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Preeclampsia is associated with an increased lifelong risk of cardiovascular disease (CVD). It is not clear whether this is induced by persistent systemic organ and vascular damage following preeclampsia or due to a predisposition to both conditions that share cardiovascular pathophysiology. Common to both CVD and preeclampsia is the dysregulation of corin and its proteolytic product, atrial natriuretic peptide (ANP). ANP, a hypotensive hormone converted from pro-ANP by corin, is involved in blood pressure homeostasis. While corin is predominantly a cardiac enzyme, both corin and pro-ANP are significantly upregulated in the gravid uterus and dysregulated in preeclampsia. Relatively little is known about ANP function in the endothelium during a pregnancy complicated by preeclampsia. Here, we investigated the effect of ANP on endothelial cell proliferation and migration, markers of endothelial dysfunction, and receptor expression in omental arteries exposed to circulating preeclamptic toxins. ANP receptor expression is significantly upregulated in preeclamptic vasculature but not because of exposure to preeclampsia toxins tumour necrosis factor α or soluble fms-like tyrosine kinase-1. The supplementation of endothelial cells with ANP did not promote proliferation or migration, nor did ANP improve markers of endothelial dysfunction. The role of ANP in preeclampsia is unlikely to be via endothelial pathways. [ABSTRACT FROM AUTHOR]

Background: Individuals with hypertensive disorders of pregnancy (HDP) have an elevated lifetime risk of chronic hypertension, metabolic syndrome, and premature cardiovascular disease. Because breastfeeding duration and exclusivity have been associated in observational studies with improved cardiovascular health, optimizing breastfeeding in those with HDP might be an unrealized cardio-prevention approach, in particular because individuals with HDP have more breastfeeding challenges. Breastfeeding supportive interventions targeting one's breastfeeding self-efficacy have been shown to improve breastfeeding rates. Methods: We designed an open-label, multi-center 1:1 randomized behavioral trial to test whether a previously validated self-efficacy enhancing breastfeeding intervention can improve breastfeeding duration and/or exclusivity, and lower postpartum blood pressure at 12 months. Randomization is computer-generated and stratified by site (four hospitals in Montreal, Quebec and one hospital in Kingston, Ontario; all in Canada). Included are breastfeeding participants with HDP (chronic/gestational hypertension or preeclampsia) who delivered a live singleton infant at > 34 weeks, speak English or French, and have no contraindications to breastfeeding. Informed and written consent is obtained at hospitalization for delivery or a re-admission with hypertension within 1 week of discharge. Participants assigned to the intervention group receive a breastfeeding self-efficacy-based intervention delivered by a trained lactation consultant in hospital, with continued reactive/proactive support by phone or text message for up to 6 months postpartum. Regardless of group assignment, participants are followed for self-reported outcomes, automated office blood pressure, and home blood pressure at several time points with end of follow-up at 12 months. Discussion: This study will assess whether an intensive nurse-led behavioral intervention can improve breastfeeding rates and, in turn, postpartum blood pressure – an early marker for atherosclerotic cardiovascular disease. If effective, this form of enhanced breastfeeding support, along with closer BP and metabolic surveillance, can be implemented broadly in individuals lactating after HDP. Trial registration: ClinicalTrials.gov, # NCT04580927, registered on Oct 9, 2020. [ABSTRACT FROM AUTHOR]

Placental dysfunction is the leading cause of both preeclampsia and fetal growth restriction. This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [<10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (<34 weeks gestation) compared to gestation‐matched controls (p <.0001). In the plasma, EPCR was also significantly elevated (p =.01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (p =.0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (p <.0001) relative to controls. At 36 weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (p =.008), but Tumor Necrosis Factor Alpha (TNF‐α) decreased EPCR mRNA. Interleukin‐6 (IL‐6) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O2) or normoxia (8% O2), EPCR mRNA expression was significantly reduced (p =.008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth‐restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR. [ABSTRACT FROM AUTHOR]

Introduction: Hypertensive disorders of pregnancy occur in approximately 7%–10% of pregnancies and are associated with adverse maternal cardiovascular health outcomes across the lifespan. In contrast, breastfeeding has been associated with a reduction in cardiovascular risk factors in a dose‐dependent manner. Despite the potential protective effects of lactation on cardiovascular risk, how hypertensive disorders of pregnancy relate to breastfeeding practices and experiences is not well understood. The aim of this study was to investigate the association between hypertensive disorders of pregnancy and breastfeeding outcomes in the first year postpartum. Material and methods: We conducted a secondary analysis of prospective data from the All Our Families Cohort, a population‐based study conducted in Calgary, Alberta, Canada. Women with a singleton pregnancy (n = 1418) who completed self‐report questionnaires at <25 weeks and 34–36 weeks of gestation, and 4 months and 12 months postpartum, and provided consent to link to electronic medical records that identified diagnoses of hypertensive disorders of pregnancy (n = 122). Logistic and multiple linear regression analyses were used to model associations between hypertensive disorders of pregnancy and breastfeeding outcomes. Outcomes included breastfeeding intention, intended duration, exclusive breastfeeding at 4 months, breastfeeding duration at 12 months and breastfeeding difficulties. Results: Hypertensive disorders of pregnancy were not associated with breastfeeding intention (odds ration [OR] 1.30, 95% confidence interval [CI] 0.47–3.03, P = 0.57), intended breastfeeding duration (b = −3.28, 95% CI −7.04 to 0.48, P = 0.09), or initiation (OR = 0.64, 95% CI 0.29– 1.65, P = 0.32), but were associated with an increase in the odds of non‐exclusive breastfeeding at 4 months postpartum (OR = 2.11, 95% CI 1.39–3.22, P < 0.001). Women with hypertensive disorders breastfed for 6.26 (95% CI −10.00 to −2.51, P < 0.001) weeks less over 12 months postpartum, had significantly higher odds of reporting insufficient milk supply (OR = 1.75, 95% CI 1.19–2.46, P < 0.05) and had lower odds of breast and/or nipple pain (OR = 0.66, 95% CI 0.44–0.92, P < 0.05) compared with those without hypertensive disorders of pregnancy. Conclusions: Hypertensive disorders of pregnancy are associated with altered breastfeeding practices and experiences during the first year postpartum. Further research is needed to examine biopsychosocial mechanisms through which hypertensive disorders associate with shorter breastfeeding duration, and to examine whether greater breastfeeding duration, intensity or exclusivity reduces short‐ or long‐term maternal cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: Subfertility and infertility treatment can be stressful experiences, but it is unknown whether each predisposes to postpartum mental illness. We sought to evaluate associations between subfertility or infertility treatment and postpartum mental illness. Methods: We conducted a population-based cohort study of individuals without pre-existing mental illness who gave birth in Ontario, Canada, from 2006 to 2014, stratified by fertility exposure: subfertility without infertility treatment; noninvasive infertility treatment (intrauterine insemination); invasive infertility treatment (in vitro fertilization); and no reproductive assistance. The primary outcome was mental illness occurring 365 days or sooner after birth (defined as ≥ 2 outpatient visits, an emergency department visit or a hospital admission with a mood, anxiety, psychotic, or substance use disorder, self-harm event or other mental illness). We used multivariable Poisson regression with robust error variance to assess associations between fertility exposure and postpartum mental illness. Results: The study cohort comprised 786 064 births (mean age 30.42 yr, standard deviation 5.30 yr), including 78 283 with subfertility without treatment, 9178 with noninvasive infertility treatment, 9633 with invasive infertility treatment and 688 970 without reproductive assistance. Postpartum mental illness occurred in 60.8 per 1000 births among individuals without reproductive assistance. Relative to individuals without reproductive assistance, those with subfertility had a higher adjusted relative risk of postpartum mental illness (1.14, 95% confidence interval 1.10–1.17), which was similar in noninvasive and invasive infertility treatment groups. Interpretation: Subfertility or infertility treatment conferred a slightly higher risk of postpartum mental illness compared with no reproductive assistance. Further research should elucidate whether the stress of infertility, its treatment or physician selection contributes to this association. [ABSTRACT FROM AUTHOR]

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses. [ABSTRACT FROM AUTHOR]

Background: Evidence on whether anxiety or mood disorders increases the risk of hypertensive disorders of pregnancy (HDP) has been conflicting. We aimed to evaluate the prevalence of maternal mental disorders over time and their associations with HDP.Methods: This was a population-based retrospective study involving 9,097,355 pregnant women using Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS) data from 2004 through 2014. We calculated the prevalence of maternal anxiety, depression, bipolar disorder and mood disorder and trends of gestational hypertension, preeclampsia and eclampsia during the study period. Multivariate logistic regression was used to examine the association between each mental disorder and HDP.Results: Mental disorders showed increasing trends among pregnant women, with anxiety showing the greatest increase in rates. Unadjusted associations suggest all mental disorders increase the likelihood of HDP. When adjusted for sociodemographic characteristics and comorbidities, only anxiety showed consistently increased risk of gestational hypertension (adjusted odds ratio (aOR) 1.324, 95% CI 1.255-1.397), preeclampsia (aOR 1.522, 95% CI 1.444-1.604), with the strongest association with eclampsia (aOR 1.813, 95% CI 1.260-2.610).Limitations: Information on medication use is not available in the HCUP-NIS database and might have been contributory to our findings.Conclusions: Rates of maternal psychopathology are rising in the United States. Our study suggests that pregnant women with anxiety are at increased risk of HDP. Targeted screening for mental disorders as possible clinical risk markers may allow for timely prophylaxis and surveillance for the development of HDP. [ABSTRACT FROM AUTHOR]

Highlights • Prefrontal-amygdalar covariance varies as a function of DHEA-cortisol ratio. • DHEA decreases prefrontal-amygdalar covariance, cortisol increases this covariance. • DHEA-cortisol ratio impacts working memory through prefrontal-amygdalar covariance. • Higher DHEA improves working memory, higher cortisol worsens working memory. • DHEA and cortisol may play antagonistic roles during brain development in humans. Abstract There is accumulating evidence that both dehydroepiandrosterone (DHEA) and cortisol play an important role in regulating physical maturation and brain development. High DHEA levels tend to be associated with neuroprotective and indirect anabolic effects, while high cortisol levels tend to be associated with catabolic and neurotoxic properties. Previous literature has linked the ratio between DHEA and cortisol levels (DC ratio) to disorders of attention, emotional regulation and conduct, but little is known as to the relationship between this ratio and brain development. Due to the extensive links between the amygdala and the cortex as well as the known amygdalar involvement in emotional regulation, we examined associations between DC ratio, structural covariance of the amygdala with whole-brain cortical thickness, and validated report-based measures of attention, working memory, internalizing and externalizing symptoms, in a longitudinal sample of typically developing children and adolescents 6–22 years of age. We found that DC ratio predicted covariance between amygdalar volume and the medial anterior cingulate cortex, particularly in the right hemisphere. DC ratio had a significant indirect effect on working memory through its impact on prefrontal-amygdalar covariance, with higher DC ratios associated with a prefrontal-amygdalar covariance pattern predictive of higher scores on a measure of working memory. Taken together, these findings support the notion, as suggested by animal and in vitro studies, that there are opposing effects of DHEA and cortisol on brain development in humans, and that these effects may especially target prefrontal-amygdalar development and working memory, in a lateralized fashion. [ABSTRACT FROM AUTHOR]

Objective: We aim to clarify whether type and timing of mental health symptoms in early pregnancy distinctly contribute to maternal-fetal vascular function, independent from the psychotropic medications given to treat these conditions.Methods: Data from a prospective cohort study (n = 1678) were used to test whether self-reported fears about giving birth and depressive symptoms prior to 16 weeks of gestation were associated with vascular outcomes predictive of hypertensive disorders of pregnancy (HDP) i.e., systolic and diastolic blood pressure (BP); uterine artery pulsatility index (UAPI); umbilical artery resistance index (UmbARI); and urine protein creatinine ratio. Multiple linear regressions models and mediation models were used to test for associations between predictors and outcomes, controlling for previously identified risk factors for vascular dysfunction such as maternal age and history of infertility.Results: Fears about giving birth in early pregnancy were inversely associated with UmbARI (β = -0.33, p = 0.03, df = 51) mid- to late-pregnancy (≥20 weeks). Depressive symptoms in early pregnancy were also inversely associated with maternal systolic BP (β = -0.13, p = 0.01, df = 387) and diastolic BP (β = -0.10, p = 0.04, df = 387) during the first trimester.Conclusions: While fears about giving birth in early pregnancy were associated with lower vascular resistance in the fetal-placental unit, early depressive symptoms were associated with lower maternal vascular tone. At the very least, our results support the notion that early maternal psychological distress is unlikely to account for the development of HDP later during pregnancy and provide preliminary evidence to support distinct roles of pregnancy-related anxiety and depressive symptoms in maternal-fetal vascular function. [ABSTRACT FROM AUTHOR]

The article presents a case study examination into the cortical thickness correlates of symptoms of inattention in healthy children in order to highlight the relationship between cortical maturation and the damages of attention-deficit/hyperactivity disorder in children. A cross-sectional analysis of children's attentive behaviors and cortical thickness is presented. Conclusions are offered highlighting associations between attention problem symptoms and cortical thinness.

• Reviews the relevance of puberty and gonadal sex steroids in human neurodevelopment. • Details the protocol and rationale of our ongoing longitudinal study. • Presents selection criteria for documenting the prepubertal state at study entry. • Describes the utility of our longitudinal endocrine and neuroimaging measures. • Documents patterns of fMRI activation and connectivity from a preliminary cohort. Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children. [ABSTRACT FROM AUTHOR]

De novo lipogenesis (DNL) has been implicated in the development and progression of liver steatosis. Hepatic DNL is strongly influenced by dietary macronutrient composition with diets high in carbohydrate increasing DNL and while diets high in fat decrease DNL. The enzymes in the core DNL pathway have been well characterised, however less is known about other liver proteins that play accessory or regulatory roles. In the current study, we associate measured rates of hepatic DNL and fat content with liver proteomic analysis in mice to identify known and unknown proteins that may have a role in DNL. Male mice were fed either a standard chow diet, a semi-purified high starch or high fat diet. Both semi-purified diets resulted in increased body weight, fat mass and liver triglyceride content compared to chow controls and hepatic DNL was increased in the high starch and decreased in high fat fed mice. Proteomic analysis identified novel proteins associated with DNL that are involved in taurine metabolism, suggesting a link between these pathways. There was no relationship between proteins that associated with DNL and those associated with liver triglyceride content. Further analysis identified proteins that are differentially regulated when comparing a non-purified chow diet to either of the semi-purified diets which provide a set of proteins that are influenced by dietary complexity. Finally, we compared the liver proteome between 4- and 30-week diet-fed mice and found remarkable similarity suggesting metabolic remodelling of the liver occurs rapidly in response to differing dietary components., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Universal screening for depression and anxiety in pregnancy has been recommended by several leading medical organizations, but the implementation of such screening protocols may overburden health care systems lacking relevant resources. Text message screening may provide a low-cost, accessible alternative to in-person screening assessments. However, it is critical to understand who is likely to participate in text message-based screening protocols before such approaches can be implemented at the population level., Objective: This study aimed to examine sources of selection bias in a texting-based screening protocol that assessed symptoms of depression and anxiety across pregnancy and into the postpartum period., Methods: Participants from the Montreal Antenatal Well-Being Study (n=1130) provided detailed sociodemographic information and completed questionnaires assessing symptoms of depression (Edinburgh Postnatal Depression Scale [EPDS]) and anxiety (State component of the State-Trait Anxiety Inventory [STAI-S]) at baseline between 8 and 20 weeks of gestation (mean 14.5, SD 3.8 weeks of gestation). Brief screening questionnaires, more suitable for delivery via text message, assessing depression (Whooley Questions) and anxiety symptoms (Generalized Anxiety Disorder 2-Item questionnaire) were also collected at baseline and then via text message at 14-day intervals. Two-tailed t tests and Fisher tests were used to identify maternal characteristics that differed between participants who responded to the text message screening questions and those who did not. Hurdle regression models were used to test if individuals with a greater burden of depression and anxiety at baseline responded to fewer text messages across the study period., Results: Participants who responded to the text messages (n=933) were more likely than nonrespondents (n=114) to self-identify as White (587/907, 64.7% vs 39/96, 40.6%; P<.001), report higher educational attainment (postgraduate: 268/909, 29.5% vs 15/94, 16%; P=.005), and report higher income levels (CAD $150,000 [a currency exchange rate of CAD $1=US $0.76 is applicable] or more: 176/832, 21.2% vs 10/84, 11.9%; P<.001). There were no significant differences in symptoms of depression and anxiety between the 2 groups at baseline or postpartum. However, baseline depression (EPDS) or anxiety (STAI-S) symptoms did predict the total number of text message time points answered by participants, corresponding to a decrease of 1% (e β =0.99; P<.001) and 0.3% (e β =0.997; P<.001) in the number of text message time points answered per point increase in EPDS or STAI-S score, respectively., Conclusions: Findings from this study highlight the feasibility of text message-based screening protocols with high participation rates. However, our findings also highlight how screening and service delivery via digital technology could exacerbate disparities in mental health between certain patient groups., (©Julia Barnwell, Cindy Hénault Robert, Tuong-Vi Nguyen, Kelsey P Davis, Chloé Gratton, Guillaume Elgbeili, Hung Pham, Michael J Meaney, Tina C Montreuil, Kieran J O'Donnell. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 03.10.2024.)

Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is an inhibitory receptor expressed on immune cells. We evaluated LAIR1 in placentas from preeclamptic or small for gestational age (SGA) pregnancies, and placental explant model (1 % O 2 , IL6 and TNFα, or control). LAIR1 mRNA was reduced in placentas from preeclamptic (p < 0.0001, n = 78) and SGA (p < 0.0001, n = 32) pregnancies. LAIR1 protein expression was reduced in placentas from preeclampsia (p < 0.0001, n = 43) and SGA (p = 0.009, n = 10) pregnancies. Hypoxia (1 % O 2 ) reduced LAIR1 mRNA expression in placental explants (p = 0.008). These findings suggest hypoxia modulates LAIR1 expression in the placenta., Competing Interests: Declaration of competing Interest None., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Introduction: This study examined (1) whether measures of paternal anxious and depressive symptoms collected prenatally and during a follow-up assessment when the child was in middle childhood, predict child neuroendocrine outcomes, and (2) whether neuroendocrine outcomes are intermediate factors between paternal mental health and child cognitive/behavioral outcomes. Middle childhood coincides with increased autonomy as the child transitions into grade school, and with adrenarche, as the maturing adrenal gland increases secretion of dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S), hormones that are implicated in corticolimbic development which regulate emotions and cognition., Methods: Participants were recruited from a subsample of a large prospective birth cohort study (3D study). We conducted a follow-up study when children were 6-8 years old ( N  = 61 families, 36 boys, 25 girls). Parental symptoms of anxiety, stress and depression were assessed via validated self-report questionnaires: prenatally using an in-house anxiety questionnaire, the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D), and at the follow up, using the Beck Anxiety and Beck Depression Inventories. Children provided salivary hormone samples, and their pituitary gland volume was measured from structural Magnetic Resonance Imaging (MRI) scans. Child behaviors were measured using the Strengths and Difficulties Questionnaire and cognitive outcomes using the WISC-V. Multiple regression analyses were used to test whether paternal mental health symptoms assessed prenatally and during childhood are associated with child neuroendocrine outcomes, adjusting for maternal mental health and child sex. Indirect-effect models assessed whether neuroendocrine factors are important intermediates that link paternal mental health and cognitive/behavioral outcomes., Results: (1) Fathers' prenatal anxiety symptoms predicted lower DHEA levels in the children, but not pituitary volume. (2) Higher prenatal paternal anxiety symptoms predicted higher child internalizing symptoms via an indirect pathway of lower child DHEA. No associations were detected between paternal anxiety symptoms measured in childhood, and neuroendocrine outcomes. No child sex differences were detected on any measure., Conclusion: These results highlight the often-overlooked role of paternal factors during pregnancy on child development, suggesting that paternal prenatal anxiety symptoms are associated with child neuroendocrine function and in turn internalizing symptoms that manifest at least up to middle childhood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jones, De Braga, Caccese, Lew, Elgbeili, Castellanos-Ryan, Parent, Muckle, Herba, Fraser, Ducharme, Barnwell, Trasler, Séguin, Nguyen and Montreuil.)

Introduction: Paternal mental health has been associated with adverse consequences on offspring psychosocial development, and family environmental factors may partly explain those associations. To clarify this, we need comprehensive prospective studies, particularly in middle-childhood when the child enters school and is expected to make use of behavioral and cognitive skills as part of their interactions and learning., Method: Using data from a sub-sample of the prospective 3D birth cohort study comprised of mother-father-child triads, and a follow-up of the parents and the children at 6-8 years of age ( n = 61; 36 boys, 25 girls), we examined whether paternal anxious and depressive symptoms measured during the pregnancy period (i.e., prenatally) or concurrently when the child was assessed at 6-8 years old were associated with children's cognition/behavior., Results: In contrast to our hypotheses, we found that greater prenatal paternal depressive symptoms predicted fewer child behavioral difficulties; and that greater concurrent childhood paternal depression or anxiety symptoms were associated with higher child full-scale IQ, controlling for the equivalent maternal mental health assessment and parental education. Father parenting perception did not mediate these associations, nor were they moderated by maternal mental health at the concurrent assessment, or paternal ratings of marital relationship quality., Discussion: These findings suggest that higher symptoms of paternal mental health symptoms are associated with fewer child behavioral difficulties and higher cognitive performance in middle childhood. Potential clinical implications and future research directions are discussed., Competing Interests: The authors declare that this work was funded by Merck, Sharp & Dohme corp. (T-VN), Canadian Institutes of Health Research (T-VN, MY5-155371), Montreal General Hospital Foundation, McGill University Health Center Foundation (T-VN), and Fonds de Recherche Québec Santé (T-VN, 36776). The 3D and 3D-Transition Studies were both supported by the Canadian Institutes of Health Research (CRI 88413 and PJT-148551, respectively). The authors also declare that they received salary support through the Graduate Excellence Fellowship in Mental Health Research, awarded by the Department of Psychiatry at McGill University (CC), and a Ferring Postdoctoral Fellowship in Reproductive Health awarded by McGill Faculty of Medicine (SLJ). JRS was supported by the Fonds Monique Gaumond pour la Recherche en Maladies Affectives. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jones, Caccese, Davis, Lew, Elgbeili, Herba, Barnwell, Robert, Gavanski, Horsley, Fraser, Da Costa, Séguin, Nguyen and Montreuil.)

Importance: Depressive symptoms during pregnancy influence the development and health of the offspring, underscoring the need for timely intervention. However, the course of depressive symptoms across the perinatal period remains unclear, thus complicating screening and referral guidelines., Objective: To examine the course and stability of depressive symptoms across the perinatal period in multiple, ethnically diverse independent observational cohorts., Design, Setting, and Participants: This cohort study included self-reported depressive symptoms at multiple time points from 7 prospective cohorts spanning 3 continents (United Kingdom: Avon Longitudinal Study of Parents and Children from 1991 to 1995; Canada: Maternal Adversity, Vulnerability and Neurodevelopment from 2003 to 2007; Montreal Antenatal Well-being Study from 2019 to 2022; Alberta Pregnancy Outcomes and Nutrition from 2009 to 2014; and Singapore: Growing Up in Singapore Toward Healthy Outcomes from 2009 to 2013; Singapore Preconception Study of Long-Term Maternal and Child Outcomes from 2015 to 2019; and Mapping Antenatal Maternal Stress from 2019 to 2022). Participants were recruited either during preconception or pregnancy and observed into the postnatal period. All data from each cohort were analyzed from July 2022 to April 2023., Main Outcomes and Measures: Self-reported depressive symptoms from pregnancy to 2 years following childbirth using either the Edinburgh Postnatal Depression Scale or the Center for Epidemiological Studies Depression were analyzed independently within each cohort using item response theory (IRT) techniques. K-means clustering was used to identify groups of participants with similar trajectories., Results: A total of 11 563 pregnant women (mean [SD] age, 29 [5] years; 569 [4.9%] East Asian women; 304 [2.6%] Southeast Asian women; 10 133 [87.6%] White women) self-reported depressive symptoms from pregnancy to 2 years following childbirth. Analytic methods from Item Response Theory identified 3 groups of mothers based on depressive symptoms: low, mild, and high levels in each of the 7 cohorts. Mothers within and across all cohorts had stable trajectories of maternal depressive symptoms from pregnancy onwards. Mothers with clinical levels of depressive symptoms likewise showed stable trajectories from pregnancy into the postnatal period., Conclusions and Relevance: In this study, trajectories of depressive symptoms remained stable from pregnancy across the perinatal period, a finding that conflicts with a continuing emphasis on postpartum or postnatal onset of depression that persists in some health policy guidelines. Interventions and public health initiatives should focus on reducing depressive symptoms during pregnancy in addition to following birth.

Background: Mucins are a family of proteins that protect the epithelium. A particular type of mucin, MUC15 is highly expressed in the placenta. This study aimed to characterise MUC15 in preeclampsia and investigate its role in placental stem cell biology., Methods: MUC15 mRNA and protein were measured in placentas from patients with early onset (<34 weeks' gestation) preeclampsia. Circulating serum MUC15 was measured via ELISA. MUC15 was localised in the placenta using in situ hybridisation. MUC15 mRNA expression was measured across differentiation of human trophoblast stem cells (hTSCs) to syncytiotrophoblast and extravillous trophoblasts. MUC15 was measured after syncytialised hTSCs were cultured in hypoxic (1% O 2 ) and proinflammatory (TNF α, IL-6) conditions. MUC15 secretion was assessed when syncytialised hTSCs were treated with brefeldin A (impairs protein trafficking) and batimastat (inhibits matrix metalloproteinases)., Results: MUC15 protein was significantly increased in the placenta (P = 0.0003, n = 32 vs n = 20 controls) and serum (P = 0.016, n = 32 vs n = 22 controls) of patients with preeclampsia, whilst MUC15 mRNA remained unchanged (n = 61 vs n = 18 controls). MUC15 mRNA (P = 0.005) and protein secretion (P = 0.006) increased following differentiation to syncytiotrophoblast cells. In situ hybridisation confirmed MUC15 localised to the syncytiotrophoblast cell within the placenta. Neither hypoxic or inflammatory conditions changed MUC15 mRNA expression or secretion. Brefeldin A treated hTSCs did not alter MUC15 secretion, whilst batimastat reduced MUC15 secretion (P = 0.044)., Conclusions: MUC15 is increased in early onset preeclampsia and is cleaved by matrix metalloproteinases. Increased MUC15 may reflect a protective mechanism associated with placental dysfunction. Further research will aid in confirming this., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare for this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors., Methods: 10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m 2 plus nab paclitaxel 220 mg/m 2 every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response., Results: With cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue., Conclusions: Priming patients' chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses., Trial Registration: This clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853., (© 2023. The Author(s).)

Background: Preeclampsia is a severe complication of pregnancy. Chemerin is an adipokine secreted from adipose tissue and highly expressed in placenta. This study evaluated the biomarker potential of circulating chemerin to predict preeclampsia., Methods: Maternal plasma and placenta were collected from women with early-onset preeclampsia (<34 weeks), with preeclampsia and eclampsia, or before preeclampsia diagnosis (36 weeks). Human trophoblast stem cells were differentiated into syncytiotrophoblast or extravillous trophoblasts across 96 hours. Cells were cultured in 1% O2 (hypoxia) or 5% O2 (normoxia). Chemerin was measured by enzyme-linked immunosorbent assay (ELISA) and RARRES2 (gene coding chemerin) by reverse transcription-quantitative polymerase chain reaction., Results: Circulating chemerin was increased in 46 women with early-onset preeclampsia (<34 weeks) compared to 17 controls (P < .0006). Chemerin was increased in placenta from 43 women with early-onset preeclampsia compared to 24 controls (P < .0001). RARRES2 was reduced in placenta from 43 women with early-onset preeclampsia vs 24 controls (P < .0001). Chemerin was increased in plasma from 26 women with established preeclampsia (P = .006), vs 15 controls. Circulating chemerin was increased in 23 women who later developed preeclampsia vs 182 who did not (P = 3.23 × 10-6). RARRES2 was reduced in syncytiotrophoblast (P = .005) or extravillous trophoblasts (P < .0001). Hypoxia increased RARRES2 expression in syncytiotrophoblast (P = .01) but not cytotrophoblast cells., Conclusions: Circulating chemerin was elevated in women with early-onset preeclampsia, established preeclampsia, and preceding preeclampsia diagnosis of preeclampsia. RARRES2 was dysregulated in placenta complicated by preeclampsia and may be regulated through hypoxia. Chemerin may have potential as a biomarker for preeclampsia but would need to be combined with other biomarkers., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor of soft tissue. It typically presents as a low-grade sarcoma with myxoid stroma, has a predilection for distal extremities, and displays a high propensity for local recurrence, but low metastatic potential. The risk factors associated with high-risk lesions metastasizing are poorly defined. In cases where the tumor metastasizes, therapeutic options are few, and death is rare. Our case discusses an aggressive MIFS that progressed from a painless lesion on a patient's calf, to her death from a malignant pleural effusion within 21 months. The 58-year-old woman presented with a mass on her left calf. It was excised and was originally thought to be a benign process. It re-grew quickly after the initial resection, and she underwent re-excision of the mass. The pathologic examination was consistent with an MIFS. Despite negative margins on her second resection and an attempt at local control with radiotherapy, it metastasized to her lungs within less than 2 years. This resulted in a malignant pleural effusion that caused her death. An MIFS is typically benign but can metastasize in atypical cases. Even if the disease is metastatic, it is unlikely to be the cause of death. Treatment of metastatic MIFS is poorly defined, but there are suggested therapies beyond surgical resection and radiotherapy. Successful treatment of an MIFS should include a high index of suspicion in extremity lesions, screening for metastasis, and possible targeted therapies based on tumor genomics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Obesity is generally associated with insulin resistance in liver and muscle and increased risk of developing type 2 diabetes, however there is a population of obese people that remain insulin sensitive. Similarly, recent work suggests that mice fed high carbohydrate diets can become obese without apparent glucose intolerance. To investigate this phenomenon further, we fed mice either a high fat (Hi-F) or high starch (Hi-ST) diet and measured adiposity, glucose tolerance, insulin sensitivity, and tissue lipids compared to control mice fed a standard laboratory chow. Both Hi-ST and Hi-F mice accumulated a similar amount of fat and tissue triglyceride compared to chow-fed mice. However, while Hi-F diet mice developed glucose intolerance as well as liver and muscle insulin resistance (assessed via euglycaemic/hyperinsulinaemic clamp), obese Hi-ST mice maintained glucose tolerance and insulin action similar to lean, chow-fed controls. This preservation of insulin action despite obesity in Hi-ST mice was associated with differences in de novo lipogenesis and levels of C22:0 ceramide in liver and C18:0 ceramide in muscle. This indicates that dietary manipulation can influence insulin action independently of the level of adiposity and that the presence of specific ceramide species correlates with these differences., Competing Interests: AB, LS, TN, ES, HG, CY, SH, TP, SS, LP, MK, BY, LQ, GK, CB, NT, GC No competing interests declared, (© 2022, Brandon, Small et al.)

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma., Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030., Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events., Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests SL reports consulting fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Takeda; institution grants or contracts from Bristol Myers Squibb, Janssen, and Takeda; membership on an entity's Board of Directors or advisory committees for TG Therapeutics; and stock ownership in TG Therapeutics. RP reports honoraria and travel grants from Bristol Myers Squibb. CH reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Cilag, Janssen Pharmaceuticals, Sanofi, and Takeda. SJ reports consulting fees from Bristol Myers Squibb, Elsevier, Janssen Pharmaceuticals, Karyopharm Therapeutics, Legend Biotech, Sanofi, and Takeda. AO reports honoraria and consulting fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi. PGR reports institution grants or contracts from Bristol Myers Squibb, Karyopharm Therapeutics, Oncopeptides, and Takeda; consulting fees from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. KW reports institution grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Janssen Pharmaceuticals, GlaxoSmithKline, and Sanofi; honoraria and consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; and membership of an advisory board for German Society for Hematology and Medical Oncology and Stiftung Immunonkologie. MCM reports honoraria from Alnylam Pharmaceuticals, Bristol Myers Squibb, Cilag, Gilead Sciences, Janssen Pharmaceuticals, and Medscape; travel grants from Celgene, a Bristol Myers Squibb Company; and membership on an entity's Board of Directors or advisory committees for Bristol Myers Squibb. AZB reports research support from GlaxoSmithKline. SK reports honoraria, research support, and consulting fees from Bristol Myers Squibb. EAS reports institution grants or contracts from AbbVie and Bristol Myers Squibb; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, and GlaxoSmithKline; and membership on an entity's Board of Directors or advisory committees for Amgen. YC, TVN, AA, and TP are employees of Bristol Myers Squibb and have stock ownership in Bristol Myers Squibb. MA is an employee of Bristol Myers Squibb, has stock ownership in Bristol Myers Squibb, and has received travel grants from Bristol Myers Squibb. MC is an employee of Bristol Myers Squibb. NWCJvdD reports institution grants or contracts from Amgen, Cellectis, and Janssen Pharmaceuticals; and membership on an entity's Board of Directors or advisory committees for Adaptive Biotechnologies, Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Roche Sanofi, and Takeda. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Preeclampsia is a disease of pregnancy responsible for significant maternal and neonatal mortality. Galectin-3 is a β -Galactoside binding protein. This study aimed to characterise galectin-3 in women with preeclampsia and human trophoblast stem cells (hTSCs). Galectin-3 was measured in placental lysates and plasma collected from patients with early-onset preeclampsia (delivered <34 weeks' gestation) and gestation matched controls. Placental galectin-3 protein was significantly reduced in 43 women with early-onset preeclampsia compared to 21 controls. mRNA expression of LGALS3 (galectin-3 encoding gene) was reduced in 29 women with early-onset preeclampsia, compared to 18 controls ( p = 0.009). There was no significant difference in plasma galectin-3 protein in 46 women with early-onset preeclampsia compared to 20 controls. In a separate cohort of samples collected at 36 weeks' gestation, circulating galectin-3 was not altered in 23 women who later developed preeclampsia, versus 182 who did not. In syncytialised hTSCs, hypoxia increased mRNA expression of LGALS3 ( p = 0.01). Treatment with inflammatory cytokines (TNF-α and IL-6) had no effect on LGALS3 mRNA expression . However, TNF-α treatment caused an increase in mRNA expression of LGALS3BP (galectin-3 binding protein encoding gene) in hTSCs ( p = 0.03). This study showed a reduction of galectin-3 in placenta from pregnancies complicated by early-onset preeclampsia. LGALS3 mRNA expression was dysregulated by hypoxia exposure in placental stem cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kandel, Tong, Walker, Cannon, Nguyen, MacDonald, Hannan, Kaitu’u-Lino and Bartho.)

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both  ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089)., Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background Preeclampsia is pregnancy specific, involving significant maternal endothelial dysfunction. Predictive biomarkers are lacking. We evaluated the biomarker potential, expression, and function of PSG7 (pregnancy-specific β-1 glycoprotein 7) and PSG9 (pregnancy-specific β-1 glycoprotein 9) in preeclampsia. Methods and Results At 36 weeks gestation preceding term preeclampsia diagnosis, PSG7 and PSG9 (in Australian cohorts of n=918 and n=979, respectively) were significantly increased before the onset of term preeclampsia (PSG7, P =0.013; PSG9, P =0.0011). In samples collected at 28 to 32 weeks from those with preexisting cardiovascular disease and at high risk of preeclampsia (Manchester Antenatal Vascular Service, UK cohort, n=235), both PSG7 and PSG9 were also significantly increased preceding preeclampsia onset (PSG7, P <0.0001; PSG9, P =0.0003) relative to controls. These changes were validated in the plasma and placentas of patients with established preeclampsia who delivered at <34 weeks gestation (PSG7, P =0.0008; PSG9, P <0.0001). To examine whether PSG7 and PSG9 are associated with increasing disease severity, we measured them in a cohort from South Africa stratified for this outcome, the PROVE (Preeclampsia Obstetric Adverse Events) cohort (n=72). PSG7 ( P =0.0027) and PSG9 ( P =0.0028) were elevated among patients who were preeclamptic with severe features (PROVE cohort), but not significantly changed in those without severe features or with eclampsia. In syncytialized first trimester cytotrophoblast stem cells, exposure to TNFα (tumor necrosis factor α) or IL-6 (interleukin 6) significantly increased the expression and secretion of PSG7 and PSG9. In contrast, when we treated primary endothelial cells with recombinant PSG7 and PSG9, we only observed modest changes in Flt-1 (FMS-like tyrosine kinase-1) expression and Plgf (placental growth factor) expression, and no other effects on proangiogenic/antiangiogenic or endothelial dysfunction markers were observed. Conclusions Circulating PSG7 and PSG9 are increased before preeclampsia onset and among those with established disease with their production and release potentially driven by placental inflammation.

Activin A is aberrantly expressed by the preeclamptic placenta and circulating levels have been investigated as a potential biomarker for the disease. In a nested case-control study we measured Activin A levels in maternal plasma at 28- and 36-weeks' gestation preceding term preeclampsia diagnosis. At 28 weeks Activin A was not significantly altered (n = 73 destined to develop preeclampsia vs n = 191 controls). At 36 weeks' gestation Activin A was significantly increased in 40 women destined to develop preeclampsia relative to 201 controls (p < 0.0001). These findings provide further validation of Activin A as a potential biomarker for subsequent term preeclampsia., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

First trimester circulating ADAM12 is reduced in fetal growth restriction (FGR) and preeclampsia. We measured plasma ADAM12 at 36 weeks' gestation preceding diagnosis of term preeclampsia or delivery of a small for gestational age (SGA; birthweight <10th centile) infant in two independent cohorts (Cohort 1 90 SGA, 41 preeclampsia, 862 controls; Cohort 2121 SGA 23 preeclampsia; 190 controls). ADAM12 was reduced with SGA in both cohorts (p = 0.0015 and 0.011 respectively), and further reduced with birthweight <5th centile (p = 0.0013 and 0.0058 respectively). This validates ADAM12 as an SGA biomarker near term. Circulating ADAM12 preceding preeclampsia was not consistently altered., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept., (© 2021. Crown.)

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

Preeclampsia is a pregnancy complication associated with angiogenic dysbalance, maternal endothelial dysfunction and end-organ injury. A predictive test to identify those who will develop preeclampsia could substantially decrease morbidity and mortality. MicroRNAs (miRs) are small RNA molecules involved in post-transcriptional gene regulation. We screened for circulating miRs differentially expressed at 36 weeks' gestation in pregnancies before the development of preeclampsia. We used a case-control group (198 controls, 34 pre-preeclampsia diagnosis) selected from a prospective cohort (n = 2015) and performed a PCR-based microarray to measure the expression of 41 miRs. We found six circulating miRs (miRs 363, 149, 18a, 1283, 16, 424) at 36 weeks' had significantly reduced expression (p < 0.0001-0.04). miR363 was significantly downregulated at 28 weeks' gestation, 10-12 weeks before the onset of clinical disease. In the circulation of another cohort of 34 participants with established preterm preeclampsia (vs 23 controls), we found miRs363, 18a, 149 and 16 were significantly down regulated (p < 0.0001-0.04). Combined expression of miRs149 and 363 in the circulation at 36 weeks' gestation provides a test with 45% sensitivity (at a specificity of 90%) which suggests measuring both miRs may have promise as part of a multi-marker test to predict preeclampsia.

While correlational studies suggest that lactation may confer a certain level of protection from mental illness, this benefit is not uniformly expressed in all women who choose to breastfeed. We propose here that the neuroendocrine "resetting" induced by lactation may predispose toward positive affect states in a subset of hormone-sensitive mothers, with hormone-gene and hormone-environment interactions determining the ultimate psychological outcome. We find evidence to suggest that higher secretion of prolactin/oxytocin as well as lower secretion of vasopression/androgens in lactating mothers may protect against postpartum depression and anxiety, decrease levels of irritability, and optimize stress responses. On the other hand, while the abrupt withdrawal of estradiol/progesterone in the immediate postpartum period tends to be associated with adverse psychological outcomes, the chronic suppression of estrogens/progestogens induced by lactation may have antidepressant and anxiolytic effects over time. Finally, the hypo-cortisolemic state seen in lactating mothers appears to be associated with improved stress reactivity and circadian rhythms. We also discuss hormone-gene and hormone-environment interactions likely to modulate any potential psychological benefits related to lactation and focus on those factors that are either easy to screen for or known to be modifiable. In sum, neuroendocrine alterations induced by lactation may play a key role in determining reproductive psychiatric risk in a subset of hormone-sensitive women. Using these neuroendocrine factors as an individualized index of risk can help in devising targeted programs to support these women in pursuing lactation or, for those not able or willing, accessing psychological interventions in a timely manner.

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD., (© 2019 by the American Diabetes Association.)

Sex differences in inner-ear function are detectable in infants, notably through the measurement of otoacoustic emissions (OAEs). Prevailing theories posit that prenatal exposure to high levels of androgens in boys may weaken OAEs, and that this phenomenon may predominantly affect the right ear/left hemisphere (Geschwind-Galaburda (GG) hypothesis). Yet, actual tests of these models have been difficult to implement in humans. Here we examined the relationship between markers of fetal androgen exposure collected at birth (anogenital distances (AGD); penile length/width, areolar/scrotal/vulvar pigmentation) and at 6 months of age (2 nd to 4 th digit ratio (2D:4D)) with two types of OAEs, click-evoked OAEs (CEOAEs) and distortion-product OAEs (DPOAEs) (n = 49; 25 boys; 24 girls). We found that, in boys, scrotal pigmentation was inversely associated with the amplitude and reproducibility of CEOAEs in the right ear at 4 kHz, with trends also present in the same ear for mean CEOAE amplitude and CEOAE amplitude at 2 kHz. Penile length was inversely associated with the mean amplitude of DPOAEs in both the right and left ears, as well as with DPOAE amplitude in the right ear at 2 kHz and the reproducibility of CEOAEs in the left ear at 2.8 kHz. Finally, AGD-scrotum in boys was positively associated in boys with the amplitude of DPOAEs in the left ear at 2.8 kHz. Unexpectedly, there were no sex differences in the amplitude or reproducibility of OAEs, nor, in girls, any associations between androgenic markers and auditory function. Nonetheless, these findings, reported for the first time in a sample of human infants, support both the prenatal-androgen-exposure and GG models as explanations for the masculinization of auditory function in male infants., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and end-organ injury. Adrenomedullin (ADM) is a pro-angiogenic peptide hormone which regulates blood pressure and vascular integrity. It is highly expressed in both the placenta and vascular endothelial cells. We performed a nested case-control study, selected from a large prospective cohort of over 2000 participants. Circulating ADM mRNA was reduced at both 28 (n = 39 vs 248 controls, p = 0.005) and 36 weeks' of pregnancy (n = 39 vs 205 controls, p < 0.0001) in those destined to develop term preeclampsia. It was also significantly reduced in the circulation of women with established early-onset preeclampsia (n = 34 vs 21 controls, p = 0.01). ADM mRNA (n = 34 vs 12 controls) and protein (n = 53 vs 17 controls) were significantly decreased in placental tissue from women with early-onset preeclampsia (p = 0.02, p = 0.0002 respectively), suggesting the placenta is a possible source of the reduced circulating mRNA. Functional studies in primary endothelial cells revealed significantly reduced ADM mRNA expression when cells were exposed to cytotrophoblast conditioned media (derived from normotensive pregnancies, p < 0.0001) or TNFα (p < 0.0001), suggesting another possible source of reduced circulating ADM mRNA is the endothelium. Circulating ADM mRNA, but not protein, is reduced 10-12 weeks before the diagnosis of term preeclampsia. It may be of endothelial or placental origin. Whole blood mRNA is a rich source of potential biomarker discovery in the prediction of preeclampsia., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERα WT and ERα MUT cell lines. In vivo , H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERα WT and ERα Y537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERα WT and ERα MUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs. Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERα WT and ERα MUT , promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047 ., (©2018 American Association for Cancer Research.)

Existing studies suggest that dehydroepiandrosterone (DHEA) may be important for human brain development and cognition. For example, molecular studies have hinted at the critical role of DHEA in enhancing brain plasticity. Studies of human brain development also support the notion that DHEA is involved in preserving cortical plasticity. Further, some, though not all, studies show that DHEA administration may lead to improvements in working memory in adults. Yet these findings remain limited by an incomplete understanding of the specific neuroanatomical mechanisms through which DHEA may impact the CNS during development. Here we examined associations between DHEA, cortico-hippocampal structural covariance, and working memory (216 participants [female=123], age range 6-22 years old, mean age: 13.6 +/-3.6 years, each followed for a maximum of 3 visits over the course of 4 years). In addition to administering performance-based, spatial working memory tests to these children, we also collected ecological, parent ratings of working memory in everyday situations. We found that increasingly higher DHEA levels were associated with a shift toward positive insular-hippocampal and occipito-hippocampal structural covariance. In turn, DHEA-related insular-hippocampal covariance was associated with lower spatial working memory but higher overall working memory as measured by the ecological parent ratings. Taken together with previous research, these results support the hypothesis that DHEA may optimize cortical functions related to general attentional and working memory processes, but impair the development of bottom-up, hippocampal-to-cortical connections, resulting in impaired encoding of spatial cues., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.

Objective: To investigate the extent to which subclinical variation in anxious/depressed psychopathology is associated with volume and age-related volumetric change of limbic structures in a longitudinal sample of healthy youths., Methods: Linear mixed-effects models were used to analyze longitudinal behavioral and neuroimaging data (up to 3 data points per subject, collected at 2 year-intervals) in 371 typically developing youths, from 4 to 18 years of age (196 females; 723 MRIs). Volumetric measures were obtained using a validated segmentation method. The best-fit model (cubic, quadratic, or first-order linear) was determined for the effect of age on amygdalar and hippocampal volume (adjusted for total brain volume). Next, amygdalar and hippocampal volumes were regressed against Child Behavior Checklist Anxious/Depressed (A/D) scores. Age-by-A/D and sex-by-A/D interactions were tested., Results: Analyses revealed age-related linear and quadratic volumetric change in the amygdalae and hippocampi, respectively. A/D was positively associated with total amygdalar volume (p=0.045), independent of age and sex. Age-by-A/D and sex-by-A/D interactions were not associated with amygdalar or hippocampal volume., Conclusions: Results suggest that amygdalar structure is tied to A/D among typically developing youths, independent of age and sex. Developmental trajectories of amygdalar and hippocampal volume were not associated with subclinical anxiety. Taken together, increased amygdalar volume may serve as a significant marker of anxiety, regardless of developmental phase., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone-related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA). Here we examined associations between testosterone, cortico-hippocampal structural covariance, executive function (Behavior Rating Inventory of Executive Function) and verbal memory (California Verbal Learning Test-Children's Version), in a longitudinal sample of typically developing children and adolescents 6-22 yo, controlling for the effects of estradiol, DHEA, pubertal stage, collection time, age, handedness, and total brain volume. We found prefrontal-hippocampal covariance to vary as a function of testosterone levels, but only in boys. Boys also showed a specific association between positive prefrontal-hippocampal covariance (as seen at higher testosterone levels) and lower performance on specific components of executive function (monitoring the action process and flexibly shifting between actions). We also found the association between testosterone and a specific aspect of executive function (monitoring) to be significantly mediated by prefrontal-hippocampal structural covariance. There were no significant associations between testosterone-related cortico-hippocampal covariance and verbal memory. Taken together, these findings highlight the developmental importance of testosterone in supporting sexual differentiation of the brain and sex-specific executive function., Competing Interests: The authors declare no conflict of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention. Here we examined associations between DHEA, structural covariance of the amygdala with whole-brain cortical thickness, and tests of visual attention, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DHEA predicted covariance between amygdalar volume and the left occipital pole, right somatosensory parietal cortex and right anterior cingulate cortex. Amygdala-occipital covariance predicted visual awareness; amygdala-parietal covariance predicted visuo-motor dexterity and processing speed; amygdala-prefrontal covariance predicted global attentional impairment. Further, effects of DHEA were above and beyond those of age and sex, as well as distinct from those of pubertal stage, estradiol and testosterone. These findings support the notion that DHEA may play a unique role in shaping amygdala-dependent cortical plasticity and in regulating 'bottom-up' visual attention processes from childhood to young adulthood., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Defects in the activity of enzyme complexes of the mitochondrial respiratory chain are thought to be responsible for several disorders, including renal impairment. Gene mutations that result in complex I deficiency are the most common oxidative phosphorylation disorders in humans. To determine whether an abnormality in mitochondrial complex I per se is associated with development of renal disease, mice with a knockdown of the complex I gene, Ndufs6 were studied., Results: Ndufs6 mice had a partial renal cortical complex I deficiency; Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared with wild-type mice. Both Ndufs6gt/+ and Ndufs6gt/gt mice exhibited hallmarks of renal disease, including albuminuria, urinary excretion of kidney injury molecule-1 (Kim-1), renal fibrosis, and changes in glomerular volume, with decreased capacity to generate mitochondrial ATP and superoxide from substrates oxidized via complex I. However, more advanced renal defects in Ndufs6gt/gt mice were observed in the context of a disruption in the inner mitochondrial electrochemical potential, 3-nitrotyrosine-modified mitochondrial proteins, increased urinary excretion of 15-isoprostane F2t, and up-regulation of antioxidant defence. Juvenile Ndufs6gt/gt mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C., Innovation: We have identified renal impairment in a mouse model of partial complex I deficiency, suggesting that even modest deficits in mitochondrial respiratory chain function may act as risk factors for chronic kidney disease., Conclusion: These studies identify for the first time that complex I deficiency as the result of interruption of Ndufs6 is an independent cause of renal impairment.

The history of syphilis is complex and has left its mark throughout medicine. The origin of syphilis is an important historical and scientific issue in the history of medicine. The Columbian hypothesis which assumes that syphilis originated in the New World ('America') and that Columbus and his crew imported the disease after his voyages of discovery in 1493 to the Old World ('Europe') is the most accepted theory. Misinterpretations of unethical experiments into the causes of syphilis and gonorrhoea from the 17th century to the early decades of the 19th century led to nosological misconceptions. In the late 19th century and 20th century came the great breakthroughs in the fields of microbiology, diagnosis and therapy.