or initiation at 1.5 mg with escalation to 3 mg on day 15), or placebo in the bipolar depression studies. The incidence, severity, and timing of treatment-emergent adverse events (TEAEs) of akathisia and restlessness were evaluated in this analysis.
Results:In the bipolar mania studies (N=1065), TEAEs of akathisia occurred in 20.2% of cariprazine-treated patients and 4.8% of placebo-treated patients; 2.4% of cariprazine-treated patients discontinued due to akathisia. TEAEs of restlessness occurred in 6.7% and 2.3% of cariprazine- and placebo-treated patients, respectively, and caused discontinuation of 0.3% of cariprazine-treated patients. In the bipolar depression studies (N=1407), akathisia occurred in 2.1%, 5.5%, and 9.6% of patients in the placebo, cariprazine 1.5 mg/d, and cariprazine 3 mg/d groups, respectively; <2% of patients in each group discontinued due to akathisia. Restlessness occurred in 3.2% of placebo-treated patients and 2.1% and 6.6% of patients in the 1.5 and 3 mg/d groups, respectively; discontinuations due to restlessness occurred in 0.2% and 1.1% of patients in the 1.5 and 3 mg/d groups. Akathisia and restlessness in cariprazine-treated patients was generally mild or moderate in severity (>92% in both populations). Most akathisia events in the bipolar mania studies were reported for the first time within the first 2-3 weeks of treatment.
Conclusions:In these post hoc analyses, the incidence of akathisia and restlessness were generally higher with cariprazine than with placebo. However, most incidences were mild or moderate in severity, and infrequently led to discontinuation. Akathisia appears to be dose related in both mania and depression, suggesting lower doses and slower titration may reduce occurrence.
Funding Acknowledgements:Allergan plc.
Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies
- Roger S. McIntyre, Trisha Suppes, Willie Earley, Mehul Patel, Stephen M. Stahl
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- CNS Spectrums / Volume 25 / Issue 4 / August 2020
- Published online by Cambridge University Press:
- 02 October 2019, pp. 502-510
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Objective.
Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms.
Methods.Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
Results.Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of −2.5 (p = .0033) and −2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (−3.3; p = .0008), but not for 3 mg/day (−1.9; p = .0562).
Conclusion.The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.
The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors
- Wolfgang Fleischhacker, Silvana Galderisi, István Laszlovszky, Balázs Szatmári, Ágota Barabássy, Károly Acsai, Erzsébet Szalai, Judit Harsányi, Willie Earley, Mehul Patel, György Németh
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- European Psychiatry / Volume 58 / May 2019
- Published online by Cambridge University Press:
- 07 February 2019, pp. 1-9
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Background:
Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.
Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).
Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P <.05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P <.01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P <.05).
Conclusions:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.
Site of interstage outpatient care and growth after the Norwood operation
- Mehul D. Patel, Karen Uzark, Sunkyung Yu, Janet Donohue, Sara K. Pasquali, David Schidlow, David W. Brown, Sarah Gelehrter
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- Cardiology in the Young / Volume 25 / Issue 7 / October 2015
- Published online by Cambridge University Press:
- 02 January 2015, pp. 1340-1347
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Background
Recent efforts have focused on optimising interstage outcomes, including growth, for infants following the Norwood operation. The impact of the site of interstage care remains unclear, and it has been hypothesised that care at the surgical site may be beneficial due to greater access to resources such as nutritional support. This study evaluated the relationship between site of interstage care and weight gain in a large multicentre cohort.
MethodsInfants enrolled in the National Paediatric Cardiology Quality Improvement Collaborative (2008–2013) surviving up to Stage 2 were included. Change in weight-for-age z-score between Norwood discharge and Stage 2 admission was compared in those receiving care at the surgical versus non-surgical site.
ResultsOf the 487 interstage survivors, 60% received all care at the surgical site, and 40% received care at a non-surgical site. There was no significant difference between groups in change in weight-for-age z-score: +0.36±0.96 for the surgical site group versus +0.46±1.02 for the non-surgical site group, p=0.3. Results were unchanged in multivariable analysis adjusting for differences in important baseline characteristics, duration of interstage, and home surveillance strategy. The proportion of all patients with weight-for-age z-score <−2 decreased from 40% at Norwood discharge to 29% at Stage 2, with no significant difference in change between the two groups (p=0.1).
ConclusionsThe site of interstage care was not associated with weight gain during the interstage period. Nearly one-third of patients overall had a weight-for-age z-score <−2 at Stage 2. Further study is required to identify methods to optimise weight gain in these patients.
Robust quantum-based interatomic potentials for multiscale modeling in transition metals
- John A. Moriarty, Lorin X. Benedict, James N. Glosli, Randolph Q. Hood, Daniel A. Orlikowski, Mehul V. Patel, Per Söderlind, Frederick H. Streitz, Meijie Tang, Lin H. Yang
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- Journal:
- Journal of Materials Research / Volume 21 / Issue 3 / March 2006
- Published online by Cambridge University Press:
- 01 March 2006, pp. 563-573
- Print publication:
- March 2006
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First-principles generalized pseudopotential theory (GPT) provides a fundamental basis for transferable multi-ion interatomic potentials in transition metals and alloys within density-functional quantum mechanics. In the central body-centered cubic (bcc) metals, where multi-ion angular forces are important to materials properties, simplified model GPT (MGPT) potentials have been developed based on canonical d bands to allow analytic forms and large-scale atomistic simulations. Robust, advanced-generation MGPT potentials have now been obtained for Ta and Mo and successfully applied to a wide range of structural, thermodynamic, defect, and mechanical properties at both ambient and extreme conditions. Selected applications to multiscale modeling discussed here include dislocation core structure and mobility, atomistically informed dislocation dynamics simulations of plasticity, and thermoelasticity and high-pressure strength modeling. Recent algorithm improvements have provided a more general matrix representation of MGPT beyond canonical bands, allowing improved accuracy and extension to f-electron actinide metals, an order of magnitude increase in computational speed for dynamic simulations, and the development of temperature-dependent potentials.
Robust Quantum-Based Interatomic Potentials for Multiscale Modeling in Transition Metals
- John A. Moriarty, Lorin X. Benedict, James N. Glosli, Randolph Q. Hood, Daniel A. Orlikowski, Mehul V. Patel, Per Söderlind, Frederick H. Streitz, Meijie Tang, Lin H. Yang
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- Journal:
- MRS Online Proceedings Library Archive / Volume 882 / 2005
- Published online by Cambridge University Press:
- 01 February 2011, EE4.7
- Print publication:
- 2005
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First-principles generalized pseudopotential theory (GPT) provides a fundamental basis for transferable multi-ion interatomic potentials in transition metals and alloys within density-functional quantum mechanics. In central bcc transition metals, where multi-ion angular forces are important to structural properties, simplified model GPT or MGPT potentials have been developed based on canonical d bands to allow analytic forms and large-scale atomistic simulations. Robust, advanced-generation MGPT potentials have now been obtained for Ta and Mo and successfully applied to a wide range of structural, thermodynamic, defect and mechanical properties at both ambient and extreme conditions. Selected applications to multiscale modeling discussed here include dislocation core structure and mobility, atomistically informed dislocation dynamics simulations of plasticity, and thermoelasticity and high-pressure strength modeling. Recent algorithm improvements have provided a more general matrix representation of MGPT beyond canonical bands, allowing improved accuracy and extension to f-electron actinide metals, an order of magnitude increase in computational speed for dynamic simulations, and the still-in-progress development of temperature-dependent potentials.