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Cited by 1,785Stress Responses and CortisolChild Abuse and TraumaBirth, Development, and Health

Psychological stress in childhood and susceptibility to the chronic diseases of aging: Moving toward a model of behavioral and biological mechanisms.

Open access
Miller, Gregory E., Chen, Edith, Parker, Karen J.·2011·Psychological Bulletin
DOI 10.1037/a0024768PMC PMC3202072
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Abstract

Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.

Integrity signals

Registry

Crossref · 10.1037/a0024768

Cites

379 of 379 references verified0 citation errors · 0 not checkable

Statistics

2 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 470 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the authors' sample of 246 middle-aged adults, being raised in a less educated household was associated with making more threatening appraisals of ambiguous situations.

    “A robust SES gradient was apparent. To the extent that they were raised in less educated households, middle-aged adults made more threatening appraisals of the ambiguous situations [for omnibus effect, F(4,241) = 4.63, p < .001; for linear trend, contrast = .69, SE = .21, p = .001].”
    Quote in the paperSubstantial claim
  • Findingown data

    In the authors' re-analysis controlling for current familial SES, the association between early SES and threatening appraisals remained.

    “Even with the covariate included in the model, the disparities related to early SES persisted, F(4,240) = 2.93, p = .02.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    The Biological Embedding Model proposes that childhood stress becomes programmed into macrophages through epigenetic markings, post-translational modifications, and tissue remodeling.

    “This model maintains that childhood stress gets “programmed” into macrophages through epigenetic markings, post-translational modifications, and tissue remodeling.”
    • Also stated in: § Abstract · plain
      “Briefly, it posits that childhood stress establishes a pro-inflammatory phenotype in cells of the immune system called monocytes/macrophages.”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    Early stress confers altered patterns of endocrine and autonomic discharge.

    “Hormonally, early stress confers altered patterns of endocrine and autonomic discharge.”
    • Also stated in: § Abstract · plain
      “alters patterns of endocrine and autonomic discharge.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Children raised in poverty or maltreated by parents show increased vulnerability to vascular disease, autoimmune disorders, and premature death.

    “The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality.”
    Quote in the paperSubstantial claim
  • May combine two claims. 126
  • Classified as probably not a substantial claim. 42
  • The quote only partly states this claim. 3

  • May combine two claims.

    Interpretationreasoning

    The model posits that childhood stress leads to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices.

    “Behaviorally, the model posits that early stress fosters vigilance for threat and mistrust of others, traits which make it difficult to form deep social ties. Early stress also impairs self-regulation, creating a proclivity for unhealthy behaviors, and alters patterns of endocrine and autonomic discharge.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    A study of Israeli immigrants from Europe found elevated cancer rates in post-WWII immigrants, many Holocaust survivors; those born 1940-1945 had 3.5-fold elevated cancer risk relative to same-aged pre-war immigrants.

    “And recently, a study of cancer in Israelis who had emigrated from Europe appeared (Keinan-Boker et al., 2009). It found that cancer rates were elevated in immigrants who arrived after World War 2, many of whom were Jews persecuted during the Holocaust. The largest effects were seen in people born 1940–1945, who would have been exposed to horrific conditions before age 5. Their cancer risk was”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Keinan-Boker et al., 2009

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    Premisecitation

    Existing mind-body models generally focus on immediate biological sequelae of stress and do not clearly explain pathology with long incubation periods.

    “However, the focus of these models is generally on the immediate biological sequelae of stress, and it is thus unclear how they would explain pathology that develops over such a lengthy incubation period (Baum et al., 1993; Miller et al., 2009b; Mohr and Pelletier, 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Baum et al., 1993

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    • cites Miller et al., 2009b

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    • cites Mohr and Pelletier, 2006

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    Premisereasoning

    Developmental psychobiology has delineated how early events shape lifelong HPA axis response tendencies, but this work has focused on psychopathology and little effort has detailed pathophysiologic mechanisms to medical problems.

    “By contrast, researchers working in developmental psychobiology have made significant progress in delineating how early events shape life-long response tendencies of the hypothalamic-pituitary-adrenocortical (HPA) axis (Gunnar and Quevedo, 2007; Heim et al., 2008; Levine, 2005; Zhang et al., 2006). However, the focus of this work has been on how disrupted HPA axis functioning could give rise to”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gunnar and Quevedo, 2007

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    • cites Heim et al., 2008

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    • cites Cameron et al., 2005

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    Premisecitation

    In that meta-analysis, effect sizes were identical in studies using objective versus subjective methodology, and maltreatment had a significant relationship with stroke and myocardial infarction (d=.66).

    “Results indicated that the magnitude of effect sizes was identical in studies that used objective versus subjective methodology. Moreover, maltreatment had a significant relationship with some fairly salient outcomes, like history of stroke and myocardial infarction (d=.66), which people could be expected to recall in a reliable fashion.”
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    • cites Wegman and Stetler, 2009

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    Premisecitation

    In ACE autoimmune analysis, odds of first hospitalization for any autoimmune disease were higher among adults with 2 or 3 kinds of childhood adversity compared with none, but statistically significant only for women; linear trend showed 20% increase per additional adversity for women and 10% for men.

    “It found that the odds of a first hospitalization for any autoimmune disease was higher among adults with 2 or 3 kinds of childhood adversity compared with those with none; however, the relationship was statistically significant only for women. In linear trend analysis there was a dose-response effect for both genders; for every additional kind of childhood adversity, the odds of an adult”
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    • cites Dube et al., 2009

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    Premisecitation

    In ACE analyses of premature mortality among family members, each additional type of adversity raised likelihood of premature death by 13% (OR 1.13); for 4+ types odds ranged 1.5-2.9 depending on age, independent of age, sex, race, and SES.

    “The analyses revealed an OR of 1.13, indicating that for every additional type of adversity, the likelihood of premature death of a family member rose by 13%. For those who had experienced 4 or more types of childhood adversity, the odds of a premature death ranged from 1.5–2.9 depending on age. These effects were independent of age, sex, race, and SES.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Anda et al., 2009

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    • The authors state this as an assumption: In the ACE premature mortality analysis, the respondent's siblings or parents were exposed to a similar household environment.

  • May combine two claims.

    Premisecitation

    A prospective study found that both maltreatment and disadvantage in early life were associated with risk factor clustering for CHD at age 32; covariance analyses showed partially overlapping effects and also unique pathways.

    “Consistent with this idea are the results of a recent prospective study, focusing on whether various forms of childhood stress presage the clustering of risk factors for CHD in adulthood (Danese et al., 2009). It found that both maltreatment and disadvantage in early life were associated with risk factor clustering at age 32. Covariance analyses showed the effects of these experiences to be”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Danese et al., 2009

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    Premisecitation

    The ACE Study assessed maltreatment retrospectively in 17,337 adults and found a dose-response association: 20% increase in CHD incidence for each additional kind of early adversity, and 2-3 fold increase in CHD among those reporting more than 4 types.

    “The most rigorous work in this area has come from the Adverse Childhood Experiences (ACE) Study, a large-scale project that assessed maltreatment retrospectively in 17,337 adults.”
    • Also stated in: § Long-Term Health Effects of Maltreatment · plain
      “There was evidence of a dose-response association, with a 20% increase in CHD incidence for each additional kind of early adversity experienced. Moreover, a 2–3 fold increase in CHD was found among those who reported more than 4 types of early life adversity (Dong et al., 2004).”
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    • cites Dong et al., 2004

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    Premisecitation

    Low childhood SES was a risk factor for CHD mortality in 7/10 studies and stroke mortality in 4/6 large studies; effects attenuated but not eliminated by adult SES adjustment.

    “In terms of disease-specific outcomes, low childhood SES emerged as a risk factor for CHD mortality in 7/10 studies and stroke mortality in 4/6 large studies. Again, these effects were attenuated but not eliminated by adjustment for adult SES.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Galobardes et al., 2004

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    • cites Galobardes et al., 2008

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    Premisecitation

    Childhood SES is fairly stable over the lifecourse, with poor children becoming poor adults more often than chance.

    “First, SES tends to be fairly stable over the lifecourse, with poor children becoming poor adults far more often than would be expected by chance (Hertzman, 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hertzman, 1999

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Under-reporting from retrospective self-report would add noise and constrain variance, reducing statistical power and making associations harder to detect.

    “Assuming this is true, the net effects would be to add noise to the data and artificially constrain variance on the maltreatment variable. In both cases this would reduce statistical power, making the study less likely to detect associations.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Retrospective self-report assessments of childhood maltreatment lead to under-reporting.

  • May combine two claims.

    Premisecitation

    Galobardes and colleagues reported that 28/33 studies found increased all-cause mortality risk (typically 20-40%) among individuals reared in low versus high-SES households; adjustment for adult SES attenuated but did not eliminate associations.

    “Galobardes and colleagues (2004; 2008) reported that 28/33 studies found an increased risk of all-cause mortality, typically of 20–40%, among individuals reared in low versus high-SES households. Adjustments for adult SES generally attenuated these associations, but did not eliminate them.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Galobardes et al., 2004

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    • cites Galobardes et al., 2008

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    Interpretationreasoning

    The evidence is suggestive of a causal influence of childhood maltreatment on later health problems, but more work is needed to rule out alternative explanations and clarify underlying pathophysiology.

    “Thus, we conclude that the evidence here is suggestive of a causal influence of childhood maltreatment on later health problems, but more work needs to be done to definitively rule out alternative explanations and clarify what the associations reflect in terms of underlying pathophysiology.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Maltreatment and socioeconomic disadvantage share enough common features to be aggregated under the rubric of chronic stress for purposes of generating a broad mechanistic model.

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    Premisecitation

    In a review of childhood SES and CVD, 19/24 prospective studies found significant inverse associations, with excess risk attributable to low SES in the 30-60% range; after adult SES control, excess CVD risk persisted in the 20-40% range.

    “19/24 prospective studies found significant inverse associations, with the excess risk attributable to low-SES in the 30–60% range. When SES in adulthood was controlled these associations were attenuated, but the excess CVD risk persisted in the 20–40% range.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Galobardes et al., 2006

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    Premisecitation

    Effects of childhood SES on CVD were stronger for stroke than for CHD, though CHD effects were reliable.

    “Mirroring the mortality data, the effects were stronger for stroke than for CHD, though the latter were reliable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Galobardes et al., 2006

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    Premisecitation

    Children exposed to disadvantage and maltreatment receive less sensory, cognitive, and emotional stimulation and are more likely to be deprived of basic necessities like food and heat than more privileged youth.

    “On the whole, children exposed to these stressors receive less sensory, cognitive, and emotional stimulation, and are more likely to be deprived of basic necessities like food and heat, than more privileged youth (Evans, 2004; Maulik and Darmstadt, 2009; McLoyd, 1998).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Evans, 2004

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    • cites Maulik and Darmstadt, 2009

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    • cites McLoyd, 1998

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    Interpretationreasoning

    The SES literature does not specifically implicate childhood exposure to stress as critical for later disease; it remains unclear whether effects are specifically attributable to early-life exposure.

    “A final limitation of the literature here is that it does not specifically implicate childhood exposure to stress as critical for later disease. Although studies link childhood SES with later medical outcomes, it remains unclear whether these effects are specifically attributable to early-life exposure in the way our interpretation presupposes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Studies addressing whether childhood is a sensitive period generally found support: excess disease risk associated with low childhood SES persists even with upward social mobility and is not generally accounted for by cumulative disadvantage.

    “Studies that have sought to address this question have generally found support for the hypothesis that childhood is a sensitive period, during which time low SES has potent and lasting effects on health. This conclusion derives from analyses suggesting that the excess disease risk associated with low childhood SES persists even when people experience upward social mobility, and is not generally”
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    • cites Hart et al., 2000

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    • cites Kuh et al., 2002

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    • cites Ljung and Hallqvist, 2006

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    Premisecitation

    In rodents, the first 8 days of life are a specific window during which variations in maternal care quality shape subsequent HPA axis stress responsivity, with lower maternal care leading to larger HPA responses that persist over the lifecourse.

    “For example, in rodents the first 8 days of life represent a specific window during which variations in the quality of maternal care shape subsequent responsivity of the HPA axis to stress (Meaney, 2001). Lower maternal care during this juncture leads animals to have larger HPA responses to stress, which persist over the lifecourse.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Meaney, 2001

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    Premisecitation

    Maternal care manipulations in week 2 of life have significantly less pronounced effects on GR expression, and manipulations in week 3 have no influence on long-term GR expression.

    “When care quality is altered during week 2 of life, the effects on GR expression are significantly less pronounced. Moreover, care manipulations in week 3 of life have no influence whatsoever on long-term GR expression (Meaney and Aitken, 1985)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Meaney and Aitken, 1985

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  • May combine two claims.

    Interpretationreasoning

    The SES studies have strengths including large representative samples, prospective designs, objective SES indicators, medical-record outcomes, control for lifestyle confounds, and cross-country consistency, which bolster confidence that observed associations reflect a causal process.

    “The studies of SES have notable strengths compared to the maltreatment literature. They make use of large and representative samples from multiple continents, use prospective designs, have objective SES indicators, and ascertain outcomes through medical records or healthcare databases, eliminating the concern that reporting styles are driving the observed associations. They also generally control”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In another study, rats stressed at 100 days with electric shocks to obtain food and drink for 4 days nearly all developed gastric ulcers, but ulcer density was five-fold greater in rats prematurely separated at 15 days.

    “In another study rats were placed in a stressful situation at 100 days of life (corresponding to early adulthood in humans). The situation required the rats to incur electric shocks to obtain food and drink for 4 days (Ader et al., 1960). Nearly all of the rats developed gastric ulcers following this experience. However, the density of these ulcers was five-fold greater in rats who had been”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ader et al., 1960

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    Interpretationreasoning

    Species differences in development are a major challenge because rodents are much less mature at birth than humans, so their physiology may need external regulation by caregivers in a manner not paralleled in full-term human newborns.

    “Species differences in development are another major challenge. At the time of birth, rodents are much less mature than humans. As a result, their physiology may need external regulation by caregivers in a manner that is not paralleled in full-term human newborns.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Social difficulties and unhealthy lifestyle amplify the chronic inflammatory state.

    “Together, these social difficulties and unhealthy lifestyle serve to amplify the chronic inflammatory state.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Dysregulated endocrine and autonomic discharge place monocytes/macrophages in a milieu that accentuates their pro-inflammatory tendencies.

    “Also contributing to this process are dysregulated patterns of endocrine and autonomic discharge, which consign monocytes/macrophages to operate in a milieu that accentuates their pro-inflammatory tendencies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Biological programming originated in research on nutritional deprivation and is now applied to various perinatal experiences, including psychosocial stress.

    “This is the notion of biological programming, which grew out of research on nutritional deprivation (Barker, 1992), but now is applied to a variety of perinatal experiences, including stress in the psychosocial domain”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Barker, 1992

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    • cites Cameron et al., 2005

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    • cites Cottrell and Seckl, 2009

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    Interpretationreasoning

    Animal findings do not prove that human studies capture a causal process, but they provide strong proof of principle that such effects can occur.

    “while the findings from animal models do not prove that the human studies are capturing a causal process, they do provide quite strong proof of the principle that such effects can occur.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Predictive adaptive responses are biological adaptations to anticipated environmental circumstances, occur during sensitive developmental periods, become embedded permanently, and calibrate physiology to match the ecology.

    “PAR’s are biological adaptations made in response to anticipated environmental circumstances. They occur during sensitive periods of development, when bodily tissues have maximal plasticity to environmental inputs. Typically PAR’s become embedded in physiology on a permanent basis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gluckman and Hanson, 2006

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    Interpretationreasoning

    Depending on genetic liabilities and other exposures, chronic inflammation drives mechanisms of pathogenesis including high blood pressure, insulin resistance, plaque growth, tissue destruction, and tumor progression.

    “Depending on the individual’s genetic liabilities and other relevant exposures (e.g., to pollutants, toxicants, carcinogens, etc.), the ensuing chronic inflammation drives forwards various mechanisms of pathogenesis. Those can include high blood pressure, insulin resistance, plaque growth, tissue destruction, and tumor progression.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Existing models offer insights into mind-body interactions but focus on the immediate biological sequelae of stress.

    “Existing models offer insights into the mechanistic basis of mind-body interactions (Glaser and Kiecolt-Glaser, 2005; Kop and Cohen, 2001; Miller et al., 2009b; Pressman and Cohen, 2005), but focus on the immediate biological sequalae of stress.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Glaser and Kiecolt-Glaser, 2005

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    • cites Kop and Cohen, 2001

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    • cites Miller et al., 2009b

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    Interpretationreasoning

    Stress becomes embedded in immune cells, causing them to mount excessive inflammatory responses to microbial challenges and to be insensitive to inhibitory hormonal signals.

    “stress gets “embedded” in these immune cells, causing them to mount excessive inflammatory responses to microbial challenges, and be insensitive to inhibitory hormonal signals.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Predictive adaptive responses enable organisms to defend themselves better, use resources optimally, reproduce more successfully, and confer enhanced fitness and survival benefits through reproductive age.

    “Functionally, PARs enable the organism to better defend itself, make optimal use of resources, and reproduce more successfully. In so doing, they confer enhanced fitness and, at least through reproductive age, survival benefits (Gluckman and Hanson, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gluckman and Hanson, 2006

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    Interpretationnone given

    Early stress leads people to become vigilant for threat and mistrusting of others.

    “Behaviorally, early stress leads people to become vigilant for threat and mistrusting of others.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These traits make people more likely to elicit conflict and rejection and less likely to garner warmth and support.

    “These traits shape the manner in which people engage their social worlds, making them more likely to elicit conflict and rejection, and less likely to garner warmth and support.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rats separated daily for two hours during the first month of life, adult ovalbumin-induced asthma produced more severe airway pathology than in controls, with increased eosinophils, T-cells, and pro-inflammatory mediators in the lungs.

    “Adult rats that had been repeatedly separated from their mothers early in life showed more severe airway pathology than adult controls, with increased numbers of eosinophils, T-cells, and other pro-inflammatory mediators found in their lungs upon dissection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kruschinski et al., 2008

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    Interpretationnone given

    Early stress leads people to develop poor self-regulation skills, discount the future in favor of immediate gratification, and have a propensity to engage in unhealthy behaviors.

    “Early stress also leads people to develop poor self-regulation skills, wherein the future is highly discounted in favor of immediate gratification, and there is a resulting propensity to engage in unhealthy behaviors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In original fetal-origins formulations, physiological adjustments cause wear and tear on organs over time, which with genetic liabilities gives rise to metabolic and coronary diseases.

    “In the original formulations of the model, physiological adjustments were thought to cause wear and tear on organs over time, which acting with genetic liabilities, gave rise to metabolic and coronary diseases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Barker, 1992

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Low birth weight reflects nutritional deprivation in utero due to poor maternal diet and/or insufficient nutrient transfer across the placenta.

    “Barker and others have argued that low birth weight reflects nutritional deprivation in utero, which arises because of poor maternal diet and/or insufficient nutrient transfer across the placenta (Barker, 1992; Gluckman et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Barker, 1992

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    • cites Gluckman et al., 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    In predator-rich settings, high vigilance for threat might confer a survival advantage by helping the organism perceive and respond to danger more rapidly.

    “For example, in a setting where predators abound, high vigilance for threat might confer a survival advantage by helping the organism to more rapidly perceive and respond to impending danger.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These adjustments spare critical organs and favor offspring with small body size, low skeletal muscle, and high visceral fat.

    “These adjustments spare critical organs like the heart, brain, and pancreas and favor the emergence of offspring with small body size, low skeletal muscle, and high visceral fat (Gluckman and Hanson, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gluckman and Hanson, 2006

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    These traits served to promote fitness in ancestral ecologies and may continue to do so today.

    “These traits served to promote fitness in ancestral ecologies, and may continue to do so today.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metabolic adjustments programmed during sensitive periods are thought to persist over the lifespan permanently and immutably.

    “Because the metabolic adjustments are programmed into physiology during sensitive periods of development, they are thought to persist over the lifespan in a fashion that is permanent and immutable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Barker, 1992

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    When Western children are reared in sufficiently perilous ecologies, a vestigial predictive adaptive response is cued that gives rise to the behavioral and biological phenotype in the model.

    “we suspect that when such children are reared in sufficiently perilous ecologies, a vestigial PAR is cued that gives rise to the behavioral and biological phenotype depicted in the model.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Few Western children today reside in settings that resemble the ancestral ecology.

  • May combine two claims.

    Interpretationcitation

    From early social context, people develop likes and dislikes, patterns of interacting with others, and strategies for regulating desires and emotions.

    “From their early social context people develop likes and dislikes, patterns of interacting with others, and strategies for regulating their desires and emotions (Bowlby, 1969; Cassidy and Shaver, 2008; Luecken and Lemery, 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bowlby, 1969

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    • cites Cassidy and Shaver, 2008

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    • cites Luecken and Lemery, 2004

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  • May combine two claims.

    Interpretationreasoning

    Early life experiences shape the kinds of environments people seek out and create later in adulthood, and how they respond to challenges in those environments.

    “it suggests that the experiences people have in early life shapes the kinds of environments they seek out (and create) for habitation later in life (in adulthood), as well as the ways in which they respond to challenges in those environments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ancestral ecologies contained recurring difficulties including predation, conflict with other humans and injuries, limited access to nutrients and resources, and accidents and infections.

    “These difficulties are likely to have included predation, conflict with other humans and the ensuing injuries, limited access to nutrients and resources, and accidents and infections.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2006

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Risky Families Model posits that some families are risky places for children because they are unstable, conflictual, lacking warmth and support, and use harsh discipline.

    “It posits that some families are “risky” places for children to develop, because they tend to be unstable and conflictual, lacking in warmth and support, and make use of harsh discipline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Repetti et al., 2002

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lifecourse epidemiology models emphasize trajectories that childhood experience sets people upon, referred to as chains of risk and accumulating chains of advantage or disadvantage.

    “These models emphasize the trajectories that childhood experience sets people upon (Pollitt et al., 2005), which are referred to as “chains of risk” (Kuh and Ben-Shlomo, 2004) and “accumulating chains of advantage or disadvantage” (Blane, 1999).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Pollitt et al., 2005

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    • cites Kuh and Ben-Shlomo, 2004

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    • cites Blane, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Over time, the impact of these hormonal surges accumulates, leading to allostatic load and subsequent health problems.

    “With time the impact of these hormonal surges accumulates, leading to wear and tear on bodily systems known as allostatic load (McEwen, 1998), and subsequent health problems.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McEwen, 1998

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  • Classified as probably not a substantial claim.

    Premisecitation

    These exposures are presumed to accumulate over the lifecourse such that more adversity increases the likelihood of illness.

    “These exposures are presumed to accumulate over the lifecourse such that the more adversity a person experiences, the more likely he or she is to become ill (Hertzman, 1999; Pollitt et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hertzman, 1999

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    • cites Pollitt et al., 2005

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    These familial dynamics trigger psychological vulnerabilities including deficits in social competence and emotion regulation, and a propensity to compensate with health-compromising behaviors.

    “These familial dynamics trigger a cascade of psychological vulnerabilities, including deficits in social competence and emotion regulation, and a propensity to compensate for them with health-compromising behaviors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Repetti et al., 2002

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  • May combine two claims.

    Premisecitation

    Adults who report having been reared in harsh family climates show relatively high levels of circulating inflammatory markers, more components of metabolic syndrome, and increasing trajectories of blood pressure.

    “In support of this view, adults who report having been reared in harsh family climates show relatively high levels of circulating inflammatory markers, more components of the metabolic syndrome, and increasing trajectories of blood pressure (Lehman et al., 2005; Lehman et al., 2009; Taylor et al., 2006b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lehman et al., 2005

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    • cites Lehman et al., 2009

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    • cites Taylor et al., 2006b

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adversity begets adversity: a child raised in poverty is likely to attend a poorly resourced school, receive a suboptimal education, become a low-income adult, and face occupational and neighborhood exposures that limit health resources.

    “The notion inherent in these models is that adversity begets adversity. A child raised in poverty is likely to attend a school with limited financial resources and receive a suboptimal education. This in turn makes it likely that s/he will be a low-income adult, have a job with routine exposure to pollutants and irritants, live in a neighborhood where fresh foods are hard to find, green spaces for”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hertzman, 1999

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    • cites Pollitt et al., 2005

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  • May combine two claims.

    Premisecitation

    Allostatic maneuvers are adaptive acutely, but repeated triggering causes dysregulation across multiple systems and declines in physical health.

    “Allostatic maneuvers are viewed as being adaptive on an acute basis. But if they are triggered repeatedly, dysregulation across multiple systems ensues, causing declines in physical health.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McEwen and Stellar, 1993

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  • May combine two claims.

    Premisecitation

    Lower SES parents often face multiple demands affecting the quantity and quality of time with children, including multiple jobs, long commutes, little schedule control, little leeway to take time off, frequent stressors, dilapidated housing, and single parenthood.

    “Lower SES parents often face multiple demands that affect the quantity and quality of time they can spend with their children. These parents often work multiple jobs with undesirable hours (Presser and Cox, 1997) and have to commute long distances to work (Osterman, 1991).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Presser and Cox, 1997

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    • cites Osterman, 1991

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    • cites Marmot et al., 1997

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  • May combine two claims.

    Interpretationreasoning

    These proclivities lead to frequent activation of stress-response systems, creating a hormonal milieu that requires immune adaptations, which exacerbate pro-inflammatory tendencies already programmed by childhood stress.

    “These proclivities lead to frequent activation of the body’s stress-response systems, creating a hormonal milieu that requires adaptations by the immune system. Ultimately, these adaptations serve to exacerbate the pro-inflammatory tendencies already programmed into cells by childhood stress.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    During stress, the body attempts to restore balance through change, known as allostasis.

    “The core of this idea is that during stress, the body attempts to restore balance through change (allostasis; McEwen and Stellar, 1993).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McEwen and Stellar, 1993

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  • May combine two claims.

    Interpretationreasoning

    These proclivities shape the environments people create later in life and how they respond to challenges in those environments.

    “These proclivities shape the kinds of environments people create for habitation later in life and the manner in which they respond to challenges in those environments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Childhood stress gets programmed into the response tendencies of monocytes/macrophages through specific molecular pathways.

    “We build on them here by proposing that childhood stress (a) gets programmed into the response tendencies of monocytes/macrophages through specific molecular pathways”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Low SES parents are more likely to use harsh strategies such as corporal punishment, impose demands without explanation, and be inconsistent in parenting.

    “They are more likely to use harsh strategies, like corporal punishment (Bradley et al., 2001; Dodge et al., 1994; McLoyd et al., 1994), and to impose demands on their children, without explaining why. Low-SES parents also tend to be inconsistent in their parenting, punishing sometimes but not others for the same offense (Conger and Donnellan, 2007; McLoyd, 1990).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bradley et al., 2001

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    • cites Dodge et al., 1994

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    • cites McLoyd et al., 1994

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  • May combine two claims.

    Premisecitation

    Low SES parents are more likely to have mental health problems, reducing their ability to attend to their children's needs.

    “Low SES parents are also more likely to have mental health problems of their own (Conger and Donnellan, 2007), reducing their ability to attend to their children’s needs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Conger and Donnellan, 2007

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  • May combine two claims.

    Premisecitation

    As a result of these demands, low SES parents spend less time each day with their children and provide less support and emotion socialization.

    “As a result of these demands, low SES parents spend less time each day with their kids (Bradley et al., 2001), and provide them with less support (Dodge et al., 1994) and emotion socialization (McLoyd, 1998).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bradley et al., 2001

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    • cites Dodge et al., 1994

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    • cites McLoyd, 1998

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  • May combine two claims.

    Premisecitation

    These family environments have been characterized as cold and neglectful, though the behaviors often stem from life circumstances rather than intentional parenting styles.

    “These types of family environments have been characterized as ‘cold’ and ‘neglectful’ (Repetti et al., 2002), although it is important to note that while the descriptive labels may be accurate, the behaviors they refer to often stem from the life circumstances that low SES families face, rather than representing intentional parenting styles.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Repetti et al., 2002

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  • May combine two claims.

    Premisecitation

    Low-SES children subjectively rate their neighborhoods as more stressful; 50% report concerns about being attacked in their neighborhood.

    “Low-SES children also subjectively rate their neighborhoods as more stressful (Overstreet and Braun, 2000; Wright, 2006). For example, 50% of low SES children report concerns about being attacked in their neighborhood (Schubiner et al., 1993).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Overstreet and Braun, 2000

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    • cites Wright, 2006

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    • cites Schubiner et al., 1993

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  • May combine two claims.

    Premisereasoning

    Although most low-SES families in Western society have basic needs met, they face material deprivation relative to modern industrialized standards.

    “In sum, although most low-SES families residing in Western society today have their most basic needs for food and shelter met, they still face a good deal of material deprivation relative to the expected standards of modern industrialized nations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Low SES parents are more likely to keep children indoors due to violence concerns, resulting in greater exposure to family conflict and adverse home environment.

    “Furthermore, low SES parents are more likely to keep their children indoors because of concerns about violence (Wright et al., 2004b), resulting in greater exposure to family conflict and other adverse features of home environment described above (Overstreet and Braun, 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wright et al., 2004b

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    • cites Overstreet and Braun, 2000

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  • May combine two claims.

    Premisecitation

    Early life is a period of marked plasticity for the immune system; long-term patterns of immune responding are established by exposures to pathogens, allergens, and irritants from utero through early childhood.

    “In recent decades, it has become evident that early life represents a period of marked plasticity for the immune system. Starting in utero and lasting through the early years of childhood, long-term patterns of immune responding are established by exposures to pathogens, allergens, and irritants (Finch and Crimmins, 2004; Prescott, 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Finch and Crimmins, 2004

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    • cites Prescott, 2006

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  • May combine two claims.

    Premisecitation

    By teenage years, 50% of low-SES children have witnessed at least one violent attack on another person, and 24% have been victims of physical assault; rates are about half among higher SES children.

    “By the time children reach their teenage years, 50% of low-SES children have witnessed at least one violent attack on another person, and 24% have themselves been the victim of a physical assault (Crouch et al., 2000). Rates of experiencing violence are about half that level among higher SES children (Crouch et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crouch et al., 2000

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Low SES is defined by limited access to material resources.

    “According to most theories, low SES is defined by limited access to material resources (Lynch and Kaplan, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lynch and Kaplan, 2000

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  • May combine two claims.

    Interpretationreasoning

    This programming manifests as more pronounced inflammatory responses to challenge and reduced ability to terminate responses due to reduced sensitivity to inhibitory hormonal signals.

    “This programming manifests in two ways: the cells show more pronounced inflammatory responses when exposed to challenge, and they are less able to terminate these responses because they have reduced sensitivity to inhibitory hormonal signals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Maltreatment often entails harsh parenting, conflict, and violence; neglect often co-occurs with conditions such as alcohol and substance disorders, marital difficulties, and intimate partner violence.

    “Maltreatment often entails harsh parenting, conflict and violence. In sexual and physical abuse, violence is by definition involved, or at least the threat of it. Children who are neglected are not necessarily treated violently by caregivers. However, neglect often co-occurs with other conditions, like alcohol and substance disorders, marital difficulties, and intimate partner violence, where the”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Leonard and Eiden, 2007

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  • May combine two claims.

    Premisecitation

    Poor children are more likely to live in run-down housing with poor water, heating, and sewage; their homes, schools, and neighborhoods tend to be noisy, crowded, and unsafe; they have limited access to toys, books, computers, learning materials, and recreational activities; and healthy food is scarcer.

    “In comparison to their more advantaged peers, children from low-SES families are more likely to live in run-down housing, with poor quality water, heating, and sewage. Their homes tend to be noisy, crowded, and unsafe, as do the schools they attend and the neighborhoods in which they reside. Low-SES children have limited access to toys, books, computers, learning materials, and recreational”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Evans, 2004

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  • May combine two claims.

    Premisecitation

    Among adults with low childhood socioeconomic status, genome-wide profiling of peripheral blood mononuclear cells found increased expression of genes carrying NF-kB response elements and decreased expression of genes carrying glucocorticoid receptor response elements.

    “These analyses revealed that among participants from low-SES families, there was significant upregulation of genes with response elements for the transcription factor NF-κB.”
    • Also stated in: § Programming of Pro-Inflammatory Tendencies · plain
      “Participants from low-SES backgrounds also showed a significant downregulation of genes with response elements for GR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller et al., 2009

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  • The quote only partly states this claim.

    Premisecitation

    Among 135 adolescents, a harsher early family climate predicted increasing monocyte resistance to cortisol's anti-inflammatory effects across 1.5 years, with statistical control for socioeconomic status, demographic and biomedical factors, and depressed mood.

    “To the extent that participants reported being raised in a harsh early family climate, they showed progressive desensitization to cortisol’s anti-inflammatory properties over the follow-up period.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller and Chen, 2010

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  • May combine two claims.

    Premisecitation

    C-reactive protein serves as a common inflammation marker because it persists for a long time, is measurable at low concentrations, and predicts outcomes across its range.

    “Though its precise biological activities are not well understood (Gabay and Kushner, 1999), CRP is widely used as a marker of inflammation (Ridker, 2003). It has a long half-life, can be detected at low levels, and values across the observed range are useful prognostically.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ridker, 2003

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  • The quote only partly states this claim.

    Premisecitation

    Among 135 teenage females, greater parental harshness in early life is associated with increasingly pronounced monocyte IL-6 responses to lipopolysaccharide over 1.5 years, with statistical control for socioeconomic status, demographic and biomedical factors, and depressed mood.

    “To the extent that participants were reared in harsh families, they showed increasingly pronounced IL-6 responses over time.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller and Chen, 2010

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  • May combine two claims.

    Premisecitation

    A higher early-life adversity composite score predicted higher levels of IL-6, fibrinogen, endothelial leukocyte adhesion molecule-1, and soluble intercellular adhesion molecule-1, but not C-reactive protein.

    “Higher scores on the adversity composite were positively associated with four markers of inflammation: IL-6, fibrinogen, endothelial leukocyte adhesion molecule-1, and soluble intercellular adhesion molecule-1 (but not CRP).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Slopen et al., 2010

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  • May combine two claims.

    Premisecitation

    In the same cohort, low childhood socioeconomic status and childhood social isolation each predicted higher C-reactive protein, with independent effects.

    “Those who came from low-SES backgrounds, and were socially isolated as children, were also more likely to show high CRP, and these effects were independent of each other.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Danese et al., 2007

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    • cites Danese et al., 2009

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Older adults who recalled childhood abuse had higher blood levels of IL-6 and TNF-alpha than those who did not, despite some participants facing a severe current stressor when blood was drawn.

    “The former group showed higher circulating IL-6 and TNF-α levels than the latter (Kiecolt-Glaser et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kiecolt-Glaser et al., 2011

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  • May combine two claims.

    Interpretationcitation

    Adults who experienced childhood stress show stronger cytokine reactions to some microbial products and reduced sensitivity to cortisol signals that normally stop this response.

    “To the extent they have been exposed to childhood stress, adults display heightened cytokine responses to certain microbial stimuli, and are less sensitive to cortisol-mediated signals that shut down this process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Among adults experimentally exposed to rhinoviruses, those raised in lower socioeconomic households were more likely to become infected and to develop symptoms judged clinically significant.

    “To the extent they were reared in low-SES households, participants were more likely to become infected with the rhinovirus, and to develop symptoms that physicians judged as clinically significant.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cohen et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cross-fostering experiments support a strong causal inference that low early maternal care, acting through epigenetic mechanisms, can durably alter hippocampal gene expression and increase HPA axis reactivity to stress.

    “These studies yielded a similar pattern of findings, providing the basis for a strong causal inference that via epigenetic mechanisms, low maternal care in early-life can have long-lasting influences on hippocampal gene expression, which manifests in greater HPA axis reactivity to stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weaver et al., 2004

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  • May combine two claims.

    Interpretationcitation

    Early stress may allow viruses to replicate more widely; if those infections persist at low levels, they could add another inflammatory stimulus.

    “They suggest that early stress enables viruses to replicate more extensively. If these infections become chronic, even at a low-level, they could function as a further stimulus for inflammation (Leinonen and Saikku, 2002; Shirtcliff et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Leinonen and Saikku, 2002

      Not checked in the free run.

    • cites Shirtcliff et al., 2009

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  • May combine two claims.

    Premisecitation

    In that study, abused individuals had lower glucocorticoid receptor mRNA and weaker NGFIA binding at the GR promoter.

    “These methylation differences appeared to be functionally significant, as abuse victims had less GR mRNA and less efficient NGFIA binding to the GR promoter.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McGowan et al., 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Post-translational modifications can alter how a protein binds, crosses membranes, degrades, or recruits other molecules, and can strongly affect cell behavior.

    “These additions can modify a protein’s binding capacity, change its ability to pass through membranes, accelerate its degradation, or recruit new molecules towards it. PTM’s can have a marked impact on cellular behavior by altering the dynamics of higher-level processes like signal transduction, transcriptional efficiency, DNA replication, and cell cycle progression (Hochstrasser, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hochstrasser, 2009

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  • May combine two claims.

    Interpretationcitation

    A self-amplifying loop in which glucocorticoid receptor phosphorylation promotes cytokine release and further receptor phosphorylation could spread to neighboring cells via paracrine cytokines.

    “This process would induce more GR phosphorylation, and presumably the cycle would begin again (Miller et al., 2009b). Moreover, because cytokines can have paracrine influences – i.e., effects on cells that are nearby – this cycle of inflammation and phosphorylation could spread.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller et al., 2009b

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  • May combine two claims.

    Premisecitation

    Handled rats had lower adolescent PVN CRH than controls, partly because handling reduced excitatory glutamatergic input to the PVN.

    “Results indicated that handled rats had lower PVN CRH during adolescence than controls. This was in part due to a handling-induced reduction in excitatory glutamatergic innervation of the PVN.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Korosi et al., 2010

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  • May combine two claims.

    Premisecitation

    In rat pups handled daily for 15 minutes during their first week, corticotropin-releasing hormone mRNA in the paraventricular nucleus and phosphorylation of extracellular-signal regulated kinase were both reduced.

    “It found that relative to a non-disturbed control condition, handling reduced mRNA for corticotropin releasing hormone (CRH) in the paraventricular nucleus (PVN).”
    • Also stated in: § Mechanisms of Embedding · plain
      “The study also found that handling reduced the degree of phosphorylation of extracellular-signal regulated kinase, a transcription factor that plays a key role in initiating expression of the CRH gene.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fenoglio et al., 2006b

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  • May combine two claims.

    Interpretationcitation

    The early social environment can influence the developing hypothalamus's structure, affecting how its neurons carry stress-related signals.

    “Together, these findings are provocative in suggesting that early social context can, to some degree, shape the architecture of the developing hypothalamus, with implications for how neurons in this structure propagate stress-related signals.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Swinny et al., 2009

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    • cites Korosi et al., 2010

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  • May combine two claims.

    Premisecitation

    Such airway remodeling lowers resting lung function and increases airway reactivity to later stimuli.

    “These changes not only reduce the person’s resting lung function, but also render his/her airway more reactive to future stimuli (see review by Prescott, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Prescott, 2006

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  • May combine two claims.

    Interpretationreasoning

    Over time, these traits lead to abrasive social exchanges and make it harder to obtain support from others.

    “Over the long term, these traits will give rise to abrasive social exchanges and make it difficult to garner support from others.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Childhood stress may increase sympathetic fiber density in bone marrow, allowing more norepinephrine to reach myeloid progenitors and favoring migration of progenitor subtypes prone to prolonged aggressive inflammatory responses.

    “Together, these findings suggest a plausible remodeling scenario, wherein childhood stress boosts the density of SNS fibers entering the bone marrow, allowing more norepinephrine signal to reach myeloid progenitors there. These signals favor the migration of specific progenitor subtypes into circulation, which are disposed towards aggressive, prolonged inflammatory responding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Monocytes released from bone marrow under stress tend to show exaggerated pro-inflammatory cytokine responses to LPS and reduced sensitivity to glucocorticoid inhibition.

    “Notably, the monocytes that egress from bone marrow under stress tend to have exaggerated pro-inflammatory cytokine responses upon exposure to LPS, and be relatively insensitive to inhibition by glucocorticoids (Avitsur et al., 2005; Engler et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Avitsur et al., 2005

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    • cites Engler et al., 2005

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  • May combine two claims.

    Premisecitation

    The amygdala evaluates biological significance and emotional salience, shapes processing of ambiguous information, and organizes biobehavioral responses to perceived threat.

    “This cell complex plays a role in evaluating the biological significance and emotional salience of stimuli, shaping the way ambiguous information is processed, and organizing biobehavioral responses to situations perceived as threatening (Davis and Whalen, 2001; Phelps, 2006; Whalen et al., 2001).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Davis and Whalen, 2001

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    • cites Phelps, 2006

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    • cites Whalen et al., 2001

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  • May combine two claims.

    Interpretationreasoning

    These tendencies make people more likely to perceive threat in ambiguous situations, more sensitive to anger, and more cynical about others' intentions and behavior.

    “These tendencies will render people more likely to read threat into ambiguous situations, be more sensitive to recognizing and responding to anger, and be cynical about others’ intentions and behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Physically abused children develop greater perceptual sensitivity to anger and identify it more readily and rapidly in faces.

    “Pollak (2008) argues that physically abused children develop increased perceptual sensitivity for anger, which leads them to identify this emotion more readily and rapidly in others’ faces, even when limited contextual information is available to support these judgments (Pollak and Sinha, 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pollak, 2008

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    • cites Pollak and Sinha, 2002

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During an observe condition, adults from harsh families showed lower amygdala reactivity, which the original authors attributed to habituation or detachment from negative emotional stimuli.

    “During the observe condition those from harsh families had lower amygdala reactivity, which the authors hypothesized was a result of habituation to, or detachment from, negative emotional stimuli.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al., 2006a

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  • May combine two claims.

    Premisecitation

    Among adults from warmer families, amygdala and ventrolateral prefrontal activity were negatively correlated, whereas among those from harsher families the relationship was strongly positive.

    “Among participants reared in warmer families, there was a negative correlation between amygdala and vlPFC activity. This relationship was strongly positive among persons from harsher families, a pattern the authors suggest is indicative of a failure to effectively recruit the relevant areas for top-down regulation of the amygdala.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Taylor et al., 2006a

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  • May combine two claims.

    Premisecitation

    Amygdala nuclei mature during childhood, while prefrontal regions continue maturing through adolescence and early adulthood.

    “There is structural variation in the timing and duration of this process, with nuclei in the amygdala maturing in childhood and prefrontal regions continuing through adolescence and early stages of adulthood (Ernst and Fudge, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ernst and Fudge, 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The amygdala consists of multiple reciprocally connected nuclei.

    “The amygdala is comprised of multiple reciprocally connected nuclei (Davis and Whalen, 2001; Ernst and Fudge, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Davis and Whalen, 2001

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    • cites Ernst and Fudge, 2009

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  • May combine two claims.

    Premisecitation

    Corticolimbic circuits mature substantially in early postnatal life and are modulated by both species-typical and species-atypical experience.

    “Research suggests that corticolimbic circuits undergo significant maturation in the early postnatal years and are subject to both experience-expectant (species typical) and experience-dependent (species atypical) modulation (Leppanen and Nelson, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leppanen and Nelson, 2009

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  • Classified as probably not a substantial claim.

    Premisecitation

    Chen interprets this appraisal style as reflecting underlying vigilance in which low-SES children monitor for danger and maintain a low threshold for judging threat.

    “Chen argues that this appraisal style reflects an underlying vigilance, wherein low-SES children closely monitor their world for danger, and maintain a low threshold for judging situations as threatening.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chen et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Appraisal tendencies are shaped by early SES and remain fairly stable across the lifespan.

    “These findings suggest that appraisal tendencies are shaped by people’s early SES and persist in a fairly stable fashion across the lifespan.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Children from low SES backgrounds frequently experience uncontrollable and unpredictable events and come to see the world as threatening and requiring high vigilance.

    “In a similar vein, Chen has argued that because children from low SES backgrounds are frequently exposed to life events that are both uncontrollable and at times unpredictable, they come to view the world as a threat-laden place that requires high levels of vigilance (Chen et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chen et al., 2004

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  • Classified as probably not a substantial claim.

    Premisecitation

    Models of children's social-information processing posit a cycle in which appraisals shape behavior, behavior elicits responses, and responses shape future appraisals.

    “Such models posit a cyclical process, wherein appraisals shape behavior towards others, and in so doing elicit particular responses, which themselves shape future appraisals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Crick and Dodge, 1994

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Children raised in harsher families have smaller social networks, more conflict with family and friends, and perceive less social support.

    “Consistent with both frameworks, research shows that children who are reared in harsher families have smaller social networks, more conflict with family and friends, and perceive less social support (Repetti et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Repetti et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These traits lead people to engage their social worlds in ways that produce conflict and rejection and reduce their ability to receive support and warmth.

    “The idea here is that these traits lead people to perceive and engage their social worlds in a manner that brings about conflict and rejection, and renders them less able to receive support and warmth from others.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The reciprocal link between individual styles and social interactions is a central tenet of interpersonal approaches to personality and of work on interaction styles.

    “It is a central tenet of interpersonal approaches to personality (Kiesler, 1996) and the literature on continuities and consequences of interaction styles (Caspi et al., 1989).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kiesler, 1996

      Not checked in the free run.

    • cites Caspi et al., 1989

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When children attribute hostile intent to others, they are more likely to respond aggressively and thereby cause others to escalate.

    “For example, when children attribute hostile intent to others, they are more likely to respond aggressively, and by doing so cause others to escalate (Dodge & Pettit, 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dodge & Pettit, 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In children, SES and hostility are inversely related, suggesting these beliefs form early in life.

    “Even in children SES and hostility are inversely related, suggesting that these beliefs are established early in life (Gump et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gump et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These adults tend to be vigilant for threat and mistrustful of others.

    “These individuals also tend to be vigilant for threat and mistrusting of others.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute marital conflict increases circulating IL-6 and TNF-α, and these elevations remain evident 24 hours later.

    “Moving to social interactions, there is evidence that acute bouts of marital conflict increase levels of IL-6 and TNF-α in circulation, which are still evident 24 hours later (Kiecolt-Glaser et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kiecolt-Glaser et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    They engage others in ways that produce abrasive exchanges and make social support difficult to obtain.

    “They engage others in a manner that leads to abrasive exchanges and makes it difficult to garner social support from others.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The nucleus accumbens can relay information back to prefrontal cortex via pallidal-thalamic loops and can direct signals to hindbrain motor structures.

    “After integrating messages, cell groups in the NAcc can relay information back to the PFC via palidal-thalamic loops, and/or direct signals to the hindbrain structures that control motoric activity (Ernst and Fudge, 2009; Grace et al., 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ernst and Fudge, 2009

      Not checked in the free run.

    • cites Grace et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These tendencies intensify the pro-inflammatory programming of monocytes and macrophages and further contribute to chronic inflammation.

    “These proclivities accentuate the tendencies already programmed into monocytes/macrophages, further contributing to the chronic inflammatory state in the body.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    This shaping produces a phenotype that strongly discounts the future, acts impulsively, and readily seeks appetitive stimuli.

    “This shaping process gives rise to a phenotype that highly discounts the future, behaves in an impulsive fashion, and readily seeks out appetitive stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Striatal and limbic regions mature through late childhood and early adolescence, while prefrontal cortex maturation continues into early adulthood.

    “There appears to be variation across structures in the onset and length of this period, with maturation of striatal and limbic regions occurring through late childhood and early adolescence. By contrast, maturation of the PFC is thought to continue well into the early stages of adulthood as mentioned previously.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ernst and Fudge, 2009

      Not checked in the free run.

    • cites Somerville and Casey, 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The nucleus accumbens acts as an interface among cortical, limbic, and motoric regions and helps the organism select and realize behavioral priorities.

    “In this way, the NAcc serves as an interface between cortical, limbic, and motoric regions, helping the organism select and realize behavioral priorities (Floresco, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Floresco, 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Childhood stress shapes the neural circuitry underlying self-regulation of appetitive behaviors.

    “The model postulates that childhood stress also shapes the functioning of the neural circuitry that underlies self-regulation of appetitive behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other studies found temporal discounting in low-SES individuals alongside greater cognitive impulsivity, including failure to plan ahead, present-minded orientation, and brief time horizons.

    “Other studies have also found evidence of temporal discounting in low-SES individuals, in parallel with greater cognitive impulsivity, marked by a failure to plan ahead, a present-minded orientation, and brief time horizons (de Wit et al., 2007; McLoyd, 1998; White et al., 1994).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites de Wit et al., 2007

      Not checked in the free run.

    • cites McLoyd, 1998

      Not checked in the free run.

    • cites White et al., 1994

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Childhood SES was not associated with neural responses to monetary loss or directly related to ventral striatal activity during gain or loss trials.

    “Interestingly, childhood SES was not associated with neural responses to monetary loss, or directly related to activity in ventral striatal circuits during either gain or loss trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gianaros et al., in press

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large birth cohort, individuals raised in low-SES households had higher BMI and waist-to-hip ratios at age 26 and were more likely to have a history of alcohol dependence.

    “In a large birth cohort study, Poulton and colleagues found that to the extent that individuals were raised in low-SES households, at the age of 26, they displayed higher body mass index and great waist: hip ratios, and were more likely to have a history of alcohol dependence (Poulton et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poulton et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This impulsive style leads individuals to develop unhealthy lifestyles such as smoking, poor diet, physical inactivity, and obesity, which likely persist and contribute to a pro-inflammatory environment.

    “One of the implications of this style is that individuals develop unhealthy lifestyles, characterized by smoking, poor diet, physical inactivity, and obesity, which are likely to persist over the lifecourse and contribute to a pro-inflammatory environment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NF-κB is upregulated in monocytes of overweight individuals, suggesting these cells are primed for pro-inflammatory responding.

    “NF-κB is upregulated in the monocytes of overweight individuals, suggesting these cells are primed for pro-inflammatory responding (Ghanim et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ghanim et al., 2004

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The model's final major premise is that childhood stress has an enduring effect on daily autonomic and endocrine discharge patterns.

    “The model’s last major premise is that childhood stress has an enduring influence on everyday patterns of autonomic and endocrine discharge.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Diet and stress may act synergistically to produce more inflammation than either does alone.

    “There are also intriguing suggestions that diet and stress may act synergistically, together fostering more pronounced inflammation than either does alone (Kiecolt-Glaser, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kiecolt-Glaser, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Across multiple countries, low childhood SES predicts greater risk of current and persistent smoking, lower probability of quitting smoking, and increased obesity risk in adult women, even after controlling for current SES.

    “Studies have found that across multiple countries, low childhood SES predicts a greater risk of current and persistent smoking, a lower probability of quitting smoking, and increased risk of obesity in adult women, even after controlling for current SES (Jefferis et al., 2004; Power et al., 2005a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jefferis et al., 2004

      Not checked in the free run.

    • cites Power et al., 2005a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low childhood SES is associated with more episodes of drunkenness, decreased physical activity, and poorer diets in adulthood.

    “Low childhood SES also is associated with more episodes of drunkenness, decreased physical activity, and poorer diets in adulthood (Lynch et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lynch et al., 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adipose tissue is a major reservoir of inflammatory mediators and accounts for almost one third of circulating IL-6.

    “Adipose tissue itself is one of the body’s major reservoir of inflammatory mediators, accounting for almost 1/3 of the IL-6 that is present in circulation (Mohamed-Ali et al., 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mohamed-Ali et al., 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings provide prospective evidence that low SES precedes and possibly instigates age-related increases in daily cortisol output over two years.

    “These findings provide prospective evidence that low SES precedes, and possibly instigates, age-related increases in daily output of cortisol over two years.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Five signaling molecules may plausibly be involved in these dynamics: cortisol, epinephrine, norepinephrine, acetylcholine, and oxytocin.

    “Below we discuss five signaling molecules that could plausibly be involved in such dynamics – the adrenal steroid cortisol, the ANS neurotransmitters epinephrine, norepinephrine, and acetylcholine, and the hypothalamic peptide oxytocin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    As a result, tonic release patterns of hormones, transmitters, and peptides become dysregulated, placing monocytes and macrophages in a pro-inflammatory milieu.

    “As a consequence the tonic release patterns of various hormones, transmitters, and peptides is dysregulated, consigning monocytes/macrophages to operate in a milieu that accentuates their pro-inflammatory tendencies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    A plausible hypothesis is that stress initially activates the HPA axis.

    “One plausible hypothesis is that stress initially activates the HPA axis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    This counter-regulatory response involves downregulation of the glucocorticoid receptor that normally binds cortisol.

    “This would involve downregulation of GR, the receptor that binds cortisol under most conditions (Fries et al., 2005b; Miller et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fries et al., 2005b

      Not checked in the free run.

    • cites Miller et al., 2007

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A similar process in immune cells would reduce the glucocorticoid receptor's ability to inhibit NF-κB and other pro-inflammatory pathways.

    “A similar dynamic in cells of the immune system would diminish GR’s capacity to inhibit NF-κB, as well as other pro-inflammatory transcriptional-control pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies of adults' diurnal cortisol are consistent with the idea that low-SES rearing leaves a lasting imprint on tonic HPA axis activity, seen as greater diurnal cortisol output, though the time of day most affected is inconsistent.

    “The results of these studies are consistent with the notion that being reared in a low-SES household leaves a long-lasting imprint on tonic HPA axis activity, which is manifest in greater diurnal cortisol output, though there is some inconsistency across studies about which time of day (s) this is most pronounced.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gustafsson et al., 2009

      Not checked in the free run.

    • cites Li et al., 2007

      Not checked in the free run.

    • cites Miller et al., 2009a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If glucocorticoid receptor downregulation occurs in hippocampal centers that regulate HPA outflow, cortisol may partly escape negative feedback and produce the relative cortisol increase seen in low-SES individuals.

    “If this downregulation occurred in the hippocampal centers that regulate HPA outflow, it might enable cortisol to partially escape negative feedback inhibition, and lead to the relative increase in cortisol seen in persons from low-SES families.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other studies find the opposite effect of catecholamines on LPS-stimulated inflammatory cytokine production.

    “However, others find the opposite effect (Rontgen et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rontgen et al., 2004

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    HRV is viewed as an index of PNS regulation of cardiac rhythms via the vagus nerve, whose signals are propagated by acetylcholine.

    “HRV is viewed as an index of PNS regulation of cardiac rhythms via the vagus nerve, whose signals are propagated by acetylcholine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Monocytes that egress under these conditions have exaggerated pro-inflammatory cytokine responses to LPS and are relatively insensitive to glucocorticoid inhibition.

    “The monocytes that egress under these conditions have exaggerated pro-inflammatory cytokine responses to LPS and are relatively insensitive to inhibition by glucocorticoids (Avitsur et al., 2005; Engler et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Avitsur et al., 2005

      Not checked in the free run.

    • cites Engler et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In much of the maltreatment-SNS work, participants had comorbid psychiatric conditions at assessment, making it hard to determine whether SNS dysregulation came from earlier maltreatment or current symptoms.

    “However, in much of this work the participants have comorbid psychiatric conditions at the time of assessment, which make it difficult to ascertain whether the SNS dysregulation stems from earlier maltreatment or current symptomatology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    General patterns suggest that a bodily milieu rich in SNS endproducts would contribute to chronic inflammation, partly by mobilizing aggressive monocytes from bone marrow into damaged tissue and partly by shifting cellular activation patterns.

    “That said, the general patterns suggest that a bodily milieu rich in SNS endproducts would contribute to chronic inflammation, partly by selectively mobilizing aggressive monocytes from bone marrow into damaged tissue, and partly by shifting cellular activation patterns in these contexts (Kaplanski et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kaplanski et al., 2003

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Reduced HRV has been found in low-SES adults, but it is unclear whether childhood SES has a parallel association.

    “Reduced HRV has also been found in studies of low-SES adults (Hemingway et al., 2005; Lampert et al., 2005), but it is unclear whether childhood SES has a parallel association.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hemingway et al., 2005

      Not checked in the free run.

    • cites Lampert et al., 2005

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Assuming HRV accurately indexes PNS activity, childhood stress also affects bioavailable acetylcholine.

    “(And presuming that HRV accurately indexes PNS activity, stress affects bioavailable acetylcholine, too.)”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Heart-rate variability accurately indexes parasympathetic nervous system activity.

  • May combine two claims.

    Premisecitation

    In socially isolated mice at risk for CHD, OT reduced inflammation and retarded atherosclerosis progression.

    “OT likewise reduced inflammation and retarded the progression of atherosclerosis in mice at risk for CHD due to social isolation (Nation et al., 2010; Szeto et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Nation et al., 2010

      Not checked in the free run.

    • cites Szeto et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models, peripheral OT treatment reduces obesity, facilitates glucose control, and improves insulin sensitivity.

    “For example, studies in animal models have revealed that peripheral OT treatment reduces obesity, facilitates glucose control, and improves insulin sensitivity (Camerino, 2009), all of which are components of the metabolic syndrome that precedes and contributes to CHD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Camerino, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While root causes of metabolic syndrome are obesity, inactivity, and genetics, recent evidence suggests inflammation plays a key pathogenic role.

    “While the root causes of the metabolic syndrome are obesity, inactivity, and genetics, recent evidence suggests that inflammation plays a key pathogenic role as well (Hotamisligil, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hotamisligil, 2006

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If reduced OT response influences children's proclivity for affiliative behavior, it could help explain persistent social difficulties in those reared in adversity.

    “If such a tendency influences children’s proclivity for affiliative behavior, it could help explain the persistent social difficulties those reared in adversity experience.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Other biological mediators almost certainly come into play during the evolution of disease.

    “However, other biological mediators almost certainly come into play during the evolution of disease”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Maltreated children are likely to have these physical exposures because their parents are unlikely to be proactive about health promotion.

    “Maltreated children are likely to have these exposures as well, because their parents are unlikely to be proactive about health promotion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    SES literature typically indexes exposure with parental education or occupation, which remain stable across childhood and cannot differentiate early versus later exposures.

    “The SES literature typically indexes exposure with indicators like parental education or occupation. Because these markers of status generally remain stable across childhood, they cannot be used to differentiate the impact of early vs. later exposures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Depression is sometimes accompanied by chronic inflammation, excessive HPA discharge, and social difficulties.

    “Moreover, depression is sometimes accompanied by processes featured in our model, like chronic inflammation, excessive HPA discharge, and social difficulties (Coyne, 1976; Glassman and Miller, 2007; Howren et al., 2009; Stetler and Miller, in press).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Coyne, 1976

      Not checked in the free run.

    • cites Glassman and Miller, 2007

      Not checked in the free run.

    • cites Howren et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early stressors like maltreatment increase vulnerability to major depression and sub-syndromal affective difficulties.

    “Early stressors like maltreatment increase vulnerability to major depression, as well as sub-syndromal affective difficulties (Heim and Nemeroff, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Heim and Nemeroff, 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Dunedin birth cohort, clinical depression at age 32 was associated with greater inflammation, but this association disappeared when childhood maltreatment was entered into equations.

    “Similarly, work from the Dunedin birth-cohort found that at age 32 clinical depression was associated with greater inflammation. However, further analysis revealed that this association disappeared when childhood maltreatment was entered into equations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Danese et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Together these findings suggest childhood stress brings about inflammation, and perhaps disease, through mechanisms largely independent of depression.

    “Together, these findings suggest that childhood stress brings about inflammation, and perhaps disease, through mechanisms largely independent of depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    People exposed to either stressor early in life tended to have poor health practices, high inflammation, and CHD risk.

    “They also tended to have poor health practices, high levels of inflammation, and be at risk for CHD.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Childhood disadvantage and maltreatment share enough common features to be aggregated under the rubric of chronic stress.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    People exposed to either disadvantage or maltreatment early in life tended to become adults who were vigilant, mistrusting, and socially isolated.

    “There were many instances where this proved to be a tenable assumption – people who were exposed to either stressor early in life tended to become adults who were vigilant, mistrusting, and social isolated.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Childhood disadvantage and maltreatment share enough common features to be aggregated under the rubric of chronic stress.
158 of 158

  • The authors state this as an assumption.

    Maltreatment and socioeconomic disadvantage share enough common features to be aggregated under the rubric of chronic stress for purposes of generating a broad mechanistic model.

    “To us, these patterns suggest that it is reasonable to proceed on the assumption that maltreatment and disadvantage share enough common features that they can be aggregated under the rubric of chronic stress, at least for the purposes of generating a broad mechanistic model to guide research in this nascent area.”

  • The authors state this as an assumption.

    In the ACE premature mortality analysis, the respondent's siblings or parents were exposed to a similar household environment.

    “The assumption here was that the respondent’s siblings or parents would have been exposed to a similar household environment, so any long-term adverse health effects should be apparent in them as well.”

  • The authors state this as an assumption.

    Retrospective self-report assessments of childhood maltreatment lead to under-reporting.

    “However, the most likely scenario is that retrospective self-report assessments lead to under-reporting of maltreatment (Hardt and Rutter, 2004). Assuming this is true, the net effects would be to add noise to the data and artificially constrain variance on the maltreatment variable.”

  • The paper relies on this without support.

    The chronic diseases of aging have a reasonably well-understood pathogenesis that can be leveraged to construct a biologically plausible mechanistic model.

    “They also have a reasonably well understood pathogenesis, which can be leveraged here to construct a biologically plausible model of mechanisms through which early stress contributes to later disease.”

  • The paper relies on this without support.

    Animal models of early stress can serve as proof of principle for causal effects of early stress on later disease in humans.

    “However, studies of this nature can be done in animal models, and it is instructive to consider what they have revealed, as this evidence can serve as “proof of principle” that early stress can (or can not) causally influence later disease risk.”

  • The paper relies on this without support.

    Monocytes/macrophages play a key role in initiating and maintaining inflammation.

    “cells of the monocyte/macrophage lineage, which play a key role in initiating and maintaining inflammation”

  • The paper relies on this without support.

    Inflammation is central to a number of chronic diseases of aging.

    “a process that is central to a number of chronic diseases of aging”

  • The paper relies on this without support.

    Few Western children today reside in settings that resemble the ancestral ecology.

    “Today, few Western children reside in settings that resemble the ancestral ecology.”

  • The paper relies on this without support.

    The acute inflammatory response is essential for survival.

    “The acute inflammatory response is essential for survival - without it, minor injuries or infections would become lethal.”

  • The paper relies on this without support.

    Cortisol binds to glucocorticoid receptors in macrophages and other immune cells and slows inflammatory processes by tying up NF-kappa B.

    “cortisol binds to glucocorticoid receptors (GR’s) located within macrophages and other immune cells, and slows down the inflammatory processes. Mechanistically, this happens because the ligated GR moves into a cell’s nucleus, and ties up a protein called nuclear factor-kappa B (NF-κB)”

  • The authors state this as an assumption.

    The model assumes that early stress sets the upper and lower bounds of how monocytes and macrophages respond to challenge, rather than locking them into a fixed functional setpoint.

    “Note that the model does not suggest that monocytes/macrophages get locked into a functional setpoint from which they cannot deviate. Rather, it assigns early stress a role in setting the upper and lower bounds of how these cells will deal with challenge going forwards.”

  • The authors state this as an assumption.

    The model assumes that later experiences fine-tune monocyte and macrophage operating tendencies within the bounds set by early stress.

    “Within these programmed boundaries, later experiences are assumed to fine-tune these operating tendencies to meet more immediate demands.”

  • The authors state this as an assumption.

    Low childhood SES heightens cortisol output in a lasting manner.

    “Assuming low childhood SES does heighten cortisol output in a lasting manner, what might be the downstream consequences for inflammatory responding?”

  • The authors state this as an assumption.

    Early stress does not lock cells at a permanent setpoint; instead it calibrates how cells respond to challenge, with later experiences fine-tuning those tendencies.

    “As noted earlier, this is possible because early stress is not assumed to “lock” cells at a permanent setpoint. Rather, early stress calibrates the parameters of how cells deal with challenge going forwards, with later experiences fine-tuning these operating tendencies.”

  • The paper relies on this without support.

    Each of the five signaling molecules has a cognate receptor on or in macrophages that allows it to regulate the magnitude of inflammatory responses.

    “But more importantly, each has a cognate receptor in/on macrophages, which allows it to regulate the magnitude of these cells’ inflammatory responses to challenge.”

  • The paper relies on this without support.

    Stress can modulate the activity of cortisol, epinephrine, norepinephrine, acetylcholine, and oxytocin.

    “We focus on these molecules for two reasons, the first being that stress can modulate their activity.”

  • The authors state this as an assumption.

    Childhood disadvantage and maltreatment share enough common features to be aggregated under the rubric of chronic stress.

    “We made the assumption that these experiences shared enough common features that they could be aggregated under the rubric of chronic stress.”

  • The authors state this as an assumption.

    Heart-rate variability accurately indexes parasympathetic nervous system activity.

    “(And presuming that HRV accurately indexes PNS activity, stress affects bioavailable acetylcholine, too.)”
18 of 18

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Engagement of these pathways may become self-promoting as a result of neuro-inflammatory sensitization and thus drive heightened levels of inflammation and exaggerated perceptions of social threat for months or years after the original social-environmental impetus has passed.

    “engagement of these pathways may become selfpromoting as a result of neuro-inflammatory sensitization and thus drive heightened levels of inflammation and exaggerated perceptions of social threat for months or years after the original social-environmental impetus has passed”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller, Chen, & Parker, 2011

    In 'Childhood Adversity Engenders Behavioral Tendencies that Accentuate Inflammation' (page unavailable), the paper proposes that childhood stress increases threat vigilance and that vigilance and social difficulties can amplify chronic inflammation. It also describes a self-promoting cycle of mistrust and adverse social interactions. Our copy does not attribute that cycle to neuro-inflammatory sensitization or say that this mechanism sustains both inflammation and threat perceptions for months or years after the original stressor has passed. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • After years of sustained engagement, these dynamics may confer increased risk for inflammation-related disorders, infection, accelerated biological aging, and early mortality.

    “Finally, after years of sustained engagement, these dynamics may confer increased risk for inflammation-related disorders, infection, accelerated biological aging, and early mortality”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller, Chen, & Parker, 2011

    The Overview of Model and Inflammation and Disease sections propose that pro-inflammatory tendencies build over the life course and contribute to chronic disease and premature aging. The paper also reports greater susceptibility to infection and premature mortality after childhood adversity, but those passages do not establish that years of sustained engagement of the proposed dynamics produce those two outcomes. Page numbers were not available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • ELA-induced changes may mediate epidemiological links to key diseases, including obesity, dyslipidemia, type 2 diabetes, atherosclerosis, asthma, thromboembolic events, cancer onset and progression, addictions, psychopathology, and adverse social outcomes.

    “In full, ELA-induced changes may mediate epidemiological links to key diseases, including, among others, obesity, dyslipidemia, type 2 diabetes, atherosclerosis, asthma, thromboembolic events (myocardial infarction, stroke), cancer onset and progression, as well as addictions, psychopathology, and adverse social outcomes [1–6, 18].”

    From Biological embedding of childhood adversity: from physiological mechanisms to clinical implications (2017) · cites this paper as [18]

    The Overview of Model (page not given) proposes that childhood adversity alters behavior, hormonal regulation, and inflammation, contributing to diabetes, coronary heart disease, and cancers. Inflammation and Disease (page not given) also discusses lipid dysregulation, atherosclerosis, myocardial infarction, stroke, and tumor progression. The paper does not establish the same mediation pathway for every listed outcome: it treats obesity, substance use, and social difficulties partly as contributors to inflammation, and does not similarly link the proposed mechanism to asthma, psychopathology, or cancer onset. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Severe childhood stressors promote the formation of a neural-immune pipeline, wherein inflammatory cytokine signaling between the brain and the periphery is markedly amplified.

    “This hypothesis grows out of mounting evidence that severe childhood stressors promote the formation of a neural-immune pipeline (15), wherein inflammatory cytokine signaling between the brain and the periphery is markedly amplified (16).”

    From Clustering of depression and inflammation in adolescents previously exposed to childhood adversity (2012) · cites this paper as [15]

    In “Mechanisms of Embedding” (page unavailable), the paper proposes that childhood stress could alter connections between the nervous and immune systems and reports evidence that stress can change those connections. It presents the childhood-stress mechanism as a possibility, rather than establishing that severe childhood stressors form a neural-immune pipeline. The amplified cytokine-signaling clause is attached to a different citation and is not judged here. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Preclinical levels of inflammation could presage the development of chronic inflammation and disease.

    “immunological processes such as preclinical levels of inflammation, which could presage the development of chronic inflammation and disease”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller et al., 2011

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: F(4,241) = 4.63, p < .001

    Minor

    The paper reports p < .001 here; recomputing from the test statistic and its degrees of freedom gives p = .001. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p < .001 · recomputed p = .001

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upF(4, 241) = 4.63reported p < .001 · recomputed p = .001

    “F(4,241) = 4.63, p < .001”

  • ConsistentF(4, 240) = 2.93reported p = .02 · recomputed p = .022

    “F(4,240) = 2.93, p = .02”

2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. Kohn ML 1977 Social class and conformity Chicago, IL University of Chicago Press
  2. Kop WJ Cohen N Ader R Felten D Cohen N 2001 Psychological risk factors and immune system involvement in cardiovascular disease Psychoneuroimmunology 3 525 544 New York Academic Press
  3. Lynch JW Kaplan GA Berkman LF Kawachi I 2000 Socioeconomic position Social Epidemiology 13 35 Oxford Oxford University Press

Cited by

Sorted by citations

Related

Authors
Miller, G. E., Chen, E., & Parker, K. J.
Affiliations
  • University of British Columbia (CA)
  • Stanford Medicine (US)
ORCID
Venue
Psychological Bulletin
Publisher
American Psychological Association (APA)
Published
2011
Volume
137
Issue
6
Pages
959-997
ISSN
  • 0033-2909 (ISSN-L)
  • 1939-1455
DOI
10.1037/a0024768
PMC
PMC3202072
OpenAlex
W2169690159
Cited by
1,785
References
365
Citations by year
2026: 114 · 2025: 129 · 2024: 116 · 2023: 120 · 2022: 166 · 2021: 156 · 2020: 140 · 2019: 119 · 2018: 150 · 2017: 133 · 2016: 133 · 2015: 113 · 2014: 85 · 2013: 72 · 2012: 39
FWCI
24.51
Type
journal article
Language
en
Open access
Locations
  • Psychological Bulletin (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD058502)
  • National Heart, Lung, and Blood Institute (HL073975)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
childhood stress, biological embedding, epigenetics, macrophages, proinflammation, cytokine response, threat vigilance, interpersonal relationships, self-regulation, unhealthy lifestyle, endocrine dysfunction, autonomic dysfunction, vascular disease, autoimmune disease, premature mortality, poverty, child abuse, life course
MeSH terms
Adaptation, Physiological, Aging, Animals, Child, Child Abuse, Child Development, Chronic Disease, Disease Susceptibility, Female, Humans, Inflammation, Life Change Events, Male, Models, Biological, Morbidity, Socioeconomic Factors, Stress, Physiological, Stress, Psychological, Epigenesis, Genetic, Mortality, Premature

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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