Gender minority stress and diurnal cortisol profiles among transgender and gender diverse people in the United States.

The field of behavioral neuroendocrinology has only begun to explore the lived experiences of transgender and gender diverse (TGD) people exposed to stigma. In light of escalating attacks and legislation targeting TGD people in the United States, it is crucial to examine the physiological pathways through which gender minority stressors become embodied, impact health, and contribute to health inequities. The Trans Resilience and Health Study included baseline data collection from fall 2019 to spring 2020 from a sample of 124 TGD people, reflecting a diversity of gender identities (e.g., trans masculine, trans feminine, and nonbinary) and ages (range = 19-70 years old; M = 34.10), living in Michigan, Nebraska, Oregon, and Tennessee. These analyses examine experiences of gender-related enacted stigma in association with hypothalamic-pituitary-adrenal (HPA)-axis functioning. Among those experiencing the highest levels of enacted stigma, findings show a blunted cortisol awakening response and sluggish daily decline that resulted in elevated concentrations at bedtime compared to those experiencing less enacted stigma. These results of flattened diurnal activity are consistent with an emergent literature on discrimination as a social determinant of potential stress pathophysiology. In contrast, community connectedness was associated with a larger, more dynamic cortisol awakening response. These findings emphasize the importance of incorporating gender-minority stress and resilience measures when studying HPA-axis functioning among TGD people.

Lay Stakeholders in Science and Research Initiative: A Science Advisory From the American Heart Association.

The American Heart Association (AHA) is the largest not-for-profit funder of cardiovascular and cerebrovascular disease research in the United States. It has supported research of independent scientists for 7 decades with the goal of finding novel discoveries that will reduce death and disability from these diseases and ultimately improve overall health. In 2014, the AHA approved a pilot initiative to include lay stakeholders (patients, caregivers, and passionate advocates) in its research and science operations. The initiative was based on the premise that lay stakeholders would add a unique and necessary perspective that would improve decisions concerning research funding, research direction, and scientific guidelines. The AHA developed a framework for the initiative that defined lay stakeholder, created a volunteer recruitment and training program, established policies for incorporating lay stakeholders into science operations, and set metrics for evaluating the initiative over time. It has instituted creative ways to engage lay volunteers and to foster lay and scientist cooperation. Program assessments have been consistently positive and have identified needed future improvements. The benefits of lay/scientist collaboration have far exceeded the AHA's expectations. The AHA will continue to strengthen lay volunteer engagement throughout its science and research operations; to focus on developing a larger, diverse group of qualified lay stakeholders; to educate scientists on how to communicate research effectively to the public and donors; and to retain the respect of donors for the rigors of its research funding, scientific statements, and clinical guidelines.

Biocultural approaches to transgender and gender diverse experience and health: Integrating biomarkers and advancing gender/sex research.

Transgender and gender diverse (TGD) people are increasingly visible in U.S. communities and in national media. With this increased visibility, access to gender affirming healthcare is also on the rise, particularly for urban youth. Political backlash and entrenchment in a gender binary, however, continue to marginalize TGD people, increasing risk for health disparities. The 2016 National Institute of Health recognition of sexual and gender minority people as a health disparities population increases available funding for much-needed research. In this article, we speak to the need for a biocultural human biology of gender/sex diversity by delineating factors that influence physiological functioning, mental health, and physical health of TGD people. We propose that many of these factors can best be investigated with minimally invasively collected biomarker samples (MICBS) and discuss how to integrate MICBS into research inclusive of TGD people. Research use of MICBS among TGD people remains limited, and wider use could enable essential biological and health data to be collected from a population often excluded from research. We provide a broad overview of terminology and current literature, point to key research questions, and address potential challenges researchers might face when aiming to integrate MCIBS in research inclusive of transgender and gender diverse people. We argue that, when used effectively, MICBS can enhance human biologists' ability to empirically measure physiology and health-related outcomes and enable more accurate identification of pathways linking human experience, embodiment, and health.

Physical activity and depressive symptoms during pregnancy among Latina women: a prospective cohort study.

BACKGROUND: Latina women are at increased risk for antenatal depressive disorders, which are common during pregnancy and are associated with elevated risk for poor maternal health and birth outcomes. Physical activity is a potential mechanism to reduce the likelihood of depressive symptoms. The purpose of the study was to assess whether total and domain-specific physical activity in early pregnancy reduced risk for elevated antenatal depressive symptoms in mid-late pregnancy in a population of Latina women at high-risk for depression. METHODS: Data from 820 Latina participants in the prospective cohort study Proyecto Buena Salud was examined using multivariable logistic regression. Total, moderate/vigorous, and domain-specific physical activity (household/caregiving, occupational, sports/exercise, transportation) were assessed using the Pregnancy Physical Activity Questionnaire. The Edinburgh Postnatal Depression Scale was used to assess depressive symptoms and identify women with elevated symptoms indicative of at least probable minor depression and probable major depression. RESULTS: A total of 25.9% of participants experienced at least probable minor depression and 19.1% probable major depression in mid-late pregnancy. After adjusting for important risk factors, no significant associations were observed between total physical activity (4th Quartile vs.1st Quartile OR = 1.02, 95% CI = 0.61, 1.71; p-trend = 0.62) or meeting exercise guidelines in pregnancy (OR = 0.96, 95% CI = 0.65, 1.41) and at least probable minor depression; similarly, associations were not observed between these measures and probable major depression. There was a suggestion of increased risk of probable major depression with high levels of household/caregiving activity (4th Quartile vs 1st Quartile OR = 1.51, 95% CI = 0.93, 2.46), but this was attenuated and remained not statistically significant after adjustment. When we repeated the analysis among women who did not have elevated depressive symptoms in early pregnancy (n = 596), findings were unchanged, though a nonsignificant protective effect was observed for sport/exercise activity and probable major depression in fully adjusted analysis (OR = 0.63, 95% CI = 0.30, 1.33). CONCLUSION: Among Latina women at high-risk for antenatal depression, early pregnancy physical activity was not associated with elevated depressive symptoms in mid-to-late pregnancy.

Depression During Pregnancy and Adverse Birth Outcomes Among Predominantly Puerto Rican Women.

Objectives To examine associations between depression and preterm birth and small-for gestational age (SGA) among women of predominantly Puerto Rican descent, a population who experiences disparities in adverse birth outcomes and one of the highest infant mortality rates in the United States. Methods Proyecto Buena Salud (PBS) was a prospective cohort study conducted from 2006 to 2011 at a large tertiary care center in Western Massachusetts. Caribbean Islander (i.e., Puerto Rican and Dominican Republic) women were interviewed in early, mid and late pregnancy. Among 1262 participants, associations between depression, assessed using the Edinburgh Postnatal Depression Scale, and risk of preterm birth and small-for-gestational age (SGA) were evaluated. Results Women with at least probable minor depression [odds ratio (OR) = 1.77 (95% confidence interval (CI) = 1.02, 3.07)] or probable major depression [OR = 1.82 (95% CI = 1.01, 3.25)] in mid-pregnancy had an increased risk of SGA compared to non-depressed women in adjusted analyses. Borderline significant associations were observed between increasing levels of depressive symptom scores in early and mid-pregnancy [OR = 1.05 (95% CI = 1.00, 1.11) and OR = 1.04 (95% CI = 1.00, 1.09), respectively] and each additional trimester of exposure to probable major depression across mid- to late pregnancy [OR = 1.66 (95% CI = 1.00, 2.74)] and SGA. Late pregnancy depression was not associated with SGA; depression during pregnancy was not associated with preterm birth. Conclusions for Practice In this population of predominantly Puerto Rican women, mid-pregnancy depression increased risk for SGA. Findings can inform culturally appropriate, targeted interventions to identify and treat pregnant women with depression.

Plasma 25-hydroxyvitamin D and risk of premenstrual syndrome in a prospective cohort study.

BACKGROUND: Moderate to severe premenstrual syndrome (PMS) affects 8-20 percent of premenopausal women. Previous studies suggest that high dietary vitamin D intake may reduce risk. However, vitamin D status is influenced by both dietary vitamin D intake and sunlight exposure and the association of vitamin D status with PMS remains unclear. METHODS: We assessed the relation of plasma 25-hydroxyvitamin D (25OHD), total calcium and parathyroid hormone levels with risk of PMS and specific menstrual symptoms in a case-control study nested within the prospective Nurses' Health Study II. Cases were 401 women free from PMS at baseline who developed PMS during follow-up (1991-2005). Controls were women not experiencing PMS (1991-2005), matched 1:1 with cases on age and other factors. Timed luteal phase blood samples were collected between 1996 and 1999 from cases and controls. We used conditional logistic regression to model the relation of 25OHD levels with risk of PMS and individual menstrual symptoms. RESULTS: In analyses of all cases and controls, 25OHD levels were not associated with risk of PMS. However, results differed when the timing of blood collection vs. PMS diagnosis was considered. Among cases who had already been diagnosed with PMS at the time of blood collection (n = 279), 25OHD levels were positively associated with PMS, with each 10 nmol/L change in 25OHD associated with a 13% higher risk. Among cases who developed PMS after blood collection (n = 123), 25OHD levels were unrelated to risk of PMS overall, but inversely related to risk of specific menstrual symptoms. For example, each 10 nmol/L increase was associated with a significant 21% lower risk of breast tenderness (P = 0.02). Total calcium or parathyroid hormone levels were unrelated to PMS. CONCLUSIONS: 25OHD levels were not associated with overall risk of PMS. The positive association observed among women already experiencing PMS at the time of 25OHD measurement is likely due to confounding by indication related to use of dietary supplements to treat menstrual symptoms. Results from prospective analyses, which were less likely influenced by this bias, suggest that higher 25OHD levels may be inversely related to the development of specific menstrual symptoms.

Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial.

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D(3) combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995-2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D(3) along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.

Depressive Symptoms, External Stress, and Marital Adjustment: The Buffering Effect of Partner's Responsive Behavior.

Guided by theory emphasizing that partner responsiveness underlies well-functioning romantic relationships, we examined whether partners' responsive behavior buffered the degree to which a personal vulnerability (depressive symptoms) and external stress predicted declines in relationship adjustment. Using an existing dataset, we tested whether individuals' depressive symptoms and stress interacted with observer-coded partner responsive behavior during marital conflict discussions to predict change in marital adjustment at the next time point (N = 195 couples Time 1 to Time 2, 158 couples Time 2 to Time 3). Individuals experiencing greater (a) depressive symptoms or (b) stress showed sharper declines in marital adjustment. However, as predicted, the negative effects of both depressive symptoms and stress were attenuated when partners displayed high behavioral responsiveness. These findings underscore the importance of adopting a dyadic perspective to understand how partners' responsive behavior can overcome the harmful effects of personal and situational vulnerabilities on relationship outcomes.

Is Low Power Associated with Submission During Marital Conflict? Moderating Roles of Gender and Traditional Gender Role Beliefs.

Lower power during marital interactions predicts greater aggression by men, but no research has identified women's response to lower power. We tested whether women who experienced lower situational power during conflict exhibited greater submission, especially if they held traditional gender role beliefs and thus accepted structural gender differences in power. Newlywed couples (Time 1 N = 204 couples) completed questionnaires and discussed an area of conflict 3 times over 3 years. Individuals who perceived lower power during couples' discussions evidenced greater submission, but this effect was more pronounced for wives, especially wives who held traditional gender role beliefs. Among those with traditional gender role beliefs, greater submission together with lower power predicted lower marital adjustment over time. These results highlight that the low power-submission link, and associated implications for marital adjustment, need to be evaluated in the context of power-relevant situations, gender, and broader power-related beliefs about gender roles.

ROMANTIC PARTNERS' COPING STRATEGIES AND PATTERNS OF CORTISOL REACTIVITY AND RECOVERY IN RESPONSE TO RELATIONSHIP CONFLICT.

Stress in close relationships can have significant negative consequences for mental health, physical health, and long-term relationship functioning. Dysregulated physiological responses to stress are potential pathways through which relationship stress may lead to these kinds of outcomes, and the ways in which individuals attempt to cope with relationship stress are likely to impact their physiological responses. However, our understanding of the specific coping strategies that predict physiological reactivity and recovery in these contexts is rather limited. This study explored relations between young adult college students' self-reported methods of coping with stress in their romantic relationships and their physiological reactivity to and recovery from negotiating conflict with their romantic partners. Partners' coping styles were also examined as predictors of physiological stress responses. One hundred and ninety opposite-sex couples (N = 380; modal length of relationship = 1-2 years) participated in an experimental conflict discussion task. Physiological stress reactivity to the task was assessed using salivary cortisol, a primary hormonal product of the hypothalamic-pituitary-adrenocortical (HPA) axis. Growth modeling of the cortisol levels before, during, and after the conflict task indicated that men who typically coped with relationship stress by seeking social support showed greater physiological reactivity to the conflict task. Partners' need for social support predicted stronger stress responses for both men and women, as well. While seeking social support is generally thought to be an adaptive coping strategy for couples, the results suggest that within the context of conflict negotiation in which receiving and providing support may be more difficult, seeking support from a partner is associated with greater phyisological stress.

Childhood family adversity and adult cortisol response: The role of observed marital conflict behavior.

Childhood family adversity predicts adult interpersonal behavior and physiological responses to interpersonal stress. Additionally, negative marital behaviors (e.g., hostility and distress maintaining attributions) predict maladaptive stress responses and mental health problems, whereas positive marital behaviors (e.g., acceptance and relationship enhancing attributions) predict adaptive physiological and psychological outcomes. The present study examined potential marital behavior mediators and moderators of the link between childhood adversity and cortisol responses to conflict. In a sample of 218 different-sex newlywed couples, we examined (a) actors' marital conflict behaviors as candidate mediators of the link between childhood adversity and cortisol responses to marital conflict discussions, and (b) partners' marital conflict behaviors as candidate moderators of the relation between childhood adversity and cortisol responses to marital discussions. Path analysis using actor-partner interdependence modeling did not confirm mediation. Instead, wives' childhood family adversity directly predicted husbands' attenuated cortisol responses, and wives' negative behavior predicted wives' attenuated cortisol responses. As hypothesized, wives' negative behaviors moderated the association between husbands' childhood family adversity and husbands' cortisol in response to conflict; husbands showed higher cortisol if they had experienced greater family adversity and if their wives displayed more negative behavior. Results suggest that childhood family adversity may carry forward to shape adult cortisol responses to conflict and highlights the importance of wives' negative behavior for both husbands and wives. These findings add to the family psychology literature by further clarifying how the interaction of stressful childhood experiences and conflict behaviors in marriage are associated with adult physiological responses to conflict. (PsycINFO Database Record

Prenatal Perceived Stress and Adverse Birth Outcomes Among Puerto Rican Women.

BACKGROUND: Preterm birth and low birthweight contribute substantially to the disproportionately high infant mortality rates experienced by Puerto Ricans in the United States. The purpose of this study was to examine whether the timing and pattern of prenatal psychosocial stress increased risk of adverse birth outcomes in this high-risk population. MATERIALS AND METHODS: Proyecto Buena Salud was a prospective cohort study conducted from 2006 to 2011 among predominantly Puerto Rican women. Participants (n = 1,267) were interviewed in early, mid-, and late pregnancy. We evaluated associations between early and mid-pregnancy stress (Perceived Stress Scale) and preterm birth and low birthweight, and stress at each pregnancy time point and small for gestational age (SGA). RESULTS: Elevated levels of perceived stress in mid-pregnancy increased risk for preterm birth and low birthweight in adjusted analyses, with a linear trend observed for each increasing quartile of stress (ptrend = 0.01). Women in the highest quartile of stress experienced three times the risk for preterm birth (odds ratio [OR] = 3.50, confidence interval [95% CI]: 1.38-8.87) and low birthweight (OR = 3.53, 95% CI = 1.27-9.86) compared with women in the lowest quartile. Early pregnancy stress was not associated with preterm birth or low birthweight. Increase in stress from early to late pregnancy increased risk for SGA (OR = 1.90, 95% CI = 1.01-3.59); no associations were found between stress at any timepoint and SGA. CONCLUSION: Elevated levels of mid-pregnancy perceived stress increased risk for preterm birth and low birthweight, and an increase in stress over the course of pregnancy increased risk for SGA in a population of predominantly Puerto Rican women.

Emotion regulation in emerging adult couples: temperament, attachment, and HPA response to conflict.

Difficulty managing the stress of conflict in close relationships can lead to mental and physical health problems, possibly through dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine stress response system. Temperament, an individual characteristic, and attachment, a dyadic characteristic, have both been implicated in emotion regulation processes and physiological reactivity, yet there is no clear consensus on how the two work together to influence the stress response, especially after childhood. The present study investigated the ways in which temperament and attachment together predict HPA response in emerging adult couples. Analyses using multilevel modeling (HLM) found that partners' dyadic fit on attachment avoidance impacted females' cortisol response patterns, and attachment avoidance further moderated the effect of males' emotionality on both their own and their partners' cortisol. Results are discussed in terms of emotional coregulation processes in romantic attachment.

Early Pubertal Timing and Childhood Family Adversity Interact to Predict Newlywed Women's Anxiety Symptoms.

The contextual amplification hypothesis posits that girls' early pubertal timing will predict anxiety and depression symptoms most strongly when early puberty occurs under adverse conditions. Research supporting this hypothesis has consistently linked early pubertal timing occurring in adverse contexts to symptoms during adolescence, but little is known about the link to adult symptoms. The present study examined the extent to which women's reports of early pubertal timing and childhood family adversity interact to predict symptoms of anxiety and depression during the first two years of marriage. Married women (N = 226) completed questionnaires within 7 months into their first marriage (Time 1) and approximately 19 months later (Time 2). Analyses indicated that at both Time 1 and 2, women's reports of earlier pubertal timing predicted anxiety symptoms only when women reported a history of greater childhood family adversity. Additional analyses indicated that the interaction of earlier pubertal timing and greater childhood family adversity predicted symptoms of traumatic intrusions and panic, but not social anxiety, at Time 1, and panic symptoms at Times 1 and 2. These findings expand our understanding of the relation of early pubertal timing to adult emotional health and the family conditions that moderate this relation.

Stigma and diurnal cortisol among transitioning transgender men.

This study assessed diurnal cortisol functioning in relation to stigma-based transition-specific stressors experienced by transgender men during their transition from female to male. Sixty-five healthy transgender men undergoing testosterone therapy participated in in-person interviews through which transition-specific stressors were identified. Interviews were coded according to participant reported (1) Transitioning-identity stress; (2) Coming Out stress; (3) Gender-specific Public Bathroom stress; and (4) levels of general Perceived Stress. Participants provided fifteen salivary samples assessing cortisol diurnal rhythm over three days. Hierarchical linear models, adjusted for duration of time on testosterone therapy, body mass index, steroid-related medication use, mean awakening time, and CAR, confirmed that elevated diurnal cortisol levels at awakening were associated with transition-specific social stressors including experiencing Transitioning-identity stress, frequent Coming Out stress, and Gender-specific Public Bathroom stress. Transitioning-identity stress and Gender-specific Public Bathroom stress also predicted a steeper negative slope at awakening. General Perceived Stress was not associated with elevated cortisol or slope. These results clarify the relation of increased cortisol at awakening with a negative linear slope to perceived stigma and transition-related stress experience among transgender men.

Differential effects of subtypes of trauma symptoms on couples' hypothalamus-pituitary-adrenal (HPA) axis reactivity and recovery in response to interpersonal stress.

This article examined the relation of five subtypes of trauma symptoms to hypothalamus-pituitary-adrenal (HPA) functioning as assessed with salivary cortisol before, during, and after an experimentally induced interpersonal conflict task in 194 heterosexual young adult couples. Trauma history and symptoms were assessed through structured clinical interviews and standardized self-report measures. Hierarchical linear modeling was used to analyze the effects of trauma symptoms on trajectories of cortisol reactivity to and recovery from the interpersonal stress. Trauma-related anxiety, depression, sleep disturbances, and dissociation significantly predicted cortisol reactivity and recovery. Trauma-related anxiety, sleep disturbances, and sexual problems significantly predicted partners' cortisol reactivity to interpersonal stress.

Dating couples' attachment styles and patterns of cortisol reactivity and recovery in response to a relationship conflict.

This study investigated theoretically predicted links between attachment style and a physiological indicator of stress, salivary cortisol levels, in 124 heterosexual dating couples. Cortisol was assessed at 7 points before and after an experimental conflict negotiation task, creating a trajectory of stress reactivity and recovery for each participant. Growth modeling of cortisol data tested hypotheses that (a) insecurely attached individuals show patterns of greater physiological stress reactions to interpersonal conflict than do securely attached individuals and (b) people with insecurely attached partners show patterns of greater stress in reaction to relationship conflict than those with securely attached partners. Hypothesis 1 was supported, but men and women differed in the type of insecure attachment that predicted stress trajectories. Hypothesis 2 was supported for men, but not for women. The discussion emphasizes the role of gender role norms and partner characteristics in understanding connections between adult attachment and patterns of cortisol responses to interpersonal stress.

Depression and anxiety predict sex-specific cortisol responses to interpersonal stress.

Clinical theories posit interpersonal stress as an important factor in the emergence and exacerbation of depression and anxiety, while neuroendocrine research confirms the association of these syndromes with dysregulation in a major stress response system, the hypothalamic-pituitary-adrenal (HPA) axis. However, the proposal that depression and anxiety symptoms and diagnoses are associated with problematic HPA responses to close relationship stress has not been directly tested. We examined 196 heterosexual dating couples' depression and anxiety symptoms and diagnoses, assessed with questionnaires and diagnostic interviews, in relation to cortisol responses to discussion of an unresolved relationship conflict. Participants provided seven salivary samples in anticipation of and directly following the discussion, and throughout an hour-long recovery period, which were assayed for cortisol. Multilevel models of the HPA response predicted by symptoms or diagnoses showed that women's depressive symptoms predicted attenuated cortisol levels, with a flatter response curve. In contrast, men's depression symptoms and women's anxiety symptoms and diagnoses predicted higher cortisol levels. These findings highlight the importance of examining sex differences in responses to interpersonal stressors for understanding HPA dysregulation in internalizing psychopathology.

Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women.

We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only - not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu.

Attachment and Health-Related Physiological Stress Processes.

People who are more securely attached to close partners show health benefits, but the mechanisms underlying this link are not well specified. We focus on physiological pathways that are potential mediators of the connection between attachment in childhood and adulthood and health and disease outcomes. Growing evidence indicates that attachment insecurity (vs. security) is associated with distinctive physiological responses to stress, including responses involving the HPA, SAM and immune systems, but these responses vary with type of stressor (e.g., social/nonsocial) and contextual factors (e.g., partner's attachment style). Taking this more nuanced perspective will be important for understanding the conditions under which attachment shapes health-related physiological processes as well as downstream health and disease consequences.