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Background: Individuals with a family history of alcohol and other substance use disorders (FH+) are several times more likely to develop alcohol problems compared to individuals with no such family histories (FH-). Here we sought to evaluate associations of early life adversity (ELA) with two key risk-related FH+ phenotypic characteristics: increased antisocial and depressive tendencies., Methods: We examined data from 1187 FH+ and FH- young adults (average age 23.6 years old) with and without personal histories of substance use disorders. Antisocial tendencies were evaluated with the Socialization scale of the California Personality Inventory (CPI-So), while depressive tendencies were evaluated with the Beck Depression Inventory II (BDI)., Results: In general, being FH+, having a personal substance use disorder history, and experiencing greater levels of ELA were associated with lower CPI-So scores (indicating more antisocial tendencies) and higher BDI scores (indicating more depressive tendencies)., Conclusions: These results suggest that ELA is linked to increased antisocial and depressive tendencies observed in FH+ persons. Given that FH+ individuals are disproportionately exposed to ELA, this increased exposure may be a major contributor to these and other risk-related characteristics commonly present in FH+ individuals. Additional studies are needed to evaluate the impact of ELA on risk-related phenotypic characteristics, including prospective studies in early childhood and mechanistic studies evaluating pathways by which ELA exerts its effects on FH phenotypic characteristics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Some individuals are resistant to alcohol use disorders despite high levels of intake. Addiction Resistance (AR) measures the disparity between alcohol consumption and alcohol use disorder (AUD) symptoms, such that some persons exhibit few (AUD) symptoms despite higher intake. The validity of the concept and the factors contributing to AR are not well understood. The aim of this study was to predict AR based on variables related to risk for addiction that are measured in the Family Health Patterns Project., Method: Participants were healthy young adults (n = 1122) with and without a family history of alcohol and other substance use disorders who were given measures of mood stability and risk-taking tendencies, and were interviewed to determine alcohol intake, AUD symptoms, and other substance use disorders (SUD). AR was calculated using maximal lifetime alcohol intake and number of AUD symptoms., Results: A principal components analysis was run with varimax rotation, which yielded three components: Component 1 indexed behavioral and mood regulation, Component 2 encompassed family and environmental factors, and Component 3 included cognitive factors. A multiple regression analysis revealed that Component 1 and Component 2 were predictive of AR whereas Component 3 was not., Discussion: Individuals who reported greater emotional stability, norm adherence, risk avoidance, and fewer family members with substance use disorders were more resistant to AUD despite higher alcohol intake. These findings suggest that AUD risk and resistance may represent different points of the same continuum., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Women have smaller cortisol responses to psychological stress than men do, and women taking hormonal contraceptives (HC+) have smaller responses than HC- women. Cortisol secretion undergoes substantial diurnal variation, with elevated levels in the morning and lower levels in the afternoon, and these variations are accompanied by differences in response to acute stress. However, the impact of HC use on these diurnal relationships has not been examined. We tested saliva cortisol values in 744 healthy young adults, 351 men and 393 women, 254 HC- and 139 HC+, who were assigned to morning (9:00 am) or afternoon (1:00 pm) test sessions that were held both on a rest day and on a stress day that included public speaking and mental arithmetic challenges. Saliva cortisol responses to stress were largest in men and progressively smaller in HC- and in HC+ women (F = 23.26, p < .0001). In the morning test sessions, HC+ women had significantly elevated rest day cortisol levels (t = 5.99, p ≪ .0001, Cohen's d = 0.95) along with a complete absence of response on the stress day. In the afternoon sessions, both HC+ and HC- women had normal rest-day cortisol levels and normal responses to the stressors. Heart rates at rest and during stress did not vary by time of day or HC status. Cortisol stress responses in HC+ women are absent in the morning and normal in size by early afternoon. Studies of stress reactivity should account for time of day in evaluating cortisol responses in women using hormonal contraceptives.

Background: Risk for alcoholism may be enhanced by exposure to early-life adversity (ELA) in persons with genetic vulnerabilities. We examined ELA in the presence of a common variant of the gene for the enzyme catechol-O-methyltransferase (COMT, Val158Met, rs4680) in relation to cortisol reactivity, the onset of early drinking, and experimentation with drugs., Methods: Saliva cortisol reactivity to speech and mental arithmetic stress was measured in 480 healthy young adults (23.5 years of age, 50% females) who experienced either 0, 1, or ≥ 2 forms of ELA during childhood and adolescence, provided information on use of alcohol and recreational drugs, and were genotyped for the Val158Met polymorphism., Results: ELA led to progressively smaller cortisol responses in the Met/Met and Val/Met allele groups but to progressively larger responses in Val homozygotes, F = 3.29, p = 0.011. ELA independently predicted earlier age at first drink, F = 14.2, p < 0.0001, with a larger effect in Met-allele carriers, F = 13.95, p < 0.00001, and a smaller effect in Val homozygotes, F = 4.14, p = 0.02. Similar effects were seen in recreational drug use. Cortisol reactivity was unrelated to drinking behavior or drug experimentation., Conclusions: ELA leads to blunted stress reactivity and, independently, contributes to potentially risky drinking and drug-use behaviors in persons carrying 1 or 2 copies of the COMT 158Met allele. The results reinforce the impact of early experience on the stress axis and on risky behaviors, and they point to the 158Met allele as conveying a vulnerability to the early environment., (© 2019 by the Research Society on Alcoholism.)

Early life adversity (ELA) negatively affects health behaviors in adulthood, but pathways from ELA exposure to behavioral outcomes are poorly understood. ELA in childhood and adolescence may translate into adult outcomes by way of modified glucocorticoid signaling. The cortisol cotransporter, FKBP5 has a G-to-A substitution (rs9296158) that hinders cortisol trafficking within target cells, and this impaired glucocorticoid signaling may shape the long-term response to ELA. We used performance on the Stroop test to assess working memory in 546 healthy young adults who had experienced 0, 1, or > 1 forms of ELA in childhood and adolescence and were genotyped for the FKBP5 rs9296158 G-to-A polymorphism. We observed a robust Gene x Environment interaction (F = 9.49, p < .0001) in which increased ELA exposure led to progressively greater Stroop interference in persons carrying AG and AA genotypes of FKBP5 with no such effect in GG carriers. Further work is needed to explore the modification of cognitive function resulting from ELA. Impairments in working memory illustrate how ELA may use glucocorticoid pathways to influence working memory with potential implications for decision-making and risky behavior including substance use disorders., Competing Interests: I have read the journal's policy and the authors of this manuscript have no competing interests.

Background and Aims: People with blunted stress reactivity have poor impulse control and also show increased risk for alcoholism. Exposure to early life adversity (ELA) contributes to blunted reactivity, but individual differences in susceptibility to ELA are not well understood. This study aimed to determine whether exposure to ELA has a greater impact on stress reactivity in young adults with a family history of alcoholism (FH+) compared with young adults with no family history of alcoholism (FH-)., Design: Observational study using linear modeling., Setting: Oklahoma, USA., Participants: Seven hundred and nine young adults (398 females) recruited through community advertisement., Measurements: We obtained heart rates and cortisol levels in subjects while undergoing public speaking and mental arithmetic stress compared with a resting control day (1418 test sessions). ELA was quantified as 0, 1 or > 1 adverse events experienced by age 15 years. FH+ people had one or two parents with an alcohol use disorder, and FH- controls had no such history for two generations., Findings: Increasing levels of ELA predicted progressive blunting of cortisol and heart rate reactivity for the whole sample (Fs = 4.57 and 4.70, Ps ≤ 0.011), but examination by FH status showed that the effect of ELA was significant only among FH+ (Fs ≥ 3.5, Ps < 0.05) and absent in FH- (Ps > 0.40). This difference in ELA impact was not explained by the cortisol diurnal cycle or subjective evaluation of the stressors., Conclusions: People with a family history of alcoholism appear to be vulnerable, in terms of changes to physiological stress response, to the impact of exposure to early life adversity while people with no family history of alcoholism appear to be resilient. Blunted stress reactivity may reflect differential vulnerability to early life adversity in young adults with a family history of alcoholism., (© 2018 Society for the Study of Addiction. This article has been contributed to by US Government employees whose work is in the public domain in the USA.)

Early life adversity (ELA) contributes to behavioral impulsivity along with risk for substance use disorders, both accompanied by blunted stress-axis reactivity. However, the biological contributors to blunted stress reactivity are not known. We took advantage of the fact that women have significant opioid inhibition of cortisol output by using the opioid antagonist, naltrexone, to unmask opioid interactions due to ELA. We administered 50 mg of naltrexone or placebo to 72 healthy women (23 years of age) in a double-blind crossover study and observed deviations in cortisol secretion from placebo over the next 180 minutes. ELA was assessed by reported exposure to physical and sexual abuse or neglect and low socioeconomic status and scored as Low, Medium, or High (0, 1-2, and 3+). The ELA groups all had identical placebo-day cortisol secretion, indicating normal basal regulation of the hypothalamic-pituitary-adrenocortical axis. Cortisol rises to naltrexone were largest in the Low-ELA group and strongly blunted in the High-ELA group (F = 3.51, p = 0.035), indicating a lack of opioid function in women with high degrees of ELA. The Low-ELA women reported dysphoric responses to naltrexone (F = 4.05, p = .022) indicating a mild opioid withdrawal, an effect that was absent in the High-ELA group. Women exposed to ELA have blunted cortisol responses to naltrexone, indicating reduced opioid regulation of the stress axis. Central opioid changes may be one pathway linking ELA to blunted stress reactivity in adulthood., Competing Interests: The authors have declared that no competing interest exists.

Individuals with a family history of alcohol and other drug use disorders (FH+) are at increased risk for developing substance use disorders themselves relative to those with no such histories (FH-). Here we sought to identify key characteristics associated with FH+ status and alcohol and other drug use disorder status in a large cohort of FH+ and FH- young adults. We conducted principal component analyses on demographic, temperament, and cognitive measures differentiating 506 FH+ and 528 FH- young adults. Three principal components were identified, and these component scores were then used to predict the odds of being FH+ and the odds of having an alcohol or other drug use disorder. Component 1 consisted of measures indexing internalizing traits, with higher component scores indicating greater depressive, anxious, and emotional instability tendencies. Component 2 consisted of measures of externalizing traits as well as exposure to early life adversity (ELA), with higher scores indicating less impulse control, more antisocial behavior, and greater ELA exposure. Component 3 consisted of estimated intelligence, delay discounting, and demographic characteristics, with higher scores indicating lower estimated intelligence, greater discounting of delayed rewards, less education, and lower childhood socioeconomic status. For each 1-point increase in the Component 1, 2, and 3 scores, the odds of being classified FH+ increased by 2%, 8%, and 4%, respectively. Similar findings were observed when individuals with alcohol or other drug use disorders were removed from the analyses. Finally, greater Component 2 scores were also associated with increased odds of having an alcohol or other drug use disorder. Collectively, these findings provide a more comprehensive understanding of the FH+ phenotype in young adults and help form a basis for further studies on biological mechanisms underlying risk for substance use disorders. The present findings also provide further support for a prominent role of ELA in promoting risk for problem alcohol and other drug use., (Copyright © 2017. Published by Elsevier Ltd.)

Objective: Exposure to stress during critical periods of development can diminish stress reactivity by the hypothalamic-pituitary-adrenocortical axis. Genetic characteristics may further modify this effect of early adversity, leading to a gene by environment (G × E) interaction on stress reactivity in adulthood. Val-allele carriers of a common polymorphism of the COMT gene (Val158Met, rs4680) have rapid removal of catecholamines in the prefrontal cortex, limbic system, and reward centers. Carriers of the Val and Met alleles may therefore respond differently to the environment and differ in the long-term impact of exposure to early life adversity (ELA)., Methods: We measured saliva cortisol reactivity to public speaking and mental arithmetic stress in 252 healthy young adults exposed to low, medium, and high levels of ELA and who were genotyped for the Val158Met polymorphism., Results: Cortisol responses showed a G × E interaction (F(4,243) = 2.78, p = .028); simple effects tests showed that Met/Met carriers had progressively smaller cortisol responses with greater levels of ELA. In comparison, Val/Val homozygotes had blunted responses that did not vary with ELA exposure., Conclusions: Met/Met homozygotes seem sensitive to stressful events in childhood and adolescence, leading to environmental programming of the stress axis. Glucocorticoid responsivity may represent a common pathway revealing targeted genetic vulnerabilities to the long-term effects of early life stress. The results suggest that further G × E studies of ELA are warranted in relation to health behaviors and health outcomes in adulthood.

Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of psychological, physiological, and behavioral characteristics of 252 healthy young adults for the impact of early-life adversity (ELA) in relation to the G-to-A single nucleotide polymorphism (SNP), rs9296158, of the FKBP5 gene. FKBP5 is a molecular cochaperone that contributes to the functional status of the glucocorticoid receptor (GR) and to the quality of corticosteroid signaling. FKBP5 expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation seen in A-allele carriers. As such, FKBP5 expression and GR function may be environmentally sensitive in A-allele carriers and therefore suitable for the study of gene-by-environment (G × E) interactions. Compared with FKBP5, GG homozygotes (N=118), A-allele carriers (N = 132) without psychiatric morbidity had progressively worse performance on the Stroop color-word task with increasing levels of ELA exposure (Genotype × ELA, F=5.14, P=0.007), indicating a G × E interaction on working memory in early adulthood. In addition, heart rate response to mental stress was diminished overall in AA/AG-allele carriers (F=5.15, P=0.024). Diminished working memory and attenuated autonomic responses to stress are both associated with risk for alcoholism and other substance use disorders. The present data suggest that FKBP5 in the GR pathway may be a point of vulnerability to ELA, as seen in this group of non-traumatized young adults. FKBP5 is accordingly a potential target for more extensive studies of the impact of ELA on health and health behaviors in adulthood.

Differences in stress reactivity may affect long-term health outcomes, but there is little information on how these differences arise. The stress axis is regulated by, in part, the endogenous opioid, beta-endorphin, acting on mu-opioid receptors. Persons carrying one or two copies of the G allele of the mu-opioid receptor gene (OPRM1 A118G) may have higher receptor binding for beta-endorphin compared with AA homozygotes that may contribute to individual differences in cortisol reactivity to stress, leading to a relative blunting of cortisol stress reactivity in G allele genotypes. We measured cortisol in 251 young adults (69 GA/GG vs 182 AA genotypes) exposed to mental arithmetic plus public speaking stress relative to a resting control day. Women had smaller cortisol responses than men (F=10.2, p=0.002), and women with GA or GG genotypes (N=39) had an absence of cortisol response relative to AA carriers (N=110) (F=18.4, p<0.0001). Male genotypes had no such difference in response (F=0.29). Cortisol response following mu-opioid receptor blockade using naltrexone in 119 of these subjects unmasked a greater tonic opioid inhibition of cortisol secretion in women (N=64), consistent with their blunted stress reactivity. Compared with men, women may have cortisol stress responses that are more heavily regulated by endogenous opioid mechanisms, and the OPRM1 GA/GG genotypes may affect females differentially relative to males. Diminished cortisol responses to stress may have consequences for health behaviors in women with GA/GG genotypes.

Aim: This study examined the impact of early lifetime adversity (ELA) on affect regulation and personality in persons with family history (FH+) and without (FH-) a family history of alcoholism. We examined the impact of early life adversity in healthy young adults, 18-30 years of age enrolled in a long-term study on risk for alcohol and other substance abuse., Methods: ELA was assessed by a composite score of low socioeconomic status and personal experience of physical or sexual abuse and/or separation from parents before age 16, resulting in a score of 0, 1-2, or >3 adverse events. Unstable affect regulation and personality variables were obtained via self-report measures., Results: Higher ELA scores were seen in FH+ (χ(2)=109.2, p<0.0001) and in women (χ(2)=17.82, p=0.0019). Although higher ELA predicted less emotional stability and more behavioral undercontrol, further analysis including both FH and ELA showed that FH+ persons are prone to poor affect regulation, negative moods, and have risky drinking and drug abuse tendencies independent of ELA level. ELA predicts reduced stress reactivity and poorer cognitive control over impulsive behaviors as shown elsewhere., Conclusions: The present work shows that FH+ have poor mood regulation and antisocial characteristics. The greater prevalence of ELA in FH+ persons indicates that life experience and FH+ work in tandem to result in risky patterns of alcohol and drug experimentation to elevate risk for alcoholism. Further studies of genetic and environmental contributions to alcoholism are called for., (Published by Elsevier Ireland Ltd.)

Background: Individuals with a family history of alcoholism (FH+) are at enhanced risk of developing alcohol or other substance use disorders relative to those with no family history (FH-). Alcoholics and FH+ subjects have greater interference scores on the Stroop color-word task, suggesting these impairments may be a component of the cognitive phenotype of at-risk individuals., Methods: In this study, we examined whole-brain activations in 24 FH+ and 28 FH- young adults performing the counting Stroop task, a variant of the Stroop task adapted for neuroimaging studies., Results: Across all subjects, incongruent versus congruent comparisons showed activations in regions including parietal lobe areas, frontal eye fields, premotor areas, the anterior cingulate cortex, dorsolateral prefrontal cortex, and bilateral insula, indicating typical regions of activation involved in conflict resolution tasks. Compared with FH- participants, FH+ participants had greater activations in the left superior parietal lobule and precuneus (BA 7 and 19), inferior parietal lobule (BA 40), and middle temporal gyrus (BA 39 and 19), indicating a predominance of greater left hemisphere activity among FH+ in temporoparietal regions. There were no regions showing greater activations in the FH- group compared with the FH+ group., Conclusions: These results are consistent with less efficient cognitive functioning potentially due to poorer communication over long pathways connecting temporoparietal regions to prefrontal brain regions that participate in a distributed network involved in cognitive processing and working memory necessary for conflict resolution., (Copyright © 2014 by the Research Society on Alcoholism.)

Background: Central serotonergic (5-HT) function is implicated in pathways to alcohol dependence, including dysphoria manifested by symptoms of anxiety and depression. However, little is known about genetic variation in central 5-HT function and its potential impact on temperament and behavior in persons with a family history of alcoholism (FH+)., Methods: We tested 314 healthy young adults (23.5 years of age, 57% female; 193 FH- and 121 FH+) enrolled in the Oklahoma Family Health Patterns project, a study of alcoholism risk in relation to temperament and behavioral dyscontrol. Dysphoria was assessed using the Eysenck neuroticism and Beck depression scales, and Cloninger's Tridimensional Personality Questionnaire. Risk taking was assessed with the Iowa Gambling Task (IGT) and Balloon Analogue Response Task (BART). All subjects were genotyped for a functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4)., Results: FH+ subjects with the gain-of-function 5-HTTLPR genotype scored higher in neuroticism, harm avoidance, and symptoms of depression (p-values ≤ 0.03). No effect of 5-HTTLPR genotype was seen in FH-. FH+ carriers of the gain-of-function 5-HTTLPR genotype played to minimize their frequency of losses in the IGT, whereas FH- carriers played a balanced strategy (p < 0.003). No 5-HTTLPR effects were seen in the BART. Results were unaffected by sex, education, drug use, and antisocial characteristics., Conclusions: The functional 5-HTTLPR polymorphism predicted significant variation in negative moods and poorer affect regulation in FH+ persons, with possible consequences for behavior, as seen in a simulated gambling task. This pattern may contribute to a drinking pattern that is compensatory for such affective tendencies., (Copyright © 2014 by the Research Society on Alcoholism.)

The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n=72 using hormonal contraception; HC+) completed a two-session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm. A subset of seventy women (n=24 HC+) also completed a second study in which they were administered oral naltrexone (50mg) or placebo in a randomized, placebo-controlled, double blind fashion. Women who were HC+ had a significantly reduced salivary cortisol response to both the psychosocial stressor (p<0.001) and naltrexone (p<0.05) compared to HC- women. Additionally, HC+ women had a significantly altered morning diurnal cortisol rhythm (p<0.01), with a delayed peak and higher overall levels. The results of the current study confirm that HC attenuates salivary cortisol response to a psychosocial stressor and mu-opioid receptor antagonism, and also alters the morning diurnal cortisol curve., (Published by Elsevier Inc.)

Background: Stressful early life experience may have adverse consequences in adulthood and may contribute to behavioral characteristics that increase vulnerability to alcoholism. We examined early life adverse experience in relation to cognitive deficits and impulsive behaviors with a reference to risk factors for alcoholism., Methods: We tested 386 healthy young adults (18 to 30 years of age; 224 women; 171 family history positive for alcoholism) using a composite measure of adverse life experience (low socioeconomic status plus personally experienced adverse events including physical and sexual abuse and separation from parents) as a predictor of performance on the Shipley Institute of Living scale, the Stroop color-word task, and a delay discounting task assessing preference for smaller immediate rewards in favor of larger delayed rewards. Body mass index (BMI) was examined as an early indicator of altered health behavior., Results: Greater levels of adversity predicted higher Stroop interference scores (F = 3.07, p = 0.048), faster discounting of delayed rewards (F = 3.79, p = 0.024), lower Shipley mental age scores (F = 4.01, p = 0.019), and higher BMIs in those with a family history of alcoholism (F = 3.40, p = 0.035). These effects were not explained by age, sex, race, education, or depression., Conclusions: The results indicate a long-term impact of stressful life experience on cognitive function, impulsive behaviors, and early health indicators that may contribute to risk in persons with a family history of alcoholism., (Copyright © 2012 by the Research Society on Alcoholism.)

Naltrexone evokes a cortisol response through its blockade of central opioid receptors on the hypothalamic-pituitary-adrenocortical axis (HPA). The magnitude of this cortisol response may be useful as a probe for central opioid activity in different groups of subjects. Accordingly, the present study examined the effect of opioid blockade on the HPA in 70 women and 58 men with (N=41) and without (N=87) a family history of alcoholism, using a randomized, placebo-controlled, double blind administration of oral naltrexone (50mg). Saliva cortisol was sampled at baseline prior to placebo or naltrexone and again every 30 min over the next 180 min. Women had significantly larger cortisol responses to naltrexone than did the men, F=6.88, p<0.0001. There were no significant differences in cortisol response between groups differing in family history of alcoholism, F=0.65, p>0.69. The present results confirm that women have much greater central opioid restraint on the HPA than men do and that this endogenous restraint is unmasked by opioid blockade. However the results provide no evidence of a differential central opioid tonus in persons with a family history of alcoholism at this dose of naltrexone. The cortisol response to naltrexone may be a useful probe for central opioid activity in women and to a lesser degree in men., (Published by Elsevier Ltd.)

Background: Can stressful events in early life alter the response characteristics of the human stress axis? Individual differences in stress reactivity are considered potentially important in long-term health and disease; however, little is known about the sources of these individual differences. We present evidence that adverse experience in childhood and adolescence can alter core components of the stress axis, including cortisol and heart rate reactivity., Methods: We exposed 354 healthy young adults (196 women) to public speaking and mental arithmetic stressors in the laboratory. Stress responses were indexed by self-report, heart rate, and cortisol levels relative to measures on a nonstress control day. Subjects were grouped into those who had experienced 0, 1, or 2 or more significant adverse life events, including Physical or Sexual Adversity (mugged, threatened with a weapon, experienced a break-in or robbery or raped or sexually assaulted by a relative or nonrelative) or Emotional Adversity (separation from biological mother or father for at least 6 months before age 15)., Results: Experience of adversity predicted smaller heart rate and cortisol responses to the stressors in a dose-dependent fashion (0 > 1 > 2 or more events) (F values = 5.79 and 8.11, p values < .004) for both men and women. This was not explained by differences in socioeconomic status, the underlying cortisol diurnal cycle, or subjective experience during the stress procedure., Conclusions: The results indicate a long-term impact of stressful life experience on the reactivity of the human stress axis., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)