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4 An Update: Greater Apathy Associated with Selective Serotonin Reuptake Inhibitor Use in Parkinson’s Disease
- Rachel Schade, Lauren Kenney, Alyssa Ray, Lauren Santos, Francesca Lopez, Adrianna Ratajska, Katie Rodriguez
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 110-111
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Objective:
Apathy is a primary lack of motivation that is frequently reported in Parkinson’s disease (PD) and often misdiagnosed as depression. In PD, apathy worsens over time with motor symptom progression. Evidence over the past 15 years has documented that use of selective serotonin reuptake inhibitors (SSRIs) is associated with increased apathy in patients with depression, including individuals with PD. In PD, this appears to be related to downregulation of dopaminergic systems by serotonin. Despite increasing evidence, SSRIs continue to be heavily prescribed in individuals with PD— potentially worsening apathy and decreasing quality of life for these individuals. This study is an update, re-examining the relationship between apathy and the use of SSRIs and other antidepressants in a large cohort of individuals with PD.
Participants and Methods:Participants included a convenience sample of 387 nondemented individuals with idiopathic PD who were in their mid-60's (mean age=64.9+8.72 years), well-educated (mean=14.95+2.78 years), predominantly male (72.4%), non-Hispanic white (94.5%), and in mid-stage of disease severity (on medication Unified Parkinson Disease Rating Scale motor score=25.3+10.1). All scored above clinical cutoff for dementia on a cognitive screener (Dementia Rating Scale-2 (DRS) > 125). Medications, cognitive, mood, and clinical data were extracted from chart review. Depression and apathy were measured using the Beck Depression Inventory-II (BDI-Il) and the Apathy Scale (AS). Antidepressant medications were grouped into SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs) and other. Analyses included bootstrapped Pearson’s correlations, Pearson’s chi-square, and linear regressions
Results:Among 387 individuals with PD, 41.3% (N=160) were taking antidepressant medications. Of these 160, 61.3% were on SSRIs, 24.4% on SNRIs, and the remainder on other antidepressants. Approximately 36.9% of the 387 PD patients exceeded recommended clinical cutoffs for apathy (AS >14) and 23.5% for depression (BDI-II >14) (Starkstein et al., 1992; Beck et al., 1996). Individuals taking SSRIs (N=98, x2=5.14, p=0.023) or SNRIs (N=39; x2=5.43, p=0.020) were more likely to be clinically apathetic than those taking other depression medications (N=23; x2=1.28, p=0.26). Results of a multiple regression with age, education, disease duration, motor severity, DRS-2, BDI-II, and all psychotropic medications (anti-depressants, anti-anxiety, anti-psychotics) as independent variables explained 42.8% of the variance in total apathy scores (F[17,285]=12.550, p<0.001). SSRIs were the only medication to significantly predict greater AS scores (ß=0.110, p=0.020) in this model. Less education (ß=-0.119, p=0.017) worse cognition (ß=-0.128, p=0.009), and greater depressive symptoms (ß=0.561, p<0.001) were also significant predictors of apathy.
Conclusions:These findings suggest that use of SSRIs, but not other antidepressants, is associated with greater apathy in PD. Given the interactive relationship between serotonin and dopamine, the current findings highlight the importance of considering apathy as a potential adverse effect when determining which anti-depressants to prescribe to individuals with PD. Similarly, switching a SSRI for an alternative anti-depressant in individuals with PD who are apathetic may be a potential treatment for apathy that needs further study. Longitudinal studies are also needed to elucidate the relationship of apathy and anti-depressant use over time, specifically to determine potential causality of this observed association. Funding: T32-NS082168
5 Anticholinergic Medications, Cognition, and Parkinson’s Disease. Do Medications matter?
- Lauren G Santos, Lauren E Kenney, Alyssa Ray, Alfredo A Paredes, Adrianna M Ratajska, Dawn Bowers
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 111-112
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Objective:
While Parkinson’s disease (PD) is traditionally known as a movement disorder, cognitive decline is one of the most debilitating and common non-motor symptoms. Cognitive profiles of individuals with PD are notably heterogeneous (Goldman et al., 2018). While this variability may arise from the disease itself, other factors might play a role. Greater anticholinergic medication use has been linked to worse cognition in those with PD (Fox et al., 2011, Shah et al., 2013). However, past studies on this topic had small sample sizes, limited ranges of disease duration, and only used cognitive screeners. Thus, this study aimed to examine this question within a large, clinical sample, using a more comprehensive neuropsychological battery. We hypothesized that higher anticholinergic medication usage would relate to worse cognitive performance, particularly memory.
Participants and Methods:Participants included 491 nondemented individuals with PD (m=64.7, SD=9.04 years old; education m=15.01, SD=2.79; 71.9% male; 94.3% non-Hispanics white) who underwent a comprehensive neuropsychological assessment at the UF Fixel Institute’s movement disorders program. Medications at the time of the neuropsychological evaluation were identified from chart review and scored based on anticholinergic properties using the Magellan Anticholinergic Risk Scale (Rudolph J.L., et al, 2008); each medication was scored from 0 (no load) to 3 (high load). The neuropsychological battery included measures across 5 cognitive domains: (1) executive function (Trails B, Stroop Interference, Letter Fluency), (2) verbal delayed memory (WMS-III Logical Memory and Hopkin’s Verbal Learning Test-Revised delayed recalls), (3) language (Boston Naming Test-II, Animal Fluency), (4) visuospatial skills (Judgment of Line Orientation, Face Recognition Test), and (5) attention/working memory (WAIS-III Digit Span Forward and Backward). The published normative scores for each task were converted into z-scores and averaged into a domain composite. Due to non-normality of Magellan scores, Spearman correlations examined the relationship between each cognitive domain composite score and Magellan scores.
Results:As predicted, higher Magellan scores were significantly associated with worse memory (r=-0.11, p=0.016), with a small effect size. There were no significant relationships between Magellan scores and the remaining cognitive domains (EF, language, visuospatial, attention).
Conclusions:We found that greater anticholinergic burden was associated with worse performance on memory, but not other neuropsychological domains, in a large cohort of nondemented individuals with PD who underwent comprehensive assessment. This finding corresponds to previous literature in smaller PD cohorts. Though the effect size was low, this finding highlights the importance of monitoring anticholinergic burden in PD patients in order to minimize detrimental effects of medications on memory function. Future work should examine whether greater anticholinergic burden predicts future progression of memory decline.
Acknowledgement: Supported in part by the NIH, T32-NS082168
18 Regional patterns of mitochondrial function using phosphorus magnetic resonance spectroscopy in older adults at-risk for Alzheimer’s disease.
- Francesca V Lopez, Andrew O’Shea, Stacey Alvarez-Alvarado, Adrianna Ratajska, Lauren Kenney, Rachel Schade, Katie Rodriguez, Alyssa Ray, Rebecca O’Connell, Lauren Santos, Emily Van Etten, Hyun Song, Emma Armstrong, Tiffany Gin, Zhiguang Huo, Gene Alexander, Adam J Woods, Dawn Bowers
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 331-332
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Objective:
The brain is reliant on mitochondria to carry out a host of vital cellular functions (e.g., energy metabolism, respiration, apoptosis) to maintain neuronal integrity. Clinically relevant, dysfunctional mitochondria have been implicated as central to the pathogenesis of Alzheimer’s disease (AD). Phosphorous magnetic resonance spectroscopy (31p MRS) is a non-invasive and powerful method for examining in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. At least one prior 31p MRS study found temporal-frontal differences for high energy phosphates in persons with mild AD. The goal of the current study was to examine regional (i.e., frontal, temporal) 31p MRS ratios of mitochondrial function in a sample of older adults at-risk for AD. Given the high energy consumption in temporal lobes (i.e., hippocampus) and preferential age-related changes in frontal structure-function, we predicted 31p MRS ratios of mitochondrial function would be greater in temporal as compared to frontal regions.
Participants and Methods:The current study leveraged baseline neuroimaging data from an ongoing multisite study at the University of Florida and University of Arizona. Participants were older adults with memory complaints and a first-degree family history of AD [N = 70; mean [M] age [years] = 70.9, standard deviation [SD] =5.1; M education [years] = 16.2, SD = 2.2; M MoCA = 26.5, SD = 2.4; 61.4% female; 91.5% non-latinx white]. To achieve optimal sensitivity, we used a single voxel method to examine 31p MRS ratios (bilateral prefrontal and left temporal). Mitochondrial function was estimated by computing 5 ratios for each voxel: summed adenosine triphosphate to total pooled phosphorous (ATP/TP; momentary energy), ATP to inorganic phosphate (ATP/Pi; energy consumption), phosphocreatine to ATP (PCr/ATP; energy reserve), phosphocreatine to inorganic phosphate (PCr/Pi; oxidative phosphorylation), and phosphomonoesters to phosphodiesters (PME/PDE; cellular membrane turnover rate). All ratios were corrected for voxel size and cerebrospinal fluid fraction. Separate repeated measures analyses of variance controlling for scanner site differences (RM ANCOVAs) were performed.
Results:31p MRS ratios were unrelated to demographic characteristics and were not included as additional covariates in analyses. Results of separate RM ANCOVAs revealed all 31p MRS ratios of mitochondrial function were greater in left temporal relative to bilateral prefrontal voxel: ATP/TP (p < .001), ATP/Pi (p = .001), PCr/ATP (p = .004), PCr/Pi (p = .004), and PME/PDE (p = .017). Effect sizes (partial eta squared) ranged from 0.6-.20.
Conclusions:Consistent and extending one prior study, all 31p MRS ratios of mitochondrial function were greater in temporal as compared to frontal regions in older adults at-risk for AD. This may in part be related to the intrinsically high metabolic rate of the temporal region and preferential age-related changes in frontal structure-function. Alternatively, findings may reflect the influence of unaccounted factors (e.g., hemodynamics, auditory stimulation). Longitudinal study designs may inform whether patterns of mitochondrial function across different brain regions are present early in development, occur across the lifespan, or some combination. In turn, this may inform future studies examining differences in mitochondrial function (as measured using 31p MRS) in AD.
Life course of retrospective harmonization initiatives: key elements to consider
- Isabel Fortier, Tina W. Wey, Julie Bergeron, Angela Pinot de Moira, Anne-Marie Nybo-Andersen, Tom Bishop, Madeleine J. Murtagh, Milica Miočević, Morris A. Swertz, Esther van Enckevort, Yannick Marcon, Michaela. Th. Mayrhofer, Jos Pedro Ornelas, Sylvain Sebert, Ana Cristina Santos, Artur Rocha, Rebecca C. Wilson, Lauren E. Griffith, Paul Burton
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- Journal:
- Journal of Developmental Origins of Health and Disease / Volume 14 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 12 August 2022, pp. 190-198
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Optimizing research on the developmental origins of health and disease (DOHaD) involves implementing initiatives maximizing the use of the available cohort study data; achieving sufficient statistical power to support subgroup analysis; and using participant data presenting adequate follow-up and exposure heterogeneity. It also involves being able to undertake comparison, cross-validation, or replication across data sets. To answer these requirements, cohort study data need to be findable, accessible, interoperable, and reusable (FAIR), and more particularly, it often needs to be harmonized. Harmonization is required to achieve or improve comparability of the putatively equivalent measures collected by different studies on different individuals. Although the characteristics of the research initiatives generating and using harmonized data vary extensively, all are confronted by similar issues. Having to collate, understand, process, host, and co-analyze data from individual cohort studies is particularly challenging. The scientific success and timely management of projects can be facilitated by an ensemble of factors. The current document provides an overview of the ‘life course’ of research projects requiring harmonization of existing data and highlights key elements to be considered from the inception to the end of the project.
The Relevance of Ultrastructural Studies of Metastatic Cells from Women with Breast Cancer History
- Isabela Delfino Moreira, André Peres, Ariane Campos, Claudia Giuliano Bica, Giovana Tavares dos Santos, João Carlos Prolla, Lauren Arrusul Carús, Mariana Simões Ferreira, Marilda da Cruz Fernandes, Naiane Carlesso Bassani, Gisele Orlandi Introíni
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- Journal:
- Microscopy and Microanalysis / Volume 28 / Issue 1 / February 2022
- Published online by Cambridge University Press:
- 17 November 2021, pp. 210-217
- Print publication:
- February 2022
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The interaction between cancer cells and the surrounding microenvironment is determinant for metastasis success. In this study, the ultrastructural relevance of cells in the malignant pleural effusion (MPE) of women with breast cancer history was investigated. In MPE, it is possible to observe single cells and clusters. Women whose MPE presents carcinomas in aggregates have a better prognosis when compared to cases in which metastatic single cells are found. Samples were collected via fine-needle aspiration puncture (US-FNA). Subsequent to the material preparation and ultrathin cuts, they were observed using light and transmission electron microscopy (LM/TEM). LM and TEM images served as a basis for the creation of a digital sculpture using ZBrush® software. Clusters exhibited structural stability, en route vesicles allowing exocytosis of electron-dense fibrous elements, and cytoplasmic protrusions contributing to migratory and invasive skills. Single cells presented different necrotic phenotypes and many displayed leukocyte-like characteristics. Cluster cooperative relationships seem to be related to a long-term permanence in MPE. The absence of a collaborative network presumably triggers a more aggressive behavior of single cells. Its putative fusion with leukocytes can maximize the efficiency for transendothelial migration, increasing chances of metastatic success and, unfortunately, reducing survival of women with recidivism.
The Impact of Natural Hazards on Older Adult Health: Lessons Learned From Hurricane Maria in Puerto Rico
- Elizabeth L. Andrade, Megan Jula, Carlos E. Rodriguez-Diaz, Lauren Lapointe, Mark C. Edberg, Maria I. Rivera, Carlos Santos-Burgoa
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- Disaster Medicine and Public Health Preparedness / Volume 17 / 2023
- Published online by Cambridge University Press:
- 02 November 2021, e52
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Objective:
With natural hazards increasing in frequency and severity and global population aging, preparedness efforts must evolve to address older adults’ risks in disasters. This study elucidates potential contributors to the elevated older adult mortality risk following Hurricane Maria in Puerto Rico through an examination of community stakeholder preparedness, response, and recovery experiences.
Methods:In April 2018, qualitative interviews (n = 22) were conducted with stakeholders in 7 Puerto Rican municipalities. Interview transcripts were deductively and inductively coded and analyzed to identify salient topics and themes representing participant response patterns.
Results:The hurricane’s detrimental impact on older adult health emerged as a prominent finding. Through 6 months post-hurricane, many older adults experienced unmet needs that contributed to declining physical and emotional health, inadequate non-communicable disease management, social isolation, financial strain, and excess morbidity and mortality. These needs were predominantly consequences of lengthy public service gaps, unsafe living conditions, interrupted health care, and the incongruence between preparedness and event severity.
Conclusions:In a landscape of increasing natural hazard frequency and magnitude, a pattern of older adult risk has become increasingly clear. Study findings compel practitioners to engage in natural hazard preparedness planning, research, and policy-making that considers the multiple facets of older adult well-being.
3166 Association between HIV and early weight loss and the impact on subsequent treatment outcomes among patients with tuberculosis
- Lauren A Saag, Peter F. Rebeiro, Marcelo Cordeiro-Santos, Afranio Kritski, Bruno B. Andrade, Betina Durovni, Solange Calvacante, Megan Turner, Marina C. Figueiredo, Valeria C. Rolla, Timothy R. Sterling
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, p. 34
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OBJECTIVES/SPECIFIC AIMS: Previous research suggests that weight loss during early TB treatment (first two months of anti-TB therapy) is a predictor of poor tuberculosis (TB) treatment outcomes among HIV-negative populations, but the relationship has not been well studied in the context of HIV. We examined the association between HIV and weight change during the first two months of anti-tuberculosis treatment, and also assessed the effects of HIV and early weight change on tuberculosis (TB) treatment outcomes. METHODS/STUDY POPULATION: Adults with culture-confirmed, drug-susceptible, pulmonary TB, regardless of HIV status, were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil cohort and followed on standard anti-TB therapy. For the primary analysis, we compared weight change in persons living with HIV (PLWH) and HIV-negative patients between baseline and two months using multivariable bootstrapped quantile regression and modified Poisson regression. For secondary analysis, we examined the separate effects of HIV and weight change on poor TB treatment outcome (treatment failure, TB recurrence, or death) using Cox proportional hazards regression. RESULTS/ANTICIPATED RESULTS: Among 323 participants, 45 (14%) were HIV-positive. On average, PLWH lost 0.7% (interquartile range (IQR): −5.1%, 4.4%) of their baseline body weight between baseline and two months; those without HIV gained 3.5% (IQR: 0.8%, 6.7%). After adjusting for age, sex, and baseline BMI, PLWH lost 4.1% (95% confidence interval (CI): −6.5%, −1.6%) more weight during the first two months of anti-TB treatment than HIV-negative individuals. HIV infection was associated with weight loss ≥5% (adjusted odds ratio = 9.3; 95% CI: 4.2-20.6). Regarding the secondary analysis, 14 patients had a poor TB treatment outcome: 2 treatment failures, 4 cases of recurrent TB, and 8 deaths. PLWH and patients who lost ≥5% weight had significantly increased risk of poor TB treatment outcome with hazard ratios of 8.77 (95% CI: 2.96-25.94) and 4.09 (95% CI: 1.11-15.14), respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that HIV is associated with weight loss during early TB treatment, and both HIV and early weight loss were associated with poor treatment outcome. Future research should examine the potential etiologies of these findings and identify the types of interventions that would best promote weight gain during TB treatment, especially among PLWH, in order to prevent poor TB treatment outcomes.
2300 Association between source case cavitation on chest radiograph and QuantiFERON-TB Gold In-Tube conversion among close contacts of active tuberculosis cases in Brazil
- Lauren A. Saag, Marcelo Cordeiro-Santos, Afranio Kritski, Bruno Andrade, Solange Cavalcante, Betina Durovni, Megan Turner, Marina Figueiredo, Valeria Rolla, Timothy Sterling
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- Journal:
- Journal of Clinical and Translational Science / Volume 2 / Issue S1 / June 2018
- Published online by Cambridge University Press:
- 21 November 2018, p. 4
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OBJECTIVES/SPECIFIC AIMS: QuantiFERON-TB Gold In-Tube (QFT) conversion from negative to positive, is regarded as a marker of recent latent tuberculosis infection and may be predictive of incident active tuberculosis (TB) disease. However, it remains unclear how conversion is influenced by individual and environmental factors, including the infectiousness of the source case to whom the contact was exposed. We aimed to examine the effect of infectiousness of TB in the source case, as measured by presence of cavitation on chest X-ray, on the incidence of QFT conversion among close contacts of the pulmonary TB index case, after adjusting for potential confounding by contact and source case characteristics. METHODS/STUDY POPULATION: The Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil is an ongoing prospective cohort study that enrolls close contacts of culture-confirmed pulmonary TB patients and follows them for 24 months for development of active TB. Demographic, clinical, and diagnostic information are obtained at baseline and during follow-up at clinical visits and by telephone. QFT testing is performed at baseline and repeated after 6 months if the baseline QFT is negative. A positive IFN-γ value is defined as >0.35 IU/mL, as recommended by the manufacturer and the CDC, and QFT conversion is defined as a negative QFT at baseline followed by a positive QFT at 6 months. RESULTS/ANTICIPATED RESULTS: Among 260 enrolled contacts with nonpositive baseline QFT results and 6 months of follow-up, 198 (76%) were retested with QFT 6 months after enrollment. Of those retested, 26 (13%) converted to positive. Presence of any cavitation in the source case, based on chest radiography, was significantly associated with QFT-conversion (ORunadjusted=2.4, 95% CI: 1.0–5.7). Additional univariate analyses revealed that QFT conversion was associated with black and brown race (compared with white race) of the contact, current smoking and current alcohol use in the source case. After adjusting for potential confounders (age, sex, and race of the contact and current smoking of the source case), the association between source case cavitation and QFT conversion remained (ORadjusted=2.5 95% CI: 1.0–6.2). As of December 6, 2017, none of the QFT-retested contacts had developed active TB, with a median follow-up of 12.3 months (IQR: 7.1–13.1). We anticipate that ongoing enrollment and follow-up may yield cases of active TB; future analyses will provide greater precision for examining predictors of QFT-conversion and its association with incident TB. DISCUSSION/SIGNIFICANCE OF IMPACT: Our preliminary results agree with published literature suggesting the infectiousness of TB in the index case is a predictor of incident LTBI. Along with recent LTBI, immune suppression, HIV co-infection, and type 2 diabetes are considered risk factors for progression to active TB disease. Because only a small proportion of persons progress from LTBI to active TB disease, it is not appropriate to treat all persons with LTBI. Thus, more research is needed to identify groups at highest risk for QFT-conversion and incident TB disease, so these groups can be targeted for TB prevention, interventions, and facilitate a decline in TB incidence and mortality.
Rogues' Gallery of Contributing Authors
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- By Ramon Abola, Rishimani Adsumelli, Syed Azim, Tazeen Beg, Helene Benveniste, Louis Chun, Ramtin Cohanim, Dominick Coleman, Joseph Conrad, Tommy Corrado, Jason Daras, Michelle DiGuglielmo, Vedan Djesevic, Andrew Drollinger, Kathleen Dubrow, Brian Durkin, Ralph Epstein, Christopher J. Gallagher, Xiaojun Guo, Sofie Hussain, Ron Jasiewicz, Anna Kogan, Ursula Landman, Rany Makaryus, Daryn Moller, Tate Montgomery, Matthew Neal, Khoa Nguyen, Marco Palmieri, Shaji Poovathor, Eric Posner, Deborah Richman, Andrew Rozbruch, Misako Sakamaki, Joy Schabel, Bharathi Scott, Peggy Seidman, Shiena Sharma, Vishal Sharma, Ellen Steinberg, Neera Tewari, Jane Yi, Jonida Zeqo, Peter Chung, John Denny, Steven H. Ginsberg, Jeremy Grayson, Jonathan Kraidin, Stephen Lemke, Tejal Patel, Salvatore Zisa, Charles Cowles, Marc Rozner, Shawn Banks, Deborah Brauer, Lebron Cooper, V. Samepathi David, Steve Gayer, Steven Gil, Eric A. Harris, Murlikrishna Kannan, Michael C. Lewis, David A. Lindley, Carlos M. Mijares, Sana Nini, Shafeena Nurani, Sujatha Pentakota, Edgar Pierre, Amy Klash Pulido, Michael Rossi, Miguel Santos, Nancy Setzer-Saade, Adam Sewell, Omair H. Toor, Ashish Udeshi, Patricia Wawroski, Lauren C. Berkow, Dan Berkowitz, Ramola Bhambhani, Kerry K. Blaha, Veronica Busso, Adam J. Carinci, Paul J. Christo, R. Blaine Easley, Ralph J. Fuchs, Samuel M. Galvagno, Nishant Gandhi, Andrew Goins, Robert S. Greenberg, Sayeh Hamzehzadeh, Theresa L. Hartsell, Eugenie Heitmiller, Jeremy M. Huff, Brijen L. Joshi, Sapna Kudchadkar, Jennifer K. Lee, Ira Lehrer, Peter Lin, Justin Lockman, Christine L. Mai, Christina Miller, Nanhi Mitter, Gillian Newman, Daniel Nyhan, Lale Odekon, Rabi Panigrahi, Melissa Pant, Alexander Papangelou, Mark Rossberg, Adam Schiavi, Steven J. Schwartz, Deborah A. Schwengel, Brandon M. Togioka, Tina Tran, Emmett Whitaker, Bradford D. Winters, Christopher Wu, Elena J. Holak, Paul S. Pagel
- Edited by Christopher J. Gallagher, State University of New York, Stony Brook, Michael C. Lewis, University of Miami School of Medicine, Deborah A. Schwengel
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- Book:
- Core Clinical Competencies in Anesthesiology
- Published online:
- 06 July 2010
- Print publication:
- 12 April 2010, pp xi-xii
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