[show abstract][hide abstract] ABSTRACT: Magnetic resonance imaging has provided a wealth of information on altered brain activations and structures in individuals addicted to cocaine. However, few studies have considered the influence of age and alcohol use on these changes.
We examined gray matter volume with voxel based morphometry (VBM) and low frequency fluctuation (LFF) of BOLD signals as a measure of cerebral activity of 84 cocaine dependent (CD) and 86 healthy control (HC) subjects. We performed a covariance analysis to account for the effects of age and years of alcohol use.
Compared to HC, CD individuals showed decreased gray matter (GM) volumes in frontal and temporal cortices, middle/posterior cingulate cortex, and the cerebellum, at p<0.05, corrected for multiple comparisons. The GM volume of the bilateral superior frontal gyri (SFG) and cingulate cortices were negatively correlated with years of cocaine use, with women showing a steeper loss in the right SFG in association with duration of use. In contrast, the right ventral putamen showed increased GM volume in CD as compared to HC individuals. Compared to HC, CD individuals showed increased fractional amplitude of LFF (fALFF) in the thalamus, with no significant overlap with regions showing GM volume loss.
These results suggested that chronic cocaine use is associated with distinct changes in cerebral structure and activity that can be captured by GM volume and fALFF of BOLD signals.
Drug and alcohol dependence 09/2013; · 3.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Little is known about the smoking cessation and smoking relapse behavior of adults with alcohol use disorders (AUDs) and drug use disorders (DUDs), Objective: The current study used longitudinal data from a representative sample of the US adult population to examine changes in smoking over 3 years for men and women with and without AUD and DUD diagnoses, Methods: Participants were current or former daily cigarette smokers at Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions who completed the Wave 2 assessment 3 years later (n = 11,973; 46% female). Analyses examined the main and gender-specific effects of AUD and DUD diagnoses on smoking cessation and smoking relapse, Results: Wave 1 current daily smokers with a current AUD (OR = .70, 95% CI = .55, .89), past AUD (OR = .73, 95% CI = .60, .89), current DUD (OR = .48, 95% CI = .31, .76), and past DUD (OR = .62, 95% CI = .49, .79) were less likely to have quit smoking at Wave 2 than those with no AUD or DUD diagnosis. Wave 1 former daily smokers with a current AUD (OR = 2.26, 95% CI = 1.36, 3.73), current DUD (OR = 7.97, 95% CI = 2.51, 25.34), and past DUD (OR = 2.69, 95% CI = 1.84, 3.95) were more likely to have relapsed to smoking at Wave 2 than those with no AUD or DUD diagnosis. The gender by diagnosis interactions were not significant, Conclusion: Current and past AUDs and DUDs were associated with a decreased likelihood of quitting smoking, while current AUDs, current DUDs, and past DUDs were associated with an increased likelihood of smoking relapse.
The American Journal of Drug and Alcohol Abuse 05/2013; 39(3):186-93. · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Deficits in cognitive control are implicated in cocaine dependence. Previously, combining functional magnetic resonance imaging and a stop signal task, we demonstrated altered cognitive control in cocaine-dependent individuals. However, the clinical implications of these cross-sectional findings and, in particular, whether the changes were associated with relapse to drug use, were not clear. In a prospective study, we recruited 97 treatment-seeking individuals with cocaine dependence to perform the stop signal task during functional magnetic resonance imaging and participate in follow-up assessments for 3 months, during which time cocaine use was evaluated with timeline follow back and ascertained by urine toxicology tests. Functional magnetic resonance imaging data were analysed using general linear models as implemented in Statistical Parametric Mapping 8, with the contrast 'stop error greater than stop success trials' to index error processing. Using voxelwise analysis with logistic and Cox regressions, we identified brain activations of error processing that predict relapse and time to relapse. In females, decreased error-related activations of the thalamus and dorsal anterior cingulate cortex predicted relapse and an earlier time to relapse. In males, decreased error-related activations of the dorsal anterior cingulate cortex and left insula predicted relapse and an earlier time to relapse. These regional activations were validated with data resampling and predicted relapse with an average area under the curve of 0.849 in receiver operating characteristic analyses. These findings provide direct evidence linking deficits in cognitive control to clinical outcome in a moderate-sized cohort of cocaine-dependent individuals. These results may provide a useful basis for future studies to examine how psychosocial factors interact with cognitive control to determine drug use and to evaluate the efficacy of pharmacological or behavioural treatment in remediating deficits of cognitive control in cocaine addicts.
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: Adults with depression smoke at higher rates than other adults leaving a large segment of this population, who already incur increased health-related risks, vulnerable to the enormous harmful consequences of smoking. Yet, the impact that depression has on smoking cessation is not clear due to the mixed results of past research. The primary aims of this review were to synthesize the research examining the relationship of depression to smoking cessation outcomes over a 20-year period, to examine the gender and racial composition of these studies, and to identify directions for future research. METHODS: Potential articles published between January 1, 2000 and December 31, 2010 were identified through a MEDLINE search of the terms "clinical trial," "depression," and "smoking cessation." 68 studies used all three terms and met the inclusion criteria. RESULTS: The majority of studies examined either a past diagnosis of major depression or current depression symptoms. Within the few studies that examined the interaction of gender and depression on smoking cessation, depression had a greater impact on treatment outcomes for women than men. No study reported examining the interactive impact of race and depression on treatment outcomes. Conclusions:Although attention to the relationship of depression and smoking cessation outcomes has increased over the past 20 years, little information exists to inform a treatment approach for smokers with Current Major Depressive Disorder, Dysthymia, and Minor Depression and few studies report gender and racial differences in the relationship of depression and smoking cessation outcomes, thus suggesting major areas for targeted research.
Nicotine & Tobacco Research 10/2012; · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Although data clearly link major depression and smoking, little is known about the association between dysthymia and minor depression and smoking behavior. The current study examined changes in smoking over 3years for current and former smokers with and without dysthymia and minor depression. METHODS: Participants who were current or former daily cigarette smokers at Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions and completed the Wave 2 assessment were included in these analyses (n=11,973; 46% female). Analyses examined the main and gender-specific effects of current dysthymia, lifetime dysthymia, and minor depression (a single diagnostic category that denoted current and/or lifetime prevalence) on continued smoking for Wave 1 current daily smokers and continued abstinence for Wave 1 former daily smokers. RESULTS: Wave 1 current daily smokers with current dysthymia (OR=2.13, 95% CI=1.23, 3.70) or minor depression (OR=1.53, 95% CI=1.07, 2.18) were more likely than smokers without the respective diagnosis to report continued smoking at Wave 2. Wave 1 former daily smokers with current dysthymia (OR=0.44, 95% CI=0.20, 0.96) and lifetime dysthymia (OR=0.37, 95% CI=0.15, 0.91) were less likely than those without the diagnosis to remain abstinent from smoking at Wave 2. The gender-by-diagnosis interactions were not significant, suggesting that the impact of dysthymia and minor depression on smoking behavior is similar among men and women. CONCLUSIONS: Current dysthymia and minor depression are associated with a greater likelihood of continued smoking; current and lifetime dysthymia are associated with a decreased likelihood of continued smoking abstinence.
Drug and alcohol dependence 07/2012; · 3.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and response to nicotine therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β(2) subunit (β(2)*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men.
To examine β(2)*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among β(2)*-nAChR availability, tobacco smoking characteristics, and female sex steroid hormone levels.
Male (n = 26) and female (n = 28) tobacco smokers participated in an iodide 123-labeled 5-iodo-A-85380 ([(123)I]5-IA) single-photon emission computed tomography (SPECT) imaging session at 7 to 9 days of abstinence. Age-matched male (n = 26) and female (n = 30) nonsmokers participated in a [(123)I]5-IA SPECT imaging session. All participants completed a magnetic resonance imaging study.
Academic imaging center.
Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56).
The [(123)I]5-IA SPECT images were converted to equilibrium distribution volumes and were analyzed using regions of interest.
The β(2)*-nAChR availability was significantly higher in male smokers compared with male nonsmokers in striatum, cortex, and cerebellum, but female smokers did not have higher β(2)*-nAChR availability than female nonsmokers in any region. In women, β(2)*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the SPECT imaging day. In female smokers on imaging day, the progesterone level was positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal.
The regulatory effects of nicotine in the brain (ie, tobacco smoking-induced upregulation of β(2)*-nAChRs) seem to be distinctly different between men and women, and female sex steroid hormones likely have a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. To treat female smokers more effectively, it is critical that nonnicotinic-mediated medications should be explored.
Archives of general psychiatry 04/2012; 69(4):418-27. · 12.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aims Although depression and smoking are correlated highly, the relationship of major depressive disorder (MDD) to smoking cessation and relapse remains unclear. This study compared changes in smoking for current and former smokers with and without current and life-time MDD over a 3-year period. Design Analysis of two waves of longitudinal data from the National Institute on Alcohol Abuse and Alcoholism's National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-02; wave 2, 2004-05). Setting Data were collected through face-to-face interviews from non-institutionalized United States civilians, aged 18 years and older, in 50 states and the District of Columbia. Participants A total of 11 973 adults (54% male) classified as current or former daily smokers at wave 1 and completed wave 2. Measurements Classification as current or former smokers at wave 1 and wave 2. Findings Smoking status remained stable for most participants. Wave 1 current daily smokers with current MDD [odds ratio (OR) = 1.38, 95% confidence interval (CI): 1.03, 1.85] and life-time MDD (OR = 1.52, 95% CI: 1.15, 2.01) were more likely than those without the respective diagnosis to report continued smoking at wave 2. Wave 1 former daily smokers with current MDD (OR = 0.44, 95% CI: 0.26, 0.76) were less likely to report continued abstinence at wave 2. None of the gender × MDD diagnosis interactions were significant. Patterns of results remained similar when analyses were limited to smokers with nicotine dependence. Conclusions Current and life-time major depressive disorders are associated with a lower likelihood of quitting smoking and current major depressive disorder is associated with greater likelihood of smoking relapse.
[show abstract][hide abstract] ABSTRACT: To study the relationship between self-reported exposure to childhood maltreatment (CM) and cerebral gray matter (GM) morphology in adolescents without psychiatric diagnoses.
Associations were examined between regional GM morphology and exposure to CM (measured using a childhood trauma self-report questionnaire for physical, emotional, and sexual abuse and for physical and emotional neglect).
Forty-two adolescents without psychiatric diagnoses.
Correlations between childhood trauma self-report questionnaire scores and regional GM volume were assessed in voxel-based analyses of structural magnetic resonance images. Relationships among GM volume, subtypes of exposure to CM, and sex were explored.
Childhood trauma self-report questionnaire total scores correlated negatively (P < .005) with GM volume in prefrontal cortex, striatum, amygdala, sensory association cortices, and cerebellum. Physical abuse, physical neglect, and emotional neglect were associated with rostral prefrontal reductions. Decreases in dorsolateral and orbitofrontal cortices, insula, and ventral striatum were associated with physical abuse. Decreases in cerebellum were associated with physical neglect. Decreases in dorsolateral, orbitofrontal, and subgenual prefrontal cortices, striatum, amygdala, hippocampus, and cerebellum were associated with emotional neglect. Decreases in the latter emotion regulation regions were also associated with childhood trauma self-report questionnaire scores in girls, while caudate reductions (which may relate to impulse dyscontrol) were seen in boys.
Exposure to CM was associated with corticostriatal-limbic GM reductions in adolescents. Even if adolescents reporting exposure to CM do not present with symptoms that meet full criteria for psychiatric disorders, they may have corticostriatal-limbic GM morphologic alterations that place them at risk for behavioral difficulties. Vulnerabilities may be moderated by sex and by subtypes of exposure to CM.
Archives of pediatrics & adolescent medicine 12/2011; 165(12):1069-77. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Childhood maltreatment (CM) has been associated with diminished executive functioning in children and adults; however, there is a relative paucity of study of executive function in adolescents exposed to CM. Yet, executive dysfunction in adolescence may have important adverse consequences including increased vulnerability to risky behaviors and impaired school functioning. This study investigates the relationship between self-reported CM and an executive function, cognitive flexibility, in adolescents without identified psychiatric disorders. Effects of physical and emotional, abuse and neglect, maltreatment subtypes were explored. Thirty adolescents ages 12-17 years, 50% females, completed the retrospective self-report Childhood Trauma Questionnaire (CTQ) and were administered the Wisconsin Card Sorting Test (WCST). Correlational analyses assessed the relationship between WCST perseverative error scores norm-referenced for age and education with CTQ total scores. The relationship with nonperseverative errors, as well as with physical and emotional abuse and neglect CM subscores, were explored. Total CTQ scores showed significant associations with perseverative errors on the WCST, but not with nonperseverative errors. Significant associations with perseverative errors were seen for physical abuse and physical neglect among the CTQ subscales. The results suggest both physical abuse and physical neglect are associated with diminished cognitive flexibility in adolescents. These effects were detected in adolescents without identified psychiatric diagnoses suggesting the importance of considering executive dysfunction in adolescents exposed to CM who may not meet diagnostic criteria for an Axis I disorder and that tests of perseverative errors, such as those of the WCST, may be sensitive indicators of this dysfunction.
[show abstract][hide abstract] ABSTRACT: This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. "Social context" refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences.
The American Journal of Bioethics 05/2011; 11(5):24-30. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Quit attempts may have different outcomes based on menstrual cycle phase on quit day. This is the first preliminary study examining whether smoking cessation outcomes vary by menstrual cycle phase of quit date in women receiving a 6-week open trial of sustained release (SR) bupropion.
Thirty-three treatment-seeking premenopausal women were studied. Abstinence outcomes were compared for women quitting during the luteal versus follicular phase.
Women receiving bupropion SR whose self-selected quit date occurred in the luteal phase had significantly higher rates of point prevalence abstinence during the final week of a 6-week post-quit treatment period than women quitting in the follicular phase (62.5% versus 29.4%; p<0.05). A similar, but non-significant, pattern of findings was demonstrated for continuous abstinence during the treatment phase and for point prevalence abstinence at 3-month follow-up.
Women receiving bupropion SR were significantly more likely to be abstinent at treatment completion if quitting occurred during the luteal phase. This is consistent with recent findings of outcome related to cycle phase at quit date in the absence of pharmacotherapy, and differs from findings utilizing nicotine replacement. Results add to emerging data suggesting that smoking cessation interventions with varying mechanisms of action may result in different outcomes for premenopausal women based on gonadal hormones at quit date.
Drug and alcohol dependence 03/2011; 114(1):68-72. · 3.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Emergency physicians as front-line clinical specialists can directly advance patient care by understanding how gender-specific approaches may affect evaluation and management of diseases in the acute setting. Yet, it is unclear whether the role of gender is systematically examined in research focusing on emergency care.
The objective was to determine if the effect of gender on health outcomes is examined in published studies targeting emergency medicine (EM).
Using MEDLINE, the term "emergency" was used to identify all English-language, EM-related studies of adult human subjects published between January 2006 and April 2009 in which the first, second, or last author belonged to an EM section, division, center, or institution functioning as an emergency department (ED). The alternative chance-corrected statistic was used for intercoder reliability, and chi-square was used to calculate odds ratios (OR) with 95% confidence intervals (CIs). Articles were coded for gender composition, as well as use of gender as a control variable, independent variable, or part of the primary hypothesis.
The search revealed 2,487 articles using the selected "emergency" terms, and 750 original studies coded as EM-related publications were reviewed. The five topics contributing the most articles (44%) were administration/crowding, cardiovascular disease, emergency medical services, trauma, and sepsis. Seventy-nine percent of articles reported the gender composition of the sample, with 11% including gender as a control variable, 18% including gender as an independent variable, and 2% including gender in the primary hypothesis. The alternative chance-corrected statistic for evaluating gender composition was 0.90 (95% CI = 0.75 to 1.00). Use of gender in the analysis did not differ between federally funded studies versus non-federally funded studies (OR = 0.86; 95% CI = 0.5 to 1.4). The number of articles analyzing the effect of gender on a health outcome increased by 5% over the study period (27%-32%).
The majority of research articles targeted EM report gender as a demographic variable; however, few studies examined the effect of gender on health outcome. As the specialty advances into the next decade, the authors recommend that EM researchers 1) include both men and women in their study designs for appropriate gender comparisons; 2) report gender composition of study subjects and gender-specific comparisons study findings; and 3) report prognoses, outcomes, and interventions using gender as an independent variable in the study model.
Academic Emergency Medicine 02/2011; 18(2):e1-4. · 1.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Despite an increasingly recognized relationship between depression and smoking, little is known about the degree to which treatment studies for depression consider the impact of smoking on outcomes. The aim of this study is to examine the extent to which smoking is considered in current antidepressant treatment research. We conducted a MEDLINE search of recent randomized clinical trials of pharmacotherapy for depression published between 1 January and 31 December 2007, and a search of current pharmacological intervention studies for depression using www.ClinicalTrials.gov. Only 5% of the 107 pharmacological trials for depression published in 2007 reported the smoking status of their samples. Two studies (1.9%) controlled for smoking in the analyses and no studies analyzed outcomes by smoking status. Excluding the eight studies of combined treatment for depression and nicotine dependence, no other study on www.ClinicalTrials.gov (total n = 920) reported an intention to analyze outcomes by smoking status. Emerging data link smoking and depression, however, little attention has been directed toward the effects of smoking on antidepressant treatment outcomes. Conducting research to understand how nicotine and smoking affect responsiveness to antidepressants would advance our understanding of the neurobiology of depression and the development of new and targeted treatments.
Journal of Psychopharmacology 12/2010; 25(10):1269-76. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a series of exploratory analyses, we examined the roles of gender, reproductive status and negative affect on smoking abstinence in subjects participating in a large (n=385) 6-week randomized clinical trial (RCT) of nicotine patch therapy, with varying doses of oral naltrexone (0mg, 25mg, 50mg, 100mg) treatment. Negative affect was assessed daily during the first post-quit week via telephone interactive voice response (IVR). Weight and adverse events were recorded weekly. In the intent to treat sample, the effects of dose on continuous abstinence were non-significant in the overall model for men and women. In the 295 study completers, there was a significant effect of dose on continuous abstinence in women only (F=8.53, p=0.04). In the 100mg group, 71% of women were continuously abstinent compared to 41% in the placebo group (p<0.05). Women in the active naltrexone groups gained less weight (F=2.91, df=3, p=0.04). Women in the 100mg vs. placebo group were less adherent with medication (F=3.19, p<0.05). These effects were not significant in men. Naltrexone treatment condition (100mg vs. placebo, p=0.02, odds ratio (OR)=0.28), gender (OR=0.55 p=0.09), and IVR ratings of negative affect (OR 1.02, p=0.04) predicted abstinence at Week 1 in study completers. Menstrual cycle status on quit day had a modest affect on abstinence. These data suggest that naltrexone dose, gender, and negative affect play a role in smoking abstinence, particularly in the early stages of treatment. When used in conjunction with nicotine replacement therapy, naltrexone dose may be important in women.
Drug and alcohol dependence 11/2010; 112(1-2):1-8. · 3.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: The higher prevalence and cost of depression for women compared with men and the possible gender differences in treatment response demand the inclusion of women in clinical trials of depression treatments. The 1993 National Institutes of Health (NIH) Revitalization Act set a new standard, requiring investigators to consider the inclusion of women and analyze outcomes by gender, yet compliance with these standards in depression research has not been examined systematically. The purpose of this study is to examine the inclusion of women and gender-specific analyses in recent randomized clinical trials (RCTs) for depression.
RCTs were identified through a MEDLINE search for trials published between January 1 and December 31, 2007, and a Clinicaltrials.gov search of self-identified interventional studies to treat depression.
Of the 150 RCTs for depression published in 2007, 15% did not report the gender composition of their sample, 50% of studies did not analyze outcomes by gender, and 12% controlled for gender but did not analyze for gender differences. Of the 768 trials reviewed on Clinicaltrials.gov, 89% reported recruiting male and female participants, yet <1% reported an intention to analyze results by gender.
Many recent studies of depression treatments include women but do not examine outcomes by gender. Understanding how women differ from men in response to treatment is critical for enhancing treatment efficacy for the greatest number of adults with depression.
Journal of Women s Health 09/2010; 19(9):1727-32. · 1.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: Little is known about beliefs about quitting and treatment motivation in non-treatment seeking smokers. One hundred eight-eight daily cigarette smokers not currently motivated to quit smoking completed measures of perceived risks and benefits of quitting and motivation to quit. Self esteem related to quitting was positively related to desire to quit, expected success at quitting, confidence in quitting, and motivation to quit. Greater perceived risks of cravings were related to greater expected difficulty of remaining abstinent, and greater perceived risk of increased negative affect was related to decreased expectation of success at quitting, confidence for quitting, and increased expectation for difficulty remaining abstinent. Greater perceived risk of weight gain was related to being less likely to have a goal of complete abstinence. There were no gender, ethnicity, age, or education differences in the relationship of perceived risks and benefits of quitting and motivation. Knowing the risks and benefits that relate to motivation to quit for non-treatment seeking smokers provides the foundation for targeting this group in campaigns to increase quit motivation.
Addiction Research and Theory 08/2010; 18(4):456-463. · 1.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with depression (n=20) or bipolar disorder (n=21) completed computerized ambulatory monitoring for three consecutive days. Results indicate satisfactory rates of acceptance and compliance, with no salient fatigue effects. However, some evidence for reactive effects was found. The findings provide support for this approach in the study of mood disorders.
Psychiatry Research 07/2010; 178(2):440-2. · 2.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Men and women show important differences in clinical conditions in which deficits in cognitive control are implicated. We used functional magnetic resonance imaging to examine gender differences in the neural processes of cognitive control during a stop-signal task. We observed greater activation in men, compared to women, in a wide array of cortical and sub-cortical areas, during stop success (SS) as compared to stop error (SE). Conversely, women showed greater regional brain activation during SE > SS, compared to men. Furthermore, compared to women, men engaged the right inferior parietal lobule to a greater extent during post-SE go compared to post-go go trials. Women engaged greater posterior cingulate cortical activation than men during post-SS slowing in go trial reaction time (RT) but did not differ during post-SE slowing in go trial RT. These findings extended our previous results of gender differences in regional brain activation during response inhibition. The results may have clinical implications by, for instance, helping initiate studies to understand why women are more vulnerable to depression while men are more vulnerable to impulse control disorders.
Brain Imaging and Behavior 09/2009; 3(3):262-276. · 2.67 Impact Factor