Sociopolitical stressors are associated with psychological distress in a cohort of Latina women during early pregnancy.

Research suggests that the 2016 US election was a potential stressor among Latinos residing in the United States. Sociopolitical stressors targeted toward ethnic minority communities and become embodied through psychosocial distress. The current study investigates if and how sociopolitical stressors related to the 45th President, Donald Trump, and his administration are associated with psychological distress in early pregnancy of Latina women living in Southern California during the second half of his term. This cross-sectional analysis uses data from the Mothers' Cultural Experiences study (n = 90) collected from December 2018 to March 2020. Psychological distress was assessed in three domains: depression, state anxiety, and pregnancy-related anxiety. Sociopolitical stressors were measured through questionnaires about sociopolitical feelings and concerns. Multiple linear regression models examined the relationship between sociopolitical stressors and mental health scores, adjusting for multiple testing. Negative feelings and a greater number of sociopolitical concerns were associated with elevated pregnancy-related anxiety and depressive symptoms. The most frequently endorsed concern was about issues of racism (72.3%) and women's rights (62.4%); women endorsing these particular concerns also had higher scores on depression and pregnancy-related anxiety. No significant associations were detected with state anxiety after correction for multiple testing. This analysis is cross-sectional and cannot assess causality in the associations between sociopolitical stressors and distress. These results are consistent with the hypothesis that the 2016 election, the subsequent political environment, and the anti-immigrant rhetoric and policies of former President Trump and his administration were sources of stress for Latinos residing in the United States.

Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin.

Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet-induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum ferroportin mRNA expression, with undetectable ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by ferroportin and that, in these models, significant paracellular absorption does not occur.

Maternal hepcidin determines embryo iron homeostasis in mice.

Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic, hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

BACKGROUND: Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models. METHODS: We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose. RESULTS: Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models. CONCLUSION: EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice.

In the setting of normal kidney function, iron deficiency is associated with increased FGF23 production and cleavage, altering circulating FGF23 levels. Our objective was to determine how chronic kidney disease (CKD) and dietary iron intake affect FGF23 production and metabolism in wild-type (WT) and hepcidin knockout (HKO) mice. For 8 wk, the mice were fed diets that contained adenine (to induce CKD) or no adenine (control group), with either low-iron (4 ppm) or standard-iron (335 ppm) concentrations. The low-iron diet induced iron deficiency anemia in both the WT and HKO mice. Among the WT mice, in both the control and CKD groups, a low-iron compared with a standard-iron diet increased bone Fgf23 mRNA expression, C-terminal FGF23 (cFGF23) levels, and FGF23 cleavage as manifested by a lower percentage intact FGF23 (iFGF23). Independent of iron status, CKD was associated with inhibition of FGF23 cleavage. Similar results were observed in the HKO control and CKD groups. Dietary iron content was more influential on FGF23 parameters than the presence or absence of hepcidin. In the CKD mice (WT and HKO, total n = 42), independent of the effects of serum phosphate, iron deficiency was associated with increased FGF23 production but also greater cleavage, whereas worse kidney function was associated with increased FGF23 production but decreased cleavage. Therefore, in both the WT and HKO mouse models, dietary iron content and CKD affected FGF23 production and metabolism.

Thiol-derivatized minihepcidins retain biological activity.

Minihepcidins are small peptides that mimic biological activity of the iron-regulatory hormone hepcidin. Structurally, they contain thiol-free-cysteine residue in position 7 which is crucial for their bioactivity. Nonetheless, free sulfhydryl group is not desirable in pharmaceutical entities as it may lead to dermatological side effects. Moreover free thiol moiety is quite reactive and depending on conditions/reagents may be alkylated and/or oxidized giving various Cys-derivatives: S-alkyl cysteines, sulfoxides, sulfones, disulfides, cysteinesulfinic and cysteic acids. To limit such reactivity and maintain bioactivity of minihepcidin(s) we used thiol-protection strategy based on activated vinyl thioethers. Novel S-protected analogs of physiologically active minihepcidin PR73 were synthesized and tested in vitro showing activity comparable to parental molecule. The most active compound, PR73SH was also tested in vivo showing activity profile analogous to PR73. Collectively, our findings suggest that S-vinyl-derivatization of minihepcidin(s) may be a suitable approach in the development of physiologically active agonists of hepcidin.

Small cyclic agonists of iron regulatory hormone hepcidin.

Minihepcidins are in vitro and in vivo active mimetics of iron-regulatory hormone hepcidin. They contain various unusual amino acids including: N-substituted, ß-homo-, and d-amino acids with their combination depending on particular minihepcidin. In the current study, we sought to limit the use of unusual/more expensive amino acids derivatives by peptide cyclization. Novel cyclic mimetics of hepcidin were synthesized and tested in vitro and showed activity at low nanomolar concentration. Nonetheless, the most active cyclic compound (mHS17) is approximately ten times less active than the parental minihepcidin PR73. Collectively, our findings suggest that cyclization is viable approach in the synthesis of hepcidin mimetics.

Variation in maternal lactation practices associated with changes in diurnal maternal inflammation.

While the importance of human milk in shaping infant immune function is well established, the impact of at-the-nipple (ATN) breastfeeding on maternal immune status has been understudied. Since lactation evolved to support infant survival and boost maternal fitness, we predict that ATN breastfeeding will confer benefits on maternal immune function. We measure the absolute and relative frequency of different infant feeding methods (ATN breastfeeding, pumping, donated milk, other supplementation) used by postpartum women in Seattle, WA (USA). We implement Bayesian modeling to estimate the effects of ATN breastfeeding on diurnal change in secretion rate of "pro-inflammatory" salivary cytokines and C-reactive protein (CRP). Our results show that most mothers in our sample used a variety of infant feeding methods, with pumping as the most common alternative to ATN breastfeeding. We find that ATN breastfeeding is associated with non-linear effects on diurnal IL-8 and CRP. Furthermore, we find that women who report zero versus ubiquitous ATN breastfeeding exhibit opposing diurnal patterns in CRP secretion rate. This study provides evidence that variation in maternal lactation practices corresponds to differences in maternal immune responses, highlighting how measuring lactation as a continuous variable can further enhance understanding of postpartum maternal physiology.

Preliminary Pilot-Testing of Social Determinants of Health Screener for Individuals With Intellectual and Developmental Disabilities in Med-Peds.

In the United States, one in six children has an intellectual and/or developmental disability (I/DD), including attention deficit hyperactivity disorder (ADHD), autism, cerebral palsy, learning disabilities, seizures, and developmental delays, with or without intellectual impairment. Individuals with I/DDs experience disproportionate rates of immune, metabolic, cardiovascular, and neurological disorders, as well as anxiety, depression, functional somatic symptoms, and other co-occurring physical and mental health conditions. During the coronavirus disease 2019 (COVID-19) pandemic, having an I/DD emerged as one of the strongest predictors of contracting and dying from COVID-19. These findings spurred increased attention toward the myriad health inequities affecting this population well before the pandemic. While inequities for individuals with I/DD can be traced to many factors, social determinants of health (SDOH) - the underlying social, economic, and environmental conditions that lead to poor health outcomes and high healthcare costs - are key contributors. Our interdisciplinary combined internal medicine and pediatrics (Med-Peds) team of physicians, psychologists, and researchers within a large, diverse, academic health system aimed to pilot-test the implementation of a five-item SDOH screener within a Med-Peds specialty clinic focused on the developmental needs of individuals with I/DD and their families (Leadership Education in Neurodevelopmental Disabilities {LEND}) and a general primary care practice (PCP). The SDOH screener tested in this initiative includes five items from the Accountable Health Communities (AHC) Health-Related Social Needs Screening Tool (HRSN) assessing social isolation, food insecurity, transportation, and paying for basic needs, such as housing and medical care. In this study, we describe the process of implementing this screener and collecting initial pilot data from 747 patients between October 2022 and April 2023 across the LEND and the primary care practice. We also highlight the challenges and opportunities identified during the mid-way point of implementation and pilot testing. The results of this pilot study revealed low response rates among SDOH screeners, spurring several measures to increase uptake, including increasing the accessibility of the screener and ensuring the screener results in effective referrals. We call on additional Med-Peds healthcare teams without universal SDOH screening protocols in place - particularly those serving the I/DD population - to consider adopting these practices.

Preliminary Pilot-Testing of Intimate Partner Violence Screening for Transgender and Gender Diverse (TGD) Individuals in Med-Peds and Family Medicine.

INTRODUCTION: Transgender and gender diverse (TGD) individuals, comprised of those whose gender identity does not correspond with the sex they were assigned at birth, represent approximately 1.4 million people in the U.S., with a higher prevalence among those 18-24 years old. TGD individuals experience high levels of intimate partner violence (IPV), which leads to disproportionately negative mental and physical health outcomes for this population. As a result, there is a resounding need to connect TGD populations to health-promoting services, supports and resources. Med-Peds and Family Medicine clinics may be particularly well-positioned to support these efforts due to physicians' focus on transitional-aged youth and young adults under 30. METHODS: The current manuscript reports on processes and outcomes related to a quality improvement (QI) initiative that aimed to test the feasibility and acceptability of implementing IPV screening within both a Med-Peds and a Family Medicine specialty clinic serving TGD populations in Los Angeles, CA. This QI initiative included screeners that capture IPV in cisgender/non-TGD populations (Humiliation, Afraid, Rape, Kick [HARK]) as well as in TGD populations specifically (IPV-T). We utilized a mixed-methods approach to both quantify and qualify responses to existing IPV screening as well as informal feedback from clinic "champions" in each clinic. RESULTS: Quantitative and qualitative findings from this QI initiative, featuring both general and TGD-specific IPV screening measures with 140 TGD individuals, elucidated several important processes that can support effective IPV screening and referral to supports and services. These include the importance of interdisciplinary teams, the utility of an iterative approach to screener roll-out, and the essential role of solidifying a referral process in these efforts. This project additionally shed light on the potential utility and challenges of implementing both general and TGD-specific IPV screening measures. Our pilot test did not support the necessity of a TGD-specific IPV screener for identifying and responding to IPV in this population, yet additional data is critical to generate more conclusive recommendations. CONCLUSION: We recommend larger-scale data collection efforts to evaluate the utility of integrating general and TGD-specific screeners into clinic workflows to ensure optimal health promotion for the TGD population in Med-Peds and Family Medicine clinics.

What Do Your Neighbors Think About You? How Perceived Neighbor Attitudes Toward Latinos Influence Mental Health Among a Pregnant Latina Cohort.

Latina women living in the USA experience disproportionately higher rates of psychological distress compared to their non-Latina White counterparts. Poor maternal mental health during pregnancy can contribute to intergenerational mental health disparities. Through this pathway, mothers' experiences, environments, and exposures (henceforth "exposures") during pregnancy become biologically embodied and can negatively affect the fetus and life-long developmental trajectories of her child. One of the exposures that can affect mother-offspring dyads is the neighborhood. With the goal of integrating anthropological and sociological theories to explain mental health disparities among pregnant Latina women, we explored how perceptions of neighbor attitudes may influence mental health during pregnancy. We analyzed self-reported responses from 239 pregnant Latina women in Southern California (131 foreign-born, 108 US-born) on their mental health and perceived attitudes of their neighbors using multiple linear regression models. Among foreign-born Latina women, living in neighborhoods with more favorable views of Latinos was associated with lower depression scores (pooled ß = - .70, SE = .29, p = .019) and lower pregnancy-related anxiety scores (pooled ß = - .11, SE = .05, p = .021), but greater state anxiety scores (pooled ß = .09, SE = .04, p = .021). Among US-born women, there were no associations between neighbor attitudes and mental health. Overall, results suggest that social environments are correlated with mental health and that foreign-born and US-born Latinas have varied mental health experiences in the USA. Our findings highlight the importance of improving aspects of neighborhood cohesion as part of maternal-fetal care management.

Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease.

In chronic kidney disease, ferric citrate has been shown to be an effective phosphate binder and source of enteral iron; however, the effects of ferric citrate on the kidney have been less well-studied. Here, in Col4α3 knockout mice-a murine model of progressive chronic kidney disease, we evaluated the effects of five weeks of 1% ferric citrate dietary supplementation. As expected, ferric citrate lowered serum phosphate concentrations and increased serum iron levels in the Col4α3 knockout mice. Consistent with decreased enteral phosphate absorption and possibly improved iron status, ferric citrate greatly reduced circulating fibroblast growth factor 23 levels. Interestingly, ferric citrate also lessened systemic inflammation, improved kidney function, reduced albuminuria, and decreased kidney inflammation and fibrosis, suggesting renoprotective effects of ferric citrate in the setting of chronic kidney disease. The factors mediating possible ferric citrate renoprotection, the mechanisms by which they may act, and whether ferric citrate affects chronic kidney disease progression in humans deserves further study.

The Structure of the Mini-K and K-SF-42 : A Psychological Network Approach.

Life history theory is a fruitful source of testable hypotheses about human individual differences. However, this field of study is beset by unresolved debates about basic concepts and methods. One of these controversies concerns the usefulness of instruments that purport to tap a unidimensional life history (LH) factor based on a set of self-reported personality, social, and attitudinal variables. Here, we take a novel approach to analyzing the psychometrics of two variants of the Arizona Life History Battery: the Mini-K and the K-SF-42. Psychological network analysis generates models in which psychological variables (thoughts, feelings, or behaviors) comprise the nodes of a network, while partial correlation coefficients between these variables comprise the edges of the network. Centrality indices (strength, closeness, and betweenness) operationalize each node's importance based on the pattern of the connections in which that node plays a role. Because childhood environments are hypothesized to influence adult LH, we tested the hypothesis that among the Mini-K items, and the K-SF-42 scales, those that tap relationships with parents are central to the networks (pairwise Markov random fields) constructed from these instruments. In an MTurk sample and an undergraduate sample that completed the Mini-K, and an MTurk sample that completed the K-SF-42, this hypothesis was falsified. Indeed, the "relationships with parents" items were among the most peripheral in all three networks. We propose that network analysis, as an alternative to latent variable modeling, offers considerable potential to test hypotheses about the input-output mappings of specific evolved psychological mechanisms.

Human Life History Strategies.

Human life history (LH) strategies are theoretically regulated by developmental exposure to environmental cues that ancestrally predicted LH-relevant world states (e.g., risk of morbidity-mortality). Recent modeling work has raised the question of whether the association of childhood family factors with adult LH variation arises via (i) direct sampling of external environmental cues during development and/or (ii) calibration of LH strategies to internal somatic condition (i.e., health), which itself reflects exposure to variably favorable environments. The present research tested between these possibilities through three online surveys involving a total of over 26,000 participants. Participants completed questionnaires assessing components of self-reported environmental harshness (i.e., socioeconomic status, family neglect, and neighborhood crime), health status, and various LH-related psychological and behavioral phenotypes (e.g., mating strategies, paranoia, and anxiety), modeled as a unidimensional latent variable. Structural equation models suggested that exposure to harsh ecologies had direct effects on latent LH strategy as well as indirect effects on latent LH strategy mediated via health status. These findings suggest that human LH strategies may be calibrated to both external and internal cues and that such calibrational effects manifest in a wide range of psychological and behavioral phenotypes.

In a Mouse Model of Sepsis, Hepcidin Ablation Ameliorates Anemia More Effectively than Iron and Erythropoietin Treatment.

Intensive care unit (ICU) anemia is an extreme version of anemia of inflammation that occurs commonly in critically ill patients and is associated with increased morbidity and mortality. Currently available therapies for ICU anemia have shown inconsistent efficacies in clinical trials. We conducted a systematic study of the effects of early versus delayed iron (Fe) and/or erythropoietin (EPO) therapy in our previously characterized mouse model of ICU anemia based on an injection of heat-killed Brucella abortus. To study the effects of ongoing inflammation on the response to therapy, inflamed wild-type (WT) and hepcidin knockout (HKO) mice were treated at either early (days 1 and 2) or delayed (days 7 and 8) time points after the inflammatory stimulus. In the early treatment group, Fe and/or EPO therapy did not increase hemoglobin (Hgb) levels or reticulocyte production in either the inflamed WT or HKO groups. In the delayed treatment group, combination Fe + EPO therapy did increase Hgb and reticulocyte production in WT mice (mean ΔHgb in WT saline group -9.2 g/dL vs. Fe/EPO -5.5 g/dL; P < 0.001). The HKO mice in the delayed treatment group did not improve their Hgb, but HKO mice in all treatment groups developed a milder anemia than the WT mice. Our findings indicate that combination Fe + EPO therapy is effective in partially reversing ICU anemia when administered after the phase of acute inflammation. Hepcidin ablation alone was more effective in attenuating ICU anemia than Fe + EPO therapy, which indicates the potential of antihepcidin therapeutics in treating ICU anemia.