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Abstract Small‐for‐gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood‐based screening methods for determining SGA risk are available. We used a high‐resolution MS/MSALL shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals. Samples were acquired from 195 normal and 41 SGA pregnancies. Lipid profiles were determined serially across pregnancy. We identified specific lipid signatures of placental sEVs that define the trajectory of a normal pregnancy and their changes occurring in relation to maternal characteristics (parity and ethnicity) and birthweight centile. We constructed a multivariate model demonstrating that specific lipid features of circulating placental sEVs, particularly during early gestation, are highly predictive of SGA infants. Lipidomic‐based biomarker development promises to improve the early detection of pregnancies at risk of developing SGA, an unmet clinical need in obstetrics.

Placenta Accreta Spectrum (PAS) is a life-threatening condition in which placental trophoblastic cells abnormally invade the uterus, often up to the uterine serosa and, in extreme cases, tissues beyond the uterine wall. Currently, there is no clinical assay for the non-invasive detection of PAS, and only ultrasound and MRI can be used for its diagnosis. Considering the subjectivity of visual assessment, the detection of PAS necessitates a high degree of expertise and, in some instances, can lead to its misdiagnosis. In clinical practice, up to 50% of pregnancies with PAS remain undiagnosed until delivery, and it is associated with increased risk of morbidity/mortality. Although many studies have evaluated the potential of fetal biomarkers circulating in maternal blood, very few studies have evaluated the potential of circulating placental extracellular vesicles (EVs) and their miRNA contents for molecular detection of PAS. Thus, to purify placental EVs from maternal blood, we customized our robust ultra-sensitive immuno-purification assay, termed EV-CATCHER, with a monoclonal antibody targeting the membrane Placental Alkaline Phosphatase (PLAP) protein, which is unique to the placenta and present on the surface of placental EVs. Then, as a pilot evaluation, we compared the miRNA expression profiles of placental EVs purified from the maternal plasma of women diagnosed with placenta previa (controls, n = 16); placenta lying low in uterus but not invasive) to those of placental EVs purified from the plasma of women with placenta percreta (cases, n = 16), PAS with the highest level of invasiveness. Our analyses reveal that miRNA profiling of PLAP+ EVs purified from maternal plasma identified 40 differentially expressed miRNAs when comparing these two placental pathologies. Preliminary miRNA pathway enrichment and gene ontology analysis of the top 14 upregulated and top nine downregulated miRNAs in PLAP+ EVs, purified from the plasma of women diagnosed with placenta percreta versus those diagnosed with placenta previa, suggests a potential role in control of cellular invasion and motility that will require further investigation.

Introduction: The placenta mediates fetal growth by regulating gas and nutrient exchange between the mother and the fetus. The cell type in the placenta where this nutrient exchange occurs is called the syncytiotrophoblast, which is the barrier between the fetal and maternal blood. Residence at high-altitude is strongly associated with reduced 3rd trimester fetal growth and increased rates of complications such as preeclampsia. We asked whether altitude and/or ancestry-related placental gene expression contributes to differential fetal growth under high-altitude conditions, as native populations have greater fetal growth than migrants to high-altitude.Methods: We have previously shown that methylation differences largely accounted for altitude-associated differences in placental gene expression that favor improved fetal growth among high-altitude natives. We tested for differences in DNA methylation between Andean and European placental samples from Bolivia [La Paz (∼3,600 m) and Santa Cruz, Bolivia (∼400 m)]. One group of genes showing significant altitude-related differences are those involved in cell fusion and membrane repair in the syncytiotrophoblast. Dysferlin (DYSF) shows greater expression levels in high- vs. low-altitude placentas, regardless of ancestry. DYSF has a single nucleotide variant (rs10166384;G/A) located at a methylation site that can potentially stimulate or repress DYSF expression. Following up with individual DNA genotyping in an expanded sample size, we observed three classes of DNA methylation that corresponded to individual genotypes of rs10166384 (A/A < A/G < G/G). We tested whether these genotypes are under Darwinian selection pressure by sequencing a ∼2.5 kb fragment including the DYSF variants from 96 Bolivian samples and compared them to data from the 1000 genomes project.Results: We found that balancing selection (Tajima’s D = 2.37) was acting on this fragment among Andeans regardless of altitude, and in Europeans at high-altitude (Tajima’s D = 1.85).Discussion: This supports that balancing selection acting on dysferlin is capable of altering DNA methylation patterns based on environmental exposure to high-altitude hypoxia. This finding is analogous to balancing selection seen frequency-dependent selection, implying both alleles are advantageous in different ways depending on environmental circumstances. Preservation of the adenine (A) and guanine (G) alleles may therefore aid both Andeans and Europeans in an altitude dependent fashion.

Species interactions that can enhance habitat heterogeneity such as facilitation cascades of foundation species have been overlooked in biodiversity models. This study conducted 22 geographically distributed experiments in different ecosystems and biogeographical regions to assess the extent to which biodiversity is explained by three axes of habitat heterogeneity in facilitation cascades.

Although whole turkeys served at Thanksgiving are the ubiquitous kickoffs to the US winter holiday season, much remains unknown about shopping behaviors for holiday food items. Given the once-a-year purchase of the whole turkey for most households, collecting data about demand and preferences necessitated the collection of data during the week before Thanksgiving, while turkey shopping was at the forefront of consumers' minds. Despite a self-reported confidence in cooking turkeys, many respondents indicated they thawed frozen meat using improper methods. Ninety-five percent of respondents indicated that they consumed meat; 89% of respondents who consumed meat or had someone in the household who did, indicated they had purchased turkey products. Positive willingness to pay (WTP) was found for all attributes of whole turkeys studied: free range, fed a vegetarian diet, hormone use not permitted, and antibiotic use not permitted. Mean estimated WTP for free range ranged from $0.37/lb for industry verified free range to $0.74/lb for USDA verified free range; although those 2 estimates were not statistically different from each other, they were both statistically different from zero. The statistically significant estimated mean WTP for hormone use not permitted ranged from $0.85/lb for industry verification to $1.35 for USDA verification but were again not statistically different from each other. Mean WTP estimates, which were statistically significant but not different from one another for antibiotic use not permitted, ranged from $0.62/lb for industry certification to $0.72 for retailer certified. Turkeys certified to be fed a vegetarian diet had a mean WTP estimate of $0.39/lb for retailer verification to $0.60/lb for USDA verification; those mean WTP estimates were not statistically different from each other but were each statistically different from zero. Social desirability bias, which can be defined as the relative over-reporting of one's own goodness, was detected with respect to self-reported holiday eating and healthfulness statements. Relationships were found between social desirability bias, gender, and age for holiday eating statements using a seemingly unrelated regression.

High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)2-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)2-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with CYP2R1 (25-hydroxylase), CYP27B1 (1α-hydroxylase), CYP24A1 (24-hydroxylase), and LRP2 (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)2-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants.

Meat consumption and public concern for farm animal welfare are increasing, despite limited public understanding of agriculture and animal welfare. Turkey is important in U.S. holiday meal traditions and turkey meat is a frequently consumed processed product (i.e., lunchmeat). However, little is known about public perceptions and knowledge of commercial turkeys. An online survey was administered to 1,695 respondents in November 2018 to examine U.S. (1) demographic factors affecting meat consumption, selection of labeled meat products, and concern for animal welfare, (2) public knowledge of turkeys, and (3) concerns regarding the welfare of turkeys and other species. A total of 95% of respondents consumed meat and 10% hunted for some of the meat they consumed. Meat consumption frequency depended on region of residence, income level, gender, age, and whether respondents hunted. Of the meat consumers, 86% purchased turkey products. More meat consumers looked for the USDA organic label (39%) and the Non Genetically Modified Organism (GMO) project label (38%) than animal-welfare food labels (14%) when buying meat products. More pet owners (39%) than non-pet owners (25%) looked for animal welfare food labels. Being a pet owner increased the probability of being concerned about farm animal welfare. Concern for the commercial turkey was similar to concern for other farm animal species; self-reported knowledge of turkey production was low (mean score 2.64; scale of 1 to 7, 7 = highest). Turkey welfare concerns (mean score; rank from 1 to 5; 5 = least concerning) included poor nutrition (2.471) and illness (2.508), followed by housing (2.732), hot or cold weather (3.308) and transportation (3.981). Turkey welfare attributes that respondents cared the most about (mean score; scale of 1–5, 5 = cared the least) included space to move around (2.366), followed by veterinary health and wellness (2.680), ability to perform natural behavior (2.812), no feather loss or visible injuries (3.304), and decreased aggression (3.837). Demographic factors are important determinants of meat consumption and animal welfare concern. Public knowledge of turkey production is limited, despite a large percentage of the population purchasing turkey products.

Abstract Objective To evaluate if prophylactic hypogastric artery ligation (HAL) decreases surgical blood loss and blood products transfused. Study Design This is a retrospective cohort study comparing patients with placenta percreta undergoing prophylactic HAL at the time of cesarean hysterectomy versus those who did not. Data were presented as means ± standard deviations, proportions, or medians with interquartile ranges. Demographic and clinical data were compared in the groups using Student's t-test for normally distributed data or the Mann–Whitney U test for nonnormally distributed data. Fisher's exact test was used for proportions and categorical variables. Data are reported as significant where p was

BACKGROUND:The incidence of abnormally invasive placentation (AIP) is increasing. Most of these pregnancies are delivered preterm. We sought to characterize neonatal outcomes in AIP pregnancies. METHODS:In this retrospective case-control study (2006-2015), AIP neonates (n = 108) were matched to two controls each for gestational age, antenatal glucocorticoid exposure, sex, plurity, and delivery mode. Medical records were reviewed for neonatal and maternal characteristics/outcomes. Univariate and multivariate Poisson regressions were performed to determine relative risk ratios (RR). RESULTS:There were no mortalities. All neonatal outcomes were similar except for respiratory distress syndrome (RDS), which affected 37% of AIP neonates (versus 21% of controls). AIP neonates required respiratory support (64.8% vs. 51.9%) and continuous positive airway pressure (53.7% vs. 42.1%) for a longer duration. Univariate regression yielded elevated RRs for RDS for AIP (RR 1.78, 95% CI 1.24-2.54), placenta previa (RR = 1.94, 95% CI 1.36-2.76), and placenta previa with bleeding (RR 2.29, 95% CI 1.36-3.86). One episode of bleeding had a RR of 2.43 (95% CI 1.57-3.76), 2 or more episodes had a RR of 2.95 (95% CI 1.96-4.44), and bleeding/abruption as the delivery indication had a RR of 2.57 (95% CI 1.82-3.64). A multivariate regression stratifying for AIP and evaluating the combined and individual associations of AIP, bleeding, placenta previa, and GA, resulted in elevated RRs for placenta previa alone (RR 2.16, 95% CI 1.15-4.06) and placenta previa and bleeding (RR 1.69, 95% CI 1.001-2.85). CONCLUSIONS:The increased incidence of RDS at later gestational ages in AIP is driven by placenta previa. AIP neonates required respiratory support for a longer duration than age-matched controls. Providers should be prepared to counsel expectant parents and care for affected neonates.

Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous) uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

In vertebrates, Ran-Binding Protein in the Microtubule Organizing Center (RanBPM) appears to function as a scaffolding protein in a variety of signal transduction pathways. In Drosophila, RanBPM is implicated in the regulation of germ line stem cell (GSC) niche organization in the ovary. Here, we addressed the role of RanBPM in nervous system function in the context of Drosophila larval behavior.We report that in Drosophila, RanBPM is required for larval feeding, light-induced changes in locomotion, and viability. RanBPM is highly expressed in the Kenyon cells of the larval mushroom body (MB), a structure well studied for its role in associative learning in Drosophila and other insects. RanBPM mutants do not display major disruption in nervous system morphology besides reduced proliferation. Expression of the RanBPM gene in the Kenyon cells is sufficient to rescue all behavioral phenotypes. Through genetic epistasis experiments, we demonstrate that RanBPM participates with the Drosophila orthologue of the Fragile X Mental Retardation Protein (FMRP) in the development of neuromuscular junction (NMJ).We demonstrate that the RanBPM gene functions in the MB neurons for larval behavior. Our results suggest a role for this gene in an FMRP-dependent process. Taken together our findings point to a novel role for the MB in larval behavior.

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial - venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia.

Atrial fibrillation (AF) is a significant risk factor for stroke and peripheral thromboembolic events (TEs). Preventing blood clots in the heart to reduce stroke and TE risk is a key goal of AF therapy. Traditional stroke risk assessment tools for patients with nonvalvular AF include the CHADS2 and CHA(2)DS(2)-VASc scores, while long-term outcome data with the newer direct oral anticoagulants (DOACs) are emerging. The goals of this review were to assess traditional therapies and existing treatment guidelines and to discuss key pharmacologic properties of the DOACS, noting how these may benefit at-risk patients with AF. This narrative review was developed on the basis of the authors' clinical knowledge, extensive reading of the literature, and broad pharmacy experience in the management of patients with AF. Limitations of oral vitamin K antagonists (VKAs) include slow onset of action, the need for regular monitoring of their anticoagulation effect, significant food and drug interactions, and unpredictable dose-response properties. Key clinical trial data led to the approvals of apixaban, dabigatran etexilate, edoxaban, and rivaroxaban in the United States to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. With predictable pharmacologic properties and limited drug and/or dietary interactions, the DOACs offer several benefits over traditional oral anticoagulation therapy with VKA. However, they have limitations, including the absence of immediate reversal agents and limited options for monitoring their anticoagulation effects in clinical practice. As experience with the use of DOACs grows, optimized treatment regimens and improved patient care are expected., (© The Author(s) 2016.)

Venous thromboembolism (VTE) is a significant medical diagnosis that affects millions of patients each year. Appropriate management of VTE can help treat the initial event as well as reduce the frequency of complications such as postthrombotic syndrome, pulmonary hypertension, and death. Due to increasing regulatory requirements, hospitals nationwide are developing necessary documentation of appropriate and safe use of anticoagulants for the management of VTE. It is essential that a wide range of clinicians have an understanding of what constitutes appropriate VTE treatment in various patient populations. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE treatment can be difficult for clinicians. Therefore we have provided bibliographies of key articles and guidelines related to the treatment of VTE with a number of different strategies in a variety of special patient populations. It is our hope that this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with VTE.

The pharmacology characteristics of dihydropyridine calcium channel blockers (CCB) make them an attractive antihypertensive medication for use in the perioperative setting of coronary artery bypass graft (CABG) surgery. They lack the negative inotropic, negative chronotropic, and negative bathmotropic effects of phenylalkylamine and benzothiazepine CCB that limit the use in patients with heart failure or patients with bradyarrythmias. With the aging population and significant rise in the prevalence of heart failure, the use of dihydropyridine CCB as antihypertensive medication after CABG surgery has become more common. Furthermore, intravenous dihydropyridine CCB are being used in the perioperative setting as vasodilatory agents after radial artery harvesting for total arterial coronary revascularization. We review the pharmacological effects of intravenous dihydropyridine CCB, analyze the literature, and comment on the consequences in modern clinical practice.