Micronutrient status during pregnancy is associated with child immune status in rural Bangladesh.

Background: Poor immune function increases children's risk of infection and mortality. Several maternal factors during pregnancy may affect infant immune function during the postnatal period. Objectives: We aimed to evaluate whether maternal micronutrients, stress, estriol, and immune status during the first or second trimester of pregnancy were associated with child immune status in the first two years after birth. Methods: We conducted observational analyses within the water, sanitation, and hygiene (WASH) Benefits Bangladesh randomized controlled trial. We measured biomarkers in 575 pregnant women and postnatally in their children. Maternal biomarkers measured during the first and second trimester of pregnancy included nutrition status via vitamin D (25-hydroxy-D [25(OH)D]), ferritin, soluble transferrin receptor (sTfR), and retinol-binding protein (RBP); cortisol; estriol. Immune markers were assessed in pregnant women at enrollment and their children at ages 14 and 28 mo, including C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), and 13 cytokines (including IFN-γ). We generated a standardized sum score of log-transformed cytokines. We analyzed IFN-γ individually because it is a critical immunoregulatory cytokine. All outcomes were prespecified. We used generalized additive models and reported the mean difference and 95% confidence intervals at the 25th and 75th percentiles of exposure distribution. Results: At child age 14 mo, concentrations of maternal RBP were inversely associated with the cytokine sum score in children (-0.34 adjusted difference between the 25th and 75th percentile [95% confidence interval -0.61, -0.07]), and maternal vitamin A deficiency was positively associated with the cytokine sum score in children (1.02 [0.13, 1.91]). At child age of 28 mo, maternal RBP was positively associated with IFN-γ in children (0.07 [0.01, 0.14]), whereas maternal vitamin A deficiency was negatively associated with child AGP (-0.07 [-0.13, -0.02]). Maternal iron deficiency was associated with higher AGP concentrations in children at age 14 mo (0.13 [0.04, 0.23]), and maternal sTfR concentrations were positively associated with child CRP concentrations at age 28 mo (0.18 [0, 0.36]). Conclusion: Maternal deficiencies in vitamin A or iron during the first 2 trimesters of pregnancy may shape the trajectory of a child's immune status.

Deleterious and Protective Psychosocial and Stress-Related Factors Predict Risk of Spontaneous Preterm Birth.

OBJECTIVES: The aim of the study was to: (1) Identify (early in pregnancy) psychosocial and stress-related factors that predict risk of spontaneous preterm birth (PTB, gestational age <37 weeks); (2) Investigate whether "protective" factors (e.g., happiness/social support) decrease risk; (3) Use the Dhabhar Quick-Assessment Questionnaire for Stress and Psychosocial Factors (DQAQ-SPF) to rapidly quantify harmful or protective factors that predict increased or decreased risk respectively, of PTB. STUDY DESIGN: This is a prospective cohort study. Relative risk (RR) analyses investigated association between individual factors and PTB. Machine learning-based interdependency analysis (IDPA) identified factor clusters, strength, and direction of association with PTB. A nonlinear model based on support vector machines was built for predicting PTB and identifying factors that most strongly predicted PTB. RESULTS: Higher levels of deleterious factors were associated with increased RR for PTB: General anxiety (RR = 8.9; 95% confidence interval [CI] = 2.0,39.6), pain (RR = 5.7; CI = 1.7,17.0); tiredness/fatigue (RR = 3.7; CI = 1.09,13.5); perceived risk of birth complications (RR = 4; CI = 1.6,10.01); self-rated health current (RR = 2.6; CI = 1.0,6.7) and previous 3 years (RR = 2.9; CI = 1.1,7.7); and divorce (RR = 2.9; CI = 1.1,7.8). Lower levels of protective factors were also associated with increased RR for PTB: low happiness (RR = 9.1; CI = 1.25,71.5); low support from parents/siblings (RR = 3.5; CI = 0.9,12.9), and father-of-baby (RR = 3; CI = 1.1,9.9). These factors were also components of the clusters identified by the IDPA: perceived risk of birth complications (p < 0.05 after FDR correction), and general anxiety, happiness, tiredness/fatigue, self-rated health, social support, pain, and sleep (p < 0.05 without FDR correction). Supervised analysis of all factors, subject to cross-validation, produced a model highly predictive of PTB (AUROC or area under the receiver operating characteristic = 0.73). Model reduction through forward selection revealed that even a small set of factors (including those identified by RR and IDPA) predicted PTB. CONCLUSION: These findings represent an important step toward identifying key factors, which can be assessed rapidly before/after conception, to predict risk of PTB, and perhaps other adverse pregnancy outcomes. Quantifying these factors, before, or early in pregnancy, could identify women at risk of delivering preterm, pinpoint mechanisms/targets for intervention, and facilitate the development of interventions to prevent PTB. KEY POINTS: · Newly designed questionnaire used for rapid quantification of stress and psychosocial factors early during pregnancy.. · Deleterious factors predict increased preterm birth (PTB) risk.. · Protective factors predict decreased PTB risk..

Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning.

Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches. Objectives: The primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions. Materials and Methods: In a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF). Results: Jointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs. Conclusions: Elucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.

Sex Differences in Peritraumatic Inflammatory Cytokines and Steroid Hormones Contribute to Prospective Risk for Nonremitting Posttraumatic Stress Disorder.

Women are at higher risk for developing posttraumatic stress disorder (PTSD) compared to men, yet little is known about the biological contributors to this sex difference. One possible mechanism is differential immunological and neuroendocrine responses to traumatic stress exposure. In the current prospective study, we aimed to identify whether sex is indirectly associated with the probability of developing nonremitting PTSD through pro-inflammatory markers and whether steroid hormone concentrations influence this effect. Female (n = 179) and male (n = 197) trauma survivors were recruited from an emergency department and completed clinical assessment within 24 h and blood samples within ∼three hours of trauma exposure. Pro-inflammatory cytokines (IL-6, IL-1 ß , TNF, IFNγ), and steroid hormone (estradiol, testosterone, progesterone, cortisol) concentrations were quantified in plasma. Compared to men, women had a higher probability of developing nonremitting PTSD after trauma (p = 0.04), had lower pro-inflammatory cytokines and testosterone (p's<0.001), and had higher cortisol and progesterone (p's<0.001) concentrations. Estradiol concentrations were not different between the sexes (p = 0.24). Pro-inflammatory cytokines were a significant mediator in the relationship between sex and probability of developing nonremitting PTSD (p < 0.05), such that men had higher concentrations of pro-inflammatory cytokines which were associated with lower risk of nonremitting PTSD development. This effect was significantly moderated by estradiol (p < 0.05), as higher estradiol levels in men were associated with higher pro-inflammatory cytokine concentrations and lower risk for developing nonremitting PTSD. The current results suggest that sex differences in the pro-inflammatory cytokine response to trauma exposure partially mediate the probability of developing nonremitting PTSD, and that the protective ability to mount an pro-inflammatory cytokine response in men may depend on higher estradiol levels in the aftermath of trauma exposure.

Telomere length is associated with growth in children in rural Bangladesh.

Background: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth. Methods: We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders. Results: In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score [95% CI 0.05, 0.42; FDR-corrected p-value = 0.01]). TL was not associated with other outcomes. Conclusions: Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first 2 years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories. Funding: Funded by the Bill and Melinda Gates Foundation. Clinical trial number: NCT01590095.

Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more.

The authors highlight, from a firsthand perspective, Bruce S. McEwen's seminal influence on the field of stress neurobiology and beyond, and how these investigations have yielded important insights, principles and critical questions that continue to guide stress research today. Featured are discussion of: 1) the important inverted-U relationship between stress/glucocorticoids and optimal physiological function, 2) stress adaptation and the role of adaptive stress responses, 3) mechanisms by which the short-term stress response promotes heightened immune function and immunity, and 4) the far reaching impact of the theoretical framework of allostasis and allostatic load-concepts that have created new bridges between stress physiology, biomedical sciences, health psychology and sociology.

Deconstructing the effects of concentration meditation practice on interference control: The roles of controlled attention and inflammatory activity.

Prior work has linked meditation practice to improvements in interference control. However, the mechanisms underlying these improvements are relatively unknown. In the context of meditation training, improvements in interference control could result eitherfrom increases in controlled attention to goal-relevant stimuli, or from reductions in automatic capture by goal-irrelevant stimuli. Moreover, few studies have linked training-related changes in attention to physiological processes, such as inflammatory activity, that are thought to influence cognitive function. This study addresses these gaps by examining associations between cognitive performance and cytokines in the context of an intensive meditation retreat. Participants were randomly assigned to complete 3 months of meditation training first, or to serve as waitlist controls. The waitlist-control participants then later completed a separate 3-month training intervention. We assessed participants' interference control with a flanker task and used computational modeling to derive component processes of controlled and automatic attention. We also collected blood samples at the beginning, middle, and end of training to quantify changes in cytokine activity. Participants who completed training evidenced better controlled attention than waitlist controls during the first retreat intervention, and controls showed significant improvements in controlled attention when they completed their own, second retreat. Importantly, inflammatory activity was inversely associated with controlled attention during both interventions. Our results suggest that practice of concentration meditation influences interference control by enhancing controlled attention to goal-relevant task elements, and that inflammatory activity relates to individual differences in controlled attention.

Vitamin D and inflammation in major depressive disorder.

BACKGROUND: Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects. METHODS: We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score. RESULTS: There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p < 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03). LIMITATIONS: The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI. CONCLUSION: While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state.

Association of Prospective Risk for Chronic PTSD Symptoms With Low TNFα and IFNγ Concentrations in the Immediate Aftermath of Trauma Exposure.

OBJECTIVE: Although several reports have documented heightened systemic inflammation in posttraumatic stress disorder (PTSD), few studies have assessed whether inflammatory markers serve as prospective biomarkers for PTSD risk. The present study aimed to characterize whether peripheral immune factors measured in blood samples collected in an emergency department immediately after trauma exposure would predict later chronic development of PTSD. METHODS: Participants (N=505) were recruited from a hospital emergency department and underwent a 1.5-hour assessment. Blood samples were drawn, on average, about 3 hours after trauma exposure. Follow-up assessments were conducted 1, 3, 6, and 12 months after trauma exposure. Latent growth mixture modeling was used to identify classes of PTSD symptom trajectories. RESULTS: Three distinct classes of PTSD symptom trajectories were identified: chronic (N=28), resilient (N=160), and recovery (N=85). Multivariate analyses of covariance revealed a significant multivariate main effect of PTSD symptom trajectory class membership on proinflammatory cytokines. Univariate analyses showed a significant main effect of trajectory class membership on plasma concentrations of proinflammatory tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Concentrations of proinflammatory TNFα and IFNγ were significantly lower in individuals in the chronic PTSD class compared with those in the recovery and resilient classes. There were no significant differences in interleukin (IL) 1ß and IL-6 concentrations by PTSD symptom trajectory class. Anti-inflammatory and other cytokines, as well as chemokines and growth factor concentrations, were not associated with development of chronic PTSD. CONCLUSIONS: Overall, the study findings suggest that assessing the proinflammatory immune response to trauma exposure immediately after trauma exposure, in the emergency department, may help identify individuals most at risk for developing chronic PTSD in the aftermath of trauma.

Racial discrimination, the superwoman schema, and allostatic load: exploring an integrative stress-coping model among African American women.

Racial discrimination has been linked to allostatic load (i.e., cumulative biological stress) among African American women. However, limited attention has been given to psychosocial processes involved in the stress response-critical for understanding biological pathways to health-in studies examining racial discrimination as a social determinant of health. We examined whether the superwoman schema (SWS), a multidimensional culture-specific framework characterizing psychosocial responses to stress among African American women, modifies the association between racial discrimination and allostatic load. We used purposive sampling to recruit a community sample of African American women ages 30-50 from five San Francisco Bay Area counties (n = 208). Path analysis was used to test for interactions while accounting for the covariance among SWS subscales using both linear and quadratic models. Significant interactions were observed between racial discrimination and four of the five SWS subscales. Feeling obligated to present an image of strength and an obligation to suppress emotions were each protective whereas feeling an intense motivation to succeed and feeling an obligation to help others exacerbated the independent health risk associated with experiencing racial discrimination. Our findings affirm the need to consider individual variability in coping and potentially other psychosocial processes involved in the stress response process, and offer several insights that may help elucidate the mechanisms by which racial discrimination gets "under the skin."

The impact of psychosocial stress and stress management on immune responses in patients with cancer.

The range of psychosocial stress factors/processes (eg, chronic stress, distress states, coping, social adversity) were reviewed as they relate to immune variables in cancer along with studies of psychosocial interventions on these stress processes and immune measures in cancer populations. The review includes molecular, cellular, and clinical research specifically examining the effects of stress processes and stress-management interventions on immune variables (eg, cellular immune function, inflammation), which may or may not be changing directly in response to the cancer or its treatment. Basic psychoneuroimmunologic research on stress processes (using animal or cellular/tumor models) provides leads for investigating biobehavioral processes that may underlie the associations reported to date. The development of theoretically driven and empirically supported stress-management interventions may provide important adjuncts to clinical cancer care going forward.

Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.

Inflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines. Increased inflammasome protein expression was observed in MDD patients, indicative of an activated inflammatory response. The plasma of MDD patients was immunosuppressive on healthy donor peripheral blood mononuclear cells, inducing reduced activation of monocytes/dendritic cells and B cells and reduced T cell memory. Comparison between 33 non-responders and 71 responders at baseline and 12 weeks revealed that after treatment, anti-inflammatory cytokine levels increase in both groups, whereas 5 proinflammatory cytokine levels were stabilized in responders, but continued to increase in non-responders. MDD patients exhibit remodeling of their inflammatory landscape.

Associations between chronic caregiving stress and T cell markers implicated in immunosenescence.

Chronic psychological stress is associated with accelerated biological aging, immune dysfunction, and premature morbidity and mortality. Changes in the relative proportions of T cell subpopulations are thought to be a characteristic of immunological aging; however, understanding of whether these changes are associated with chronic psychological stress is incomplete. This study investigated associations between chronic caregiving stress and distributions of T cell phenotypes in a sample of high stress mothers of children with Autism Spectrum Disorder (caregivers; n = 91) and low stress mothers of neurotypical children (controls; n = 88). Immune markers assessed were naïve (CD45RA + CD62L+), central memory (CD45RA-CD62L+), and effector memory (CD45RA-CD62L-) CD4+ and CD8+ T cells. We also examined the ratio of effector to naïve (E:N) CD4+ and CD8+ T cells. In models adjusted for age, body mass index, race/ethnicity, and antidepressant use, caregivers displayed higher percentages of effector memory CD8+ and CD4+ T cells as well as lower percentages of naïve CD8+ T cells and central memory CD8+ and CD4+ T cells compared to controls. Caregivers also displayed significantly higher E:N ratios for both CD4+ and CD8+ T cells. These findings were also independent of cytomegalovirus infection status. Furthermore, higher parental stress, across both groups, was related to several immune parameters. These findings provide preliminary evidence that chronic parental caregiving stress is associated with changes in relative proportions of T cell subpopulations that are consistent with accelerated immunological aging.

The short-term stress response - Mother nature's mechanism for enhancing protection and performance under conditions of threat, challenge, and opportunity.

Our group has proposed that in contrast to chronic stress that can have harmful effects, the short-term (fight-or-flight) stress response (lasting for minutes to hours) is nature's fundamental survival mechanism that enhances protection and performance under conditions involving threat/challenge/opportunity. Short-term stress enhances innate/primary, adaptive/secondary, vaccine-induced, and anti-tumor immune responses, and post-surgical recovery. Mechanisms and mediators include stress hormones, dendritic cell, neutrophil, macrophage, and lymphocyte trafficking/function and local/systemic chemokine and cytokine production. Short-term stress may also enhance mental/cognitive and physical performance through effects on brain, musculo-skeletal, and cardiovascular function, reappraisal of threat/anxiety, and training-induced stress-optimization. Therefore, short-term stress psychology/physiology could be harnessed to enhance immuno-protection, as well as mental and physical performance. This review aims to provide a conceptual framework and targets for further investigation of mechanisms and conditions under which the protective/adaptive aspects of short-term stress/exercise can be optimized/harnessed, and for developing pharmacological/biobehavioral interventions to enhance health/healing, and mental/cognitive/physical performance.

Distress and quality of life in an ethnically diverse sample awaiting breast cancer surgery.

Poor breast cancer-related quality of life is associated with flattened cortisol rhythms and inflammation in breast cancer survivors and women with advanced disease. We explored the associations of cancer-specific distress (Impact of Events Scale), mood (Profile of Mood States), activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient) and cortisol (diurnal slope) circadian rhythms, and inflammation (interleukin-6) with quality of life (Functional Assessment of Cancer Therapy-Breast) among patients awaiting breast cancer surgery ( N = 57). Models were adjusted for differences in age and cancer stage. Distress and mood disturbance were significantly correlated with lower quality of life. Ethnic differences in the relationship between distress and mood disturbance with global quality of life and subscales of quality of life were observed. Actigraphic measures showed that in comparison with non-Hispanic patients, African Americans had significantly poorer activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient). Circadian disruption and inflammation were not associated with quality of life. Physiological dysregulation and associated comorbidities may take time to develop over the course of disease and treatment.

Effects of water, sanitation, handwashing, and nutritional interventions on telomere length among children in a cluster-randomized controlled trial in rural Bangladesh.

Background: Shorter childhood telomere length (TL) and more rapid TL attrition are widely regarded as manifestations of stress. However, the potential effects of health interventions on child TL are unknown. We hypothesized that a water, sanitation, handwashing (WSH), and nutritional intervention would slow TL attrition during the first two years of life. Methods: In a trial in rural Bangladesh, we randomized geographical clusters of pregnant women into individual water treatment, sanitation, handwashing, nutrition, combined WSH, combined nutrition plus WSH (N + WSH), or control arms. We conducted a substudy enrolling children from the control arm and the N + WSH intervention arm. Participants and outcome assessors were not masked; analyses were masked. Relative TL was measured at 1 and 2 years after intervention, and the change in relative TL was reported. Analysis was intention-to-treat. Results: Between May 2012 and July 2013, in the overall trial, we randomized 720 geographical clusters of 5551 pregnant women to a control or an intervention arm. In this substudy, after 1 year of intervention, we assessed a total of 662 children (341 intervention and 321 control) and 713 children after 2 years of intervention (383 intervention and 330 control). Children in the intervention arm had significantly shorter relative TL compared with controls after 1 year of intervention (difference −163 base pairs (bp), p=0.001). Between years 1 and 2, TL increased in the intervention arm (+76 bp) and decreased in the controls (−23 bp) (p=0.050). After 2 years, there was no difference between the arms (p=0.305). Conclusions: Our unexpected finding of increased telomere attrition during the first year of life in the intervention group suggests that rapid telomere attrition during this critical period could reflect the improved growth in the intervention group, rather than accumulated stress. Funding: Funded by The Bill and Melinda Gates Foundation. Clinical trial number: NCT01590095.

Stress negatively affects health by causing changes in cells. As a result, excess stress may predispose people to fall ill more often or age faster. It is difficult to measure stress. Some studies suggest that measuring the ends of chromosomes, known as telomeres, may be one way to measure stress. Like the plastic tips on shoelaces, telomeres protect chromosomes from fraying. All peoples' telomeres shorten over their lifetime with each cell division. Many studies show that telomeres shorten faster in people who experience more stress. When telomeres become too short, cells die faster without being replaced, and the body ages. Most studies on telomere length have looked at adults. Few studies have looked at children early in life or asked whether there are ways to intervene to stop or reverse stress-related telomere shortening. The first two years of life are a crucial period for the developing brain and immune system, which could set children on a lifelong course toward health or disease. Young children living in low-resource settings often encounter many sources of stress, like poor nutrition, infectious diseases or violence. Studies are needed to determine if interventions in early childhood aimed at reducing some sources of stress improve telomere length or long-term health. Now, Lin et al. show that interventions to provide safe water, sanitation, handwashing facilities, and better nutrition to children in rural Bangladesh unexpectedly shortened telomeres. As part of a larger study, pregnant women in rural Bangladesh were divided, at random, into groups. One group received a suite of interventions, which included more sanitary toilets, handwashing facilities, and nutritional supplements for their infants. Another group served as a control and did not receive this extra help. Lin et al. looked at telomere length, growth, and infections in a subset of 713 children whose mothers participated in the study. Children who got the extra help grew faster and were less likely to get diarrhea or parasitic infections than the children in the control group. Unexpectedly, children in the intervention group had shorter telomeres at 14 months of age than the children in the control group. Lin et al. suggest that the telomere shortening in the intervention group might be a consequence of rapid growth and immune system development in the first year of life rather than resulting from biological stress. More studies are needed to ask whether telomere shortening is indeed linked to faster growth and development early in life. The strong and unexpected findings highlight how little is known about how the length of telomeres can be used to predict future health or disease. Interpreting the length of telomeres over a person's lifetime could prove more nuanced than originally thought.

Increased circulating blood cell counts in combat-related PTSD: Associations with inflammation and PTSD severity.

Inflammation is reported in post-traumatic stress disorder (PTSD). Few studies have investigated circulating blood cells that may contribute to inflammation. We assessed circulating platelets, white blood cells (WBC) and red blood cells (RBC) in PTSD and assessed their relationship to inflammation and symptom severity. One-hundred and sixty-three male combat-exposed veterans (82 PTSD, 81 non-PTSD) had blood assessed for platelets, WBC, and RBC. Data were correlated with symptom severity and inflammation. All cell counts were significantly elevated in PTSD. There were small mediation effects of BMI and smoking on these relationships. After adjusting for these, the differences in WBC and RBC remained significant, while platelet count was at trend level. In all subjects, all of the cell counts correlated significantly with inflammation. Platelet count correlated with inflammation only in the PTSD subjects. Platelet count, but none of the other cell counts, was directly correlated with PTSD severity ratings in the PTSD group. Combat PTSD is associated with elevations in RBC, WBC, and platelets. Dysregulation of all three major lineages of hematopoietic cells in PTSD, as well as their significant correlation with inflammation, suggest clinical significance of these changes.

Biological predictors of insulin resistance associated with posttraumatic stress disorder in young military veterans.

Posttraumatic stress disorder (PTSD) is associated with increased risk for Type 2 diabetes and cardiovascular disease (cardiometabolic disease), warranting research into targeted prevention strategies. In the present case-control study of 160 young (mean age 32.7 years) male military veterans, we aimed to assess whether PTSD status predicted increased markers of cardiometabolic risk in otherwise healthy individuals, and further, to explore biological pathways between PTSD and these increased markers of cardiometabolic risk. Toward these aims, we compared measures of cardiometabolic risk, namely insulin resistance (IR) (HOMA-IR), metabolic syndrome (MetS) and prediabetes, between 80 PTSD cases and 80 controls without PTSD. We then determined whether PTSD-associated increases in HOMA-IR were correlated with select biological variables from pathways previously hypothesized to link PTSD with cardiometabolic risk, including systemic inflammation (increased C-reactive protein, interleukin-6, and tumor necrosis factor α), sympathetic over-activity (increased resting heart rate), and neuroendocrine dysregulation (increased plasma cortisol or serum brain-derived neurotrophic factor (BDNF)). We found PTSD diagnosis was associated with substantially higher HOMA-IR (cases 4.3±4.3 vs controls 2.4±2.0; p<0.001), and a higher frequency of MetS (cases 21.3% vs controls 2.5%; p<0.001), but not prediabetes (cases 20.0% vs controls 18.8%; p>0.05). Cases also had increased pro-inflammatory cytokines (p<0.01), heart rate (p<0.001), and BDNF (p<0.001), which together predicted increased HOMA-IR (adjusted R2=0.68, p<0.001). Results show PTSD diagnosis in young male military veterans without cardiometabolic disease is associated with increased IR, predicted by biological alterations previously hypothesized to link PTSD to increased cardiometabolic risk. Findings support further research into early, targeted prevention of cardiometabolic disease in individuals with PTSD.