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Chronic inflammatory demyelination polyradiculoneuropathy (CIDP) is a rare autoimmune neuropathy generated by cellular and humoral immune responses. Its course can be chronic, progressive, monophasic, or relapsing-remitting. Misdiagnosis and inappropriate therapy are common in CIDP. Given the scarcity of integrative information, we aimed to briefly summarize the epidemiology, pathophysiology, clinical phenotypes, diagnostic tools, and diagnostic criteria and provide a systematic diagnostic approach. We reviewed articles on Medline (PubMed) from 2018 to 2023, using Google Scholar to summarize the topics. The results are presented as a narrative review, in accordance with recommendations of the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. The included evidence showed that CIDP is a challenging neuropathy to diagnose and treat. Pathologic factors initiating typical CIDP and atypical CIDP are still clearly unknown. CIDP is diagnosed using the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with electrophysiological evidence of demyelination. However, some patients need to fulfill the requirements. Another challenge is monitoring the disease progression and recognizing patients who do not respond to evidence-based first-line therapy to individualize their treatment. Based on the evidence, we conclude that 2021 EFNS/PNS guidelines allow for a more accurate diagnosis and treatment of CIDP and its variants. New diagnostic tools and molecular approaches are helpful in the diagnosis process but cannot replace clinical and electrodiagnostic criteria., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Roman-Guzman et al.)

The 2020 American Heart Association Guidelines advise not to perform mitral valve replacement (MVR) during septal myectomy (SM) to alleviate outflow obstruction. This study aims to review outcomes after concomitant mitral valve (MV) intervention versus SM alone. We conducted a comprehensive literature search across Embase, PubMed, and Scopus. Studies published up to June 15, 2024 were considered. We included studies that compared SM alone to concomitant MV repair or replacement. Subgroup analyses based on MV intervention were performed. Seven studies met our criteria, including 1 randomized and 6 observational studies. The total sample size was 17,565 patients with hypertrophic cardiomyopathy (11,849 SM, 2303 SM + MVR, and 3390 SM + MV repair). Patients who underwent SM + MV intervention had more pronounced preoperative MV regurgitation. SM + MVR was associated with significantly higher early mortality [risk ratio (RR): 2.85, 95% confidence interval (CI): 2.37-3.43, P < 0.00001, I ² = 0%]. However, there was no difference in early mortality in patients who underwent SM + MV repair compared with SM alone (RR: 1.14, 95% CI: 0.88-1.49, P = 0.33, I ² = 0%). Thirty days systolic anterior motion was significantly lower in patients who underwent SM + MV repair compared with SM alone (RR: 0.15, 95%CI: 0.05-0.45, P = 0.0007). Peak pressure left ventricular outflow tract gradient was significantly lower in the SM + MV repair group compared with SM alone (mean difference: -3.47, 95% CI: -5.55 to -1.39, P = 0.001). Current observational evidence suggests an increased risk of in-patient mortality in patients who underwent SM + MVR. SM + MV repair did not affect early mortality but was linked to improved outcomes. Future comprehensive and matched studies are warranted., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Stress is a major risk factor for several neuropsychiatric disorders in women, including postpartum depression. During the postpartum period, diminished ovarian hormone secretion increases susceptibility to developing depressive symptoms. Pleiotropic peptide hormones, like prolactin, are markedly released during lactation and suppress hypothalamic-pituitary-adrenal axis responses in women and acute stress-induced behavioral responses in female rodents. However, the effects of prolactin on chronic stress-induced maladaptive behaviors remain unclear. Here, we used chronic variable stress to induce maladaptive physiology in ovariectomized female rats and concurrently administered prolactin to assess its effects on several depression-relevant behavioral, endocrine, and neural characteristics. We found that chronic stress increased sucrose anhedonia and passive coping in saline-treated, but not prolactin-treated rats. Prolactin treatment did not alter stress-induced thigmotaxis, corticosterone (CORT) concentrations, hippocampal cell activation or survival. However, prolactin treatment reduced basal CORT concentrations and increased dopaminergic cells in the ventral tegmental area. Further, prolactin-treated rats had reduced microglial activation in the ventral hippocampus following chronic stress exposure. Together, these data suggest prolactin mitigates chronic stress-induced maladaptive behaviors and physiology in hypogonadal females. Moreover, these findings imply neuroendocrine-immune mechanisms by which peptide hormones confer stress resilience during periods of low ovarian hormone secretion., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models., Methods and Results: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls., Conclusion: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming., (© 2024. The Author(s).)

The Gram-negative bacterium Coxiella burnetii is the causative agent of query fever in humans and coxiellosis in livestock. C. burnetii infects a variety of cell types, tissues, and animal species including mammals and arthropods, but there is much left to be understood about the molecular mechanisms at play during infection in distinct species. Human stimulator of interferon genes (STING) induces an innate immune response through the induction of type I interferons (IFNs), and IFN promotes or suppresses C. burnetii replication, depending on tissue type. Drosophila melanogaster contains a functional STING ortholog (Sting) which activates NF-κB signaling and autophagy. Here, we sought to address the role of D. melanogaster Sting during C. burnetii infection to uncover how Sting regulates C. burnetii infection in flies. We show that Sting-null flies exhibit higher mortality and reduced induction of antimicrobial peptides following C. burnetii infection compared to control flies. Additionally , Sting-null flies induce lower levels of oxidative stress genes during infection, but the provision of N-acetyl-cysteine (NAC) in food rescues Sting-null host survival. Lastly, we find that reactive oxygen species levels during C. burnetii infection are higher in Drosophila S2 cells knocked down for Sting compared to control cells. Our results show that at the host level, NAC provides protection against C. burnetii infection in the absence of Sting, thus establishing a role for Sting in protection against oxidative stress during C. burnetii infection., Competing Interests: The authors declare no conflict of interest.

Introduction: Corticotropin-releasing factor receptor 1 (CRFR1) is a key regulator of neuroendocrine and behavioral stress responses. Previous studies have demonstrated that CRFR1 in certain hypothalamic and preoptic brain areas is modified by chronic stress and during the postpartum period in female mice, although the potential hormonal contributors to these changes are unknown., Methods: This study focused on determining the contributions of hormones associated with stress and the maternal period (glucocorticoids, prolactin, estradiol/progesterone) on CRFR1 levels using a CRFR1-GFP reporter mouse line and immunohistochemistry., Results: Administration of dexamethasone, an agonist of the glucocorticoid receptor, elevated CRFR1 in the anteroventral periventricular nucleus (AVPV/PeN) and paraventricular hypothalamus (PVN) with no changes found in the medial preoptic area (MPOA) or arcuate nucleus. Treatment with prolactin for 5 days elevated CRFR1 levels in the MPOA with no changes in other regions. Finally, we utilized the hormone-simulated pseudopregnancy (HSP) paradigm to mimic changes in estradiol and progesterone across pregnancy and the early postpartum period. Female mice receiving HSP treatment, as well as mice receiving HSP treatment that then underwent 5 days of estrogen withdrawal (EW), showed alterations in CRFR1 relative to control groups that mirrored changes previously reported in postpartum mice. Specifically, CRFR1 levels increased in the AVPV/PeN and decreased in the MPOA and PVN, with no changes found in the arcuate nucleus. HSP- and EW-treated mice also showed decreases in tyrosine hydroxylase-expressing neurons in the AVPV/PeN., Discussion/conclusion: Overall, these hormone-induced changes in stress-regulating CRFR1 neurons may impact behavioral and neuroendocrine stress responses., (© 2024 S. Karger AG, Basel.)

The SARS-CoV-2 virus activates maternal and placental immune responses, which in the setting of other infections occurring during pregnancy are known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Here, we assessed the impact of maternal SARS-CoV-2 on HBCs isolated from term placentas using single-cell RNA-sequencing. We demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells, with altered morphology and impaired synaptic pruning behavior compared to HBC models from negative controls. These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

Survival for patients with recurrent central nervous system (CNS) neuroblastoma remains poor. A single-institutional study demonstrated the potential of multimodality therapy, including compartmental intrathecal radioimmunotherapy (cRIT) with 131 I-3F8 or 131 I-8H9 to increase the survival of neuroblastoma patients with CNS relapse. However, not all patients are able to receive this therapy. We report three patients with CNS neuroblastoma who remain disease-free 3-9 years after receiving multimodality treatment without cRIT. Additional studies to identify patients most likely to benefit from cRIT are warranted., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Introduction: Corticotropin-releasing factor and its primary receptor (CRFR1) are critical regulators of behavioral and neuroendocrine stress responses. CRFR1 has also been associated with stress-related behavioral changes in postpartum mice. Our previous studies indicate dynamic changes in CRFR1 levels and coupling of CRFR1 with tyrosine hydroxylase (TH) and oxytocin (OT) neurons in postpartum mice. In this study, we aimed to determine the time course of these changes during the postpartum period., Methods: Using a CRFR1-GFP reporter mouse line, we compared postpartum mice at five time points with nulliparous mice. We performed immunohistochemistry to assess changes in CRFR1 levels and changes in co-expression of TH/CRFR1-GFP and OT/CRFR1-GFP across the postpartum period. Mice were also assessed for behavioral stress responses in the open field test., Results: Relative to nulliparous mice, CRFR1 levels were elevated in the anteroventral periventricular nucleus (AVPV/PeN) but were decreased in the medial preoptic area from postpartum day 1 (P1) through P28. In the paraventricular hypothalamus (PVN), there is a transient decline in CRFR1 mid-postpartum with a nadir at P7. Co-localization of CRFR1 with TH-expressing neurons was also altered with a transient decrease found in the AVPV/PeN at P7 and P14. Co-expression of CRFR1 and OT neurons of the PVN and supraoptic nucleus was dramatically altered with virtually no co-expression found in nulliparous mice, but levels increased shortly after parturition and peaked near P21. A transient decrease in open field center time was found at P7, indicating elevated anxiety-like behavior., Conclusion: This study revealed various changes in CRFR1 across the postpartum period, which may contribute to stress-related behavior changes in postpartum mice., (© 2023 S. Karger AG, Basel.)

Background: Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine-induced immunogenicity across populations, including pregnant and lactating individuals, the rapid waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known., Objective: This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women., Study Design: This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery., Results: Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035)., Conclusion: Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Oxytocin (OT) is essential for successful reproduction, particularly during parturition and lactation. During the postpartum period, OT also influences maternal behavior to promote bonding between mothers and their newborns, and increases stress resilience. However, the mechanism by which stress influences OT neuron activity and OT release has remained unclear. Here, we provide evidence that a subpopulation of OT neurons initiate expression of the receptor for the stress neuropeptide Corticotropin Releasing Factor (CRF), CRFR1, in reproductive females. OT neuron expression of CRFR1 begins at the first parturition and increases during the postpartum period until weaning. The percentage of OT neurons that express CRFR1 increases with successive breeding cycles until it reaches a plateau of 20-25% of OT neurons. OT neuron expression of CRFR1 in reproductive females is maintained after they are no longer actively breeding. CRFR1 expression leads to activation of OT neurons when animals are stressed. We propose a model in which direct CRF signaling to OT neurons selectively in reproductive females potentiates OT release to promote stress resilience in mothers., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer., (© 2022. The Author(s).)

Stress-related mood disorders like anxiety and depression are more prevalent in women than men and are often associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Androgen actions through androgen receptors (ARs) decrease HPA axis responses and stress-associated behaviors. Corticotropin releasing factor (CRF) and its binding to CRF receptor 1 (CRFR1) is also critical for regulation of the HPA axis, anxiety, and depression. We first determined CRFR1/AR co-localization patterns in male and female CRFR1-GFP mice. High co-localization was found within the paraventricular nucleus (PVN), dorsolateral and anteroventral subdivisions of the bed nucleus of the stria terminalis (BSTdl and BSTav), medial preoptic area (MPOA), and posterodorsal medial amygdala (MePD). We next determined whether the non-aromatizable androgen dihydrotestosterone (DHT) regulates CRFR1 expression and stress-induced activation of CRFR1-expressing cells. In the PVN, CRFR1-GFP cell number decreased following gonadectomy (GDX), but DHT treatment reversed this effect. GDX-DHT treated mice also had a decreased CRFR1-GFP cell number within the BSTdl compared to gonad intact and GDX-untreated groups. Following restraint stress GDX-blank mice showed fewer c-Fos/CRFR1 co-localized neurons in the MePD compared to gonad intact and GDX-DHT groups indicating decreased stress-induced activation of CRFR1 neurons following GDX. Higher plasma corticosterone (CORT) was found in GDX males compared to GDX-DHT and sham males following restraint stress, with a negative correlation between PVN CRFR1+ neurons and corticosterone levels 30- and 90-min following restraint. Together these findings show androgens can directly alter CRFR1 levels in the brain which may have implications for sex differences in regulation of the HPA axis and stress-related behaviors., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection., Methods: Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA)., Results: Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .34) exposed to maternal SARS-CoV-2., Conclusions: Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection, which may have implications for offspring vulnerability to placental infection., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Women who do not breastfeed or discontinue breastfeeding early are more likely to develop postpartum depression (PPD) and stress is a significant risk factor for depression, including PPD. Using a rat model, we investigated whether the absence of nursing would increase the susceptibility to chronic stress-related behavioral and neural changes during the postpartum period. Adult female rats underwent thelectomy (thel; removal of teats), sham surgery, or no surgery (control) and were paired with males for breeding. All litters were rotated twice daily until postpartum day (PD) 26. Sham rats served as surrogates for thel litters, yielding a higher nursing demand for sham rats. Concurrently, rats received either no stress or chronic variable stress until PD 25. Rats were observed for maternal behaviors and tested in a series of tasks including open field, sucrose preference, and forced swim. We used immunohistochemistry (IHC) for doublecortin (DCX; to label immature neurons) or for mineralocorticoid receptor (MR). Contrary to our expectations, non-nursing thel rats were resistant to the effects of stress in all dependent measures. Our data indicate that even in chronic adverse conditions, nursing is not required for maintaining stable care to offspring or active coping responses in an acutely stressful task. We discuss the possible role of offspring contact and consider future directions for biomedical and clinical research. In rats with high nursing demand, however, chronic stress increased immobility, hippocampal neurogenesis, and MR expression (largely in opposition to the effects of stress in rats with typical nursing demand). We discuss these patterns in the context of energetics and allostatic load. This research highlights the complexity in relationships between stress, nursing, and neurobehavioral outcomes in the postpartum period and underscores the need for additional biomedical and clinical research geared toward optimizing treatments and interventions for women with PPD, regardless of breastfeeding status. SIGNIFICANCE STATEMENT: The goal of this research was to determine how the absence of nursing and higher nursing demand impact stress-coping behaviors and neural changes associated with chronic stress in order to disentangle the complex interplay of factors that contribute to psychological illness during the postpartum period., (Copyright © 2021. Published by Elsevier Inc.)

Substantial immunological changes occur throughout pregnancy to render the mother immunologically tolerant to the fetus and allow fetal growth. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against pathogens both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contributes to increased susceptibility to particular infections in pregnancy, including more severe coronavirus disease 2019 (COVID-19). Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To define potential changes in vaccine response during pregnancy and lactation, we undertook deep sequencing of the humoral vaccine response in a group of pregnant and lactating women and nonpregnant age-matched controls. Vaccine-specific titers were comparable between pregnant women, lactating women, and nonpregnant controls. However, Fc receptor (FcR) binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared with nonpregnant women after the first vaccine dose, which normalized after the second dose. Vaccine boosting resulted in high FcR-binding titers in breastmilk. These data suggest that pregnancy promotes resistance to generating proinflammatory antibodies and indicates that there is a critical need to follow prime-boost timelines in this vulnerable population to ensure full immunity is attained.

There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

Corticotropin-releasing factor (CRF) signaling through CRF receptor 1 (CRFR1) regulates autonomic, endocrine, and behavioral responses to stress, as well as behavioral changes during the maternal period. Previous work in our lab reported higher levels of CRFR1 in female, compared to male, mice within the rostral anteroventral periventricular nucleus (AVPV/PeN), a brain region involved in maternal behaviors. In this study, we used CRFR1-GFP reporter mice to investigate whether the reproductive status (postpartum vs. nulliparous) of acutely stressed females affects levels of CRFR1 in the AVPV/PeN and other regions involved in maternal functions. Compared to nulliparous, postpartum day 14 females showed increased AVPV/PeN CRFR1-GFP immunoreactivity and an elevated number of restraint stress-activated AVPV/PeN CRFR1 cells as assessed by immunohistochemical co-localization of CRFR1-GFP and phosphorylated CREB (pCREB). The medial preoptic area (MPOA) and paraventricular hypothalamus (PVN) of postpartum mice showed modest decreases in CRFR1-GFP immunoreactivity, while increased CRFR1-GFP/pCREB co-expressing cells were found in the PVN following restraint stress relative to nulliparous mice. Tyrosine hydroxylase (TH) and CRFR1-GFP co-localization was also assessed in the AVPV/PeN and other regions and revealed a decrease in co-localized neurons in the AVPV/PeN and ventral tegmental area of postpartum mice. Corticosterone analysis of restrained mice revealed blunted peak, but elevated recovery, levels in postpartum compared to nulliparous mice. Finally, we investigated projection patterns of AVPV/PeN CRFR1 neurons using female CRFR1-Cre mice and revealed dense efferent projections to several preoptic, hypothalamic, and hindbrain regions known to control stress-associated and maternal functions. Together, these findings contribute to our understanding of the neurobiology that might underlie changes in stress-related functions during the postpartum period., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Host genetics are associated with C. burnetii pathogenesis both in humans and animals; however, it remains unknown if specific genes are associated with severity of infection. We employed the Drosophila Genetics Reference Panel to perform a genome-wide association study to identify host genetic variants that affect host survival to C. burnetii infection. The genome-wide association study identified 64 unique variants (P < 10-5) associated with 25 candidate genes. We examined the role each candidate gene contributes to host survival during C. burnetii infection using flies carrying a null mutation or RNAi knockdown of each candidate. We validated 15 of the 25 candidate genes using at least one method. This is the first report establishing involvement of many of these genes or their homologs with C. burnetii susceptibility in any system. Among the validated genes, FER and tara play roles in the JAK/STAT, JNK, and decapentaplegic/TGF-β signaling pathways which are components of known innate immune responses to C. burnetii infection. CG42673 and DIP-ε play roles in bacterial infection and synaptic signaling but have no previous association with C. burnetii pathogenesis. Furthermore, since the mammalian ortholog of CG13404 (PLGRKT) is an important regulator of macrophage function, CG13404 could play a role in host susceptibility to C. burnetii through hemocyte regulation. These insights provide a foundation for further investigation regarding the genetics of C. burnetii susceptibility across a wide variety of hosts., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

Microglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo. We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.

Background: Pregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking. We sought to evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women., Methods: 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at baseline, 2nd vaccine dose, 2-6 weeks post 2nd vaccine, and delivery by Luminex, and confirmed by ELISA. Titers were compared to pregnant women 4-12 weeks from native infection (N=37). Post-vaccination symptoms were assessed. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups., Results: Vaccine-induced immune responses were equivalent in pregnant and lactating vs non-pregnant women. All titers were higher than those induced by SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. SARS-CoV-2 specific IgG, but not IgA, increased in maternal blood and breastmilk with vaccine boost. No differences were noted in reactogenicity across the groups., Conclusions: COVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placental and breastmilk.

GnRH neurons are central regulators of reproduction and respond to factors affecting fertility, such as stress. Corticotropin-releasing hormone (CRH) is released during stress response. In brain slices from unstressed controls, CRH has opposite, estradiol-dependent effects on GnRH neuron firing depending on the CRH receptor activated; activating CRHR-1 stimulates whereas activating CRHR-2 suppresses activity. We investigated possible direct and indirect mechanisms. Mice were ovariectomized and either not treated further (OVX) or given a capsule producing high positive feedback (OVX + E) or low negative feedback (OVX + low E) physiologic circulating estradiol levels. We tested possible direct effects on GnRH neurons by altering voltage-gated potassium currents. Two types of voltage-gated potassium currents (transient IA and sustained IK) were measured; neither CRHR-1 nor CRHR-2 agonists altered potassium current density in GnRH neurons from OVX + E mice. Further, neither CRH nor receptor-specific agonists altered action potential generation in response to current injection in GnRH neurons from OVX + E mice. To test the possible indirect actions, GABAergic postsynaptic currents were monitored. A CRHR-1 agonist increased GABAergic transmission frequency to GnRH neurons from OVX + E, but not OVX, mice, whereas a CRHR-2 agonist had no effect. Finally, we tested if CRH alters the firing rate of arcuate kisspeptin neurons, which provide an important excitatory neuromodulatory input to GnRH neurons. CRH did not acutely alter firing activity of these neurons from OVX, OVX + E or OVX + low E mice. These results suggest CRH increases GnRH neuron activity in an estradiol-dependent manner in part by activating GABAergic afferents. Mechanisms underlying inhibitory effects of CRH remain unknown., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated how a unique form of early-life adversity (ELA), caused by rotated nursing environment to induce underfeeding, alters anxiety-like and stress-coping behaviors in male and female Sprague Dawley rats in adolescence and adulthood. Adult female rats underwent either thelectomy (thel; surgical removal of teats), sham surgery, or no surgery (control) before mating. Following parturition, litters were rotated between sham and thel rats every 12 h to generate a group of rats that experienced ELA (rotated housing, rotated mother, and 50% food restriction) from postnatal day 0 to 26. Control litters remained with their natal, nursing dams. Regardless of age and sex, ELA reduced activity in the periphery of the open field. ELA increased immobility in the forced swim test, particularly in adults. We used doublecortin immunohistochemistry to identify immature neurons in the hippocampus. ELA increased the number and density of immature neurons in the dentate gyrus of adolescent males (but not females) and reduced the density of immature neurons in adult males (but not females). This research indicates that a unique form of ELA alters stress-related passive coping and hippocampal neurogenesis in an age- and sex-dependent manner., (Copyright © 2020. Published by Elsevier Inc.)

Most animal species operate according to a 24-h period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN modulates hippocampal-dependent memory, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we identify cell-type-specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors. Astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation, and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learning in vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings highlight important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus, and alter the temporal dynamics of cognitive processing., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo . We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.

Estradiol and testosterone are powerful steroid hormones that impact brain function in numerous ways. During development, these hormones can act to program the adult brain in a male or female direction. During adulthood, gonadal steroid hormones can activate or inhibit brain regions to modulate adult functions. Sex differences in behavioral and neuroendocrine (i.e., hypothalamic pituitary adrenal (HPA) axis) responses to stress arise as a result of these organizational and activational actions. The sex differences that are present in the HPA and behavioral responses to stress are particularly important considering their role in maintaining homeostasis. Furthermore, dysregulation of these systems can underlie the sex biases in risk for complex, stress-related diseases that are found in humans. Although many studies have explored the role of estrogen and estrogen receptors in mediating sex differences in stress-related behaviors and HPA function, much less consideration has been given to the role of androgens. While circulating androgens can act by binding and activating androgen receptors, they can also act by metabolism to estrogenic molecules to impact estrogen signaling in the brain and periphery. This review focuses on androgens as an important hormone for modulating the HPA axis and behaviors throughout life and for setting up sex differences in key stress regulatory systems that could impact risk for disease in adulthood. In particular, impacts of androgens on neuropeptide systems known to play key roles in HPA and behavioral responses to stress (corticotropin-releasing factor, vasopressin, and oxytocin) are discussed. A greater knowledge of androgen action in the brain is key to understanding the neurobiology of stress in both sexes.

Anxiety and depression are strikingly more prevalent in women compared with men. Dysregulation of corticotropin-releasing factor (CRF) binding to its cognate receptor (CRFR1) is thought to play a critical role in the etiology of these disorders. In the present study, we investigated whether there were sex differences in the effects of chronic variable stress (CVS) on CRFR1 cells using CRFR1-GFP reporter mice experiencing a 9-day CVS paradigm. Brains were collected from CVS and stress naïve female and male mice following exposure to the open field test. This CVS paradigm effectively increased anxiety-like behavior in female and male mice. In addition, we assessed changes in activation of CRFR1 cells (co-localization with c-Fos and phosphorylated CREB (pCREB)) in stress associated brain structures, including two sexually dimorphic CRFR1 cell groups in the anteroventral periventricular nucleus (AVPV/PeN; F>M) and paraventricular hypothalamus (PVN; M>F). CVS increased CRFR1-GFP cell number as well as the number of CRFR1/pCREB co-expressing cells in the female but not male AVPV/PeN. In the PVN, the number of CRFR1/pCREB co-expressing cells was overall greater in males regardless of treatment and CVS resulted in a male-specific reduction of CRFR1/c-Fos cells. In addition, CVS induced a female-specific reduction in CRFR1/c-Fos cells within the anteroventral bed nucleus of the stria terminalis and both sexes exhibited a reduction in CRFR1/c-Fos co-expressing cells following CVS within the ventral basolateral amygdala. Overall, these sex-specific effects of CVS on CRFR1 populations may have implications for sex differences in stress-induction of mood disorders., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Residents of low income neighborhoods disproportionately experience poor health, and many have unmet social needs. Clinical trials have shown the efficacy of Community Health Worker (CHW) programs in improving outcomes for a variety of health conditions. An important next step is developing and evaluating financially sustainable CHW program models in real-life settings. This program evaluation examines health care utilization among participants in a geographically targeted program led by salaried CHWs from three Medicaid health plans. Beneficiaries who reside in the Cody Rouge neighborhood of Detroit and had more than 3 Emergency Department (ED) visits or at least 1 ambulatory care-sensitive hospitalization in the prior 12 months are eligible for the program. Health plan CHWs assigned to the program reach out to eligible beneficiaries to provide an assessment; link them to resources; and provide follow-up. At 12-month follow up, claims data on ED visits, ambulatory care-sensitive hospitalizations, primary care visits, and related costs will be compared between beneficiaries who participated and eligible beneficiaries randomized to receive usual outreach. We hypothesize that patients enrolled in the CHW intervention will experience a reduction in acute care usage resulting in cost savings compared to those receiving usual health plan outreach. This study is among the first to evaluate the impact on health care utilization of augmented services delivered by health plan CHWs for high-utilizing health plan members as part of a health plan-community-academic partnership. This study will provide important information on CHW program sustainability and provide insights into effective implementation of such programs., Trial Registration: NCT03924713., (© 2019 The Authors. Published by Elsevier Inc.)

Sex differences in neural structures are generally believed to underlie sex differences reported in anxiety, depression, and the hypothalamic-pituitary-adrenal axis, although the specific circuitry involved is largely unclear. Using a corticotropin-releasing factor receptor 1 (CRFR1) reporter mouse line, we report a sexually dimorphic distribution of CRFR1 expressing cells within the paraventricular hypothalamus (PVN; males > females). Relative to adult levels, PVN CRFR1-expressing cells are sparse and not sexually dimorphic at postnatal days 0, 4, or 21. This suggests that PVN cells might recruit CRFR1 during puberty or early adulthood in a sex-specific manner. The adult sex difference in PVN CRFR1 persists in old mice (20-24 months). Adult gonadectomy (6 weeks) resulted in a significant decrease in CRFR1-immunoreactive cells in the male but not female PVN. CRFR1 cells show moderate co-expression with estrogen receptor alpha (ERα) and high co-expression with androgen receptor, indicating potential mechanisms through which circulating gonadal hormones might regulate CRFR1 expression and function. Finally, we demonstrate that a psychological stressor, restraint stress, induces a sexually dimorphic pattern of neural activation in PVN CRFR1 cells (males >females) as assessed by co-localization with the transcription/neural activation marker phosphorylated CREB. Given the known role of CRFR1 in regulating stress-associated behaviors and hormonal responses, this CRFR1 PVN sex difference might contribute to sex differences in these functions., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6-11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed 'phaser cells,' characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell's spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience., Competing Interests: The authors have declared that no competing interests exist.

Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe's genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed., (© 2019 Elsevier Inc. All rights reserved.)

Approximately 15% of women who give birth develop postpartum depression (PPD), and the risk is greater in women who do not breastfeed or who cease breastfeeding early. In some women, early cessation or absence of breastfeeding precedes PPD, but the neuroendocrine mechanisms of this relationship are unknown. We tested whether nursing demand would alter behavioral and endocrine endpoints relevant for depression in postpartum rats. Adult female Sprague-Dawley rats underwent thelectomy (thel; removal of teats), sham surgery (sham), or no surgery (control). Litters were rotated between thel and sham rats every 12 h, yielding a higher nursing burden for sham rats. We investigated behavior in the forced swim test (FST), open field test, and sucrose preference test, and serum corticosterone (CORT) concentrations. Because the hippocampus changes structurally in depression and with maternal experience, we investigated cell proliferation using Ki-67 and hippocampal neurogenesis and immature neuron development using doublecortin (DCX) immunohistochemistry. Sham rats spent less time immobile in the FST compared with control and thel rats. Sham rats also had higher CORT concentrations and fewer Ki-67 cells. Thel rats had more DCX-expressing cells and a greater proportion of mature DCX-expressing cells compared with control and sham rats. These data suggest that greater nursing demand reduces stress-related behavioral responses despite increasing CORT concentrations and suppressing hippocampal neurogenesis. This work is an important step in identifying how lactation buffers behavioral responses to stress and reorganizes stress-related neural circuitry and is crucial for identifying mechanisms of postpartum psychiatric illnesses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The vertebrate protein STING, an intracellular sensor of cyclic dinucleotides, is critical to the innate immune response and the induction of type I interferon during pathogenic infection. Here, we show that a STING ortholog (dmSTING) exists in Drosophila, which, similar to vertebrate STING, associates with cyclic dinucleotides to initiate an innate immune response. Following infection with Listeria monocytogenes, dmSTING activates an innate immune response via activation of the NF-κB transcription factor Relish, part of the immune deficiency (IMD) pathway. DmSTING-mediated activation of the immune response reduces the levels of Listeria-induced lethality and bacterial load in the host. Of significance, dmSTING triggers an innate immune response in the absence of a known functional cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) ortholog in the fly. Together, our results demonstrate that STING is an evolutionarily conserved antimicrobial effector between flies and mammals, and it comprises a key component of host defense against pathogenic infection in Drosophila., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Most of our understanding about the physiology of fasting and starvation comes from studies of vertebrates; however, for ethical reasons, studies that monitor vertebrates through the lethal endpoint are scant. Insects are convenient models to characterize the comparative strategies used to cope with starvation because they have diverse life histories and have evolved under the omnipresent challenge of food limitation. Moreover, we can study the physiology of starvation through its natural endpoint. In this study we raised populations of five species of insects (adult grasshoppers, crickets, cockroaches, and larval beetles and moths) on diets labeled with either 13C-palmitic acid or 13C-leucine to isotopically enrich the lipids or the proteins in their bodies, respectively. The insects were allowed to become postabsorptive and then starved. We periodically measured the δ13C of the exhaled breath to characterize how each species adjusted their reliance on endogenous lipids and proteins as energy sources. We found that starving insects employ a wide range of strategies for regulating lipid and protein oxidation. All of the insects except for the beetle larvae were capable of sharply reducing reliance on protein oxidation; however, this protein sparing strategy was usually unsustainable during the entire starvation period. All insects increased their reliance on lipid oxidation, but while some species (grasshoppers, cockroaches, and beetle larvae) were still relying extensively on lipids at the time of death, other species (crickets and moth larvae) allowed rates of lipid oxidation to return to prestarvation levels. Although lipids and proteins are critical metabolic fuels for both vertebrates and insects, insects apparently exhibit a much wider range of strategies for rationing these limited resources during starvation.

Pythons digesting rodent meals exhibit up to 10-fold increases in their resting metabolic rate (RMR); this increase in RMR is termed specific dynamic action (SDA). Studies have shown that SDA is partially fueled by oxidizing dietary nutrients, yet it remains unclear whether the proteins and the lipids in their meals contribute equally to this energy demand. We raised two populations of mice on diets labeled with either [(13)C]leucine or [(13)C]palmitic acid to intrinsically enrich the proteins and lipids in their bodies, respectively. Ball pythons (Python regius) were fed whole mice (and pureed mice 3 weeks later), after which we measured their metabolic rates and the δ(13)C in the breath. The δ(13)C values in the whole bodies of the protein- and lipid-labeled mice were generally similar (i.e. 5.7±4.7‰ and 2.8±5.4‰, respectively) but the oxidative kinetics of these two macronutrient pools were quite different. We found that the snakes oxidized 5% of the protein and only 0.24% of the lipids in their meals within 14 days. Oxidation of the dietary proteins peaked 24 h after ingestion, at which point these proteins provided ∼90% of the metabolic requirement of the snakes, and by 14 days the oxidation of these proteins decreased to nearly zero. The oxidation of the dietary lipids peaked 1 day later, at which point these lipids supplied ∼25% of the energy demand. Fourteen days after ingestion, these lipids were still being oxidized and continued to account for ∼25% of the metabolic rate. Pureeing the mice reduced the cost of gastric digestion and decreased SDA by 24%. Pureeing also reduced the oxidation of dietary proteins by 43%, but it had no effect on the rates of dietary lipid oxidation. Collectively, these results demonstrate that pythons are able to effectively partition the two primary metabolic fuels in their meals. This approach of uniquely labeling the different components of the diet will allow researchers to examine new questions about how and when animals use the nutrients in their meals., (© 2015. Published by The Company of Biologists Ltd.)

Background: Previous global studies examined etanercept (ETN) + methotrexate (MTX) for treatment of rheumatoid arthritis (RA), but included few subjects from Latin America., Objective: The objective of this study was to compare the safety and efficacy of ETN + MTX versus a standard-of-care disease-modifying antirheumatic drug (DMARD) + MTX in Latin American subjects with moderate to severe active RA despite MTX therapy., Methods: This open-label, active-comparator study (NCT00848354) randomized subjects 2:1 to ETN 50 mg/wk + MTX or investigator-selected DMARD (sulfasalazine or hydroxychloroquine) + MTX (ETN + MTX, n = 281; DMARD + MTX, n = 142). The primary end point was the proportion achieving American College of Rheumatology (ACR) 50 at week 24. Secondary end points included ACR20/70, disease activity score (DAS) 28 measures, and mean change in modified total Sharp score. Patient-reported outcomes were the Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA), and Caregiver Burden and Resource Utilization. Statistical analyses were stratified by country; χ test and analysis of covariance were used. Adverse events were monitored., Results: More subjects achieved ACR50 at week 24 with ETN + MTX versus DMARD + MTX (62% vs 23%, respectively), in addition to secondary end points (P < 0.0001 for all); mean change in modified total Sharp score was lower for the ETN + MTX group (0.4 vs 1.4, respectively; P = 0.0270). Improvements in patient-reported outcomes favored ETN + MTX for Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale for depression, WPAI:RA, and Caregiver Burden and Resource Utilization emergency department visits for RA (P < 0.01). Overall, adverse events were similar between the groups (69% vs 68%,); serious adverse events were also similar (4% vs 1%). The rate of overall infections was higher with ETN + MTX (38%) than DMARD + MTX (22%, P ≤ 0.001)., Conclusions: Consistent with published global data among RA patients with inadequate response to MTX, adding ETN to MTX demonstrated better efficacy than adding one other conventional DMARD to MTX. No new safety issues were observed. ETN + MTX provided favorable benefit-risk profile among RA patients from LA region.

Intergenerational photovoice groups are promising for promoting health through the topic that is explored and through group dynamics that can foster healthy relationships and communication. To investigate the potential benefits of intergenerational photovoice projects, photovoice groups were conducted in urban Minnesota, United States, and in rural Morelos, Mexico, between 2009 and 2012 with Mexican-origin adults and their adolescent relatives. Seven photovoice groups of adult-adolescent dyads met for eight sessions and developed exhibits highlighting their views on health and migration and made policy recommendations, using messages conveyed through their words and photographs. Informal process evaluation and focus groups were used to elicit feedback about photovoice project participation. Photovoice project themes were descriptively analyzed. Focus group evaluation data were thematically summarized, and facilitator reflections were descriptively summarized to identify factors associated with intergenerational photovoice groups. Seventy-five participants were recruited. Photovoice themes represented effects of migration on health, family, and well-being. The following two evaluative themes were identified: (a) participant sentiments about the benefits of photovoice participation and (b) facilitator observations of intergenerational photovoice group benefits and challenges. Participants described opportunities to learn new things and barriers to healthy relationships that the project was eliminating by providing them with time to work together. Used in health promotion, photovoice is a valuable tool that contributes to understanding the complex underlying factors influencing behaviors and health.