Role of Vascular Endothelial Growth Factor in Placental Vascularization

The ratio of a fetus’s weight to that of its placenta has been used in our laboratory as an estimate of placental efficiency, which defines the number of grams of placenta required to support a gram of fetus. Because the pig placenta is noninvasive, nutrients from the mother must diffuse from uterine blood vessels to placental blood vessels at the placental-endometrial interface. A pig placenta can respond to increasing fetal nutrient demands by either increasing in size, and thus surface area in contact with the endometrium, or by increasing the number of blood vessels per unit area at the fetal-maternal interface. Previous studies from our laboratory have shown Meishan and Yorkshire conceptuses gestated in a Meishan uterus had markedly smaller placentae than Meishan or Yorkshire conceptuses gestated in a Yorkshire uterus whereas fetal weights across the two uterine environments were much more similar. These data suggested that conceptuses in a Meishan uterine environment have a greater vascular density at the placentalendometrial interface. Greater densities of blood vessels can be achieved by either vasodilation (increasing the diameter of existing blood vessels) or angiogenesis (growth of new vessels from preexisting ones). Hypoxia, or inadequate oxygen transport, has been shown to increase angiogenic factors, such as vascular endothelial growth factor (VEGF), which stimulate blood vessel development. It is possible that VEGF may be important in stimulating increased blood vessel density in the pig placenta, as it has been to shown to do in the ovine placenta. Our objective was to determine if VEGF mRNA expression was associated with placental and/or endometrial vascular density, placental efficiency, and litter size during late gestation. We observed a positive association of both placental vascular density (r=0.37, p\u3c0.05) and VEGF mRNA levels (r=0.35; P\u3c.05) with placental efficiency . There was also a positive correlation between VEGF mRNA levels and the number of conceptuses in a litter (r=0.42; P\u3c.05) on day 70, 90, and 110 of gestation. Although Yorkshire uteri exhibited greater endometrial vascular density than Meishan uteri on day 70 of gestation, placentae of conceptuses gestated in a Meishan uterus had greater amounts of VEGF mRNA than placentae of conceptuses gestated in a Yorkshire uterus. The greater amounts of placental VEGF mRNA of conceptuses gestated in a Meishan uterus on day 70 may have resulted in the increased placental vascular density observed on day 90. We conclude that the increased litter size of the Meishan female may stem from her having smaller, more vascular placentae than placentae of conceptuses gestated in the uterus of a Yorkshire female, to allow for efficient nutrient delivery to the fetus. The increased placental vascular density of a conceptus gestated in the uterus of a Meishan female may result from increased placental VEGF mRNA production induced from an endometrial induced hypoxia on day 70 of gestation

Use of Asynchronous Embryo Transfer to Investigate the Role of Uterine-embryo Timing on Placental Size

The ability of the uterus to accommodate a finite amount of placental tissue appears to be a major limitation to litter size. Meishan preimplantation conceptuses contain fewer cells, produce less estradiol-17β, elongate to a shorter length, and exhibit a reduced placental size throughout gestation than Yorkshire conceptuses. Uterine luminal embryonic estradiol-17β and growth factor content are positively associated at elongation. Based on these data, we have argued that growth factor quantity regulates the length an embryo attains at elongation, and ultimately limits placental size. Recently, we injected Meishan gilts every 6 hours with estradiol-17β on day 12 and 13 of gestation, resulting in a 40% increase in placental size at term compared with vehicle-injected Meishan gilts. This study was conducted to determine if transfer of embryos into the oviducts of asynchronous females (more or less advanced uterine environments) would alter fetal and/or placental size at term. Embryos (1 to 4 cells) were flushed from the oviducts of each donor gilt on day 2.5 of gestation and transferred in equal numbers to the oviducts of a recipient gilt on day 1.5, 2.5, or 3.5 of their estrous cycle. Gilts were slaughtered on day 112 of gestation and fetal and placental weight, placental surface area, and implantation site lengths were determined. Although litter sizes were similar (8.4 ± 1.1), conceptuses transferred to day 3.5 recipients had heavier fetuses (1.57 ± .09 vs. 1.23 ± .04 kg, P\u3c.001), larger placental surface area (1812 ± 106 vs. 1458 ± 43 cm 2 , P\u3c.01) and occupied longer implantation site length (34 ± 3 vs. 25 ± 1 cm, P\u3c.001) than those transferred to recipients on day 1.5 or 2.5. These data demonstrate that oviductal transfer of embryos to a reproductive tract as little as 24 hours more advanced can result in dramatic alterations in placental growth and function during gestation

Management of Agitation During the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus SARS-CoV-2 has radically altered delivery of care in emergency settings. Unprecedented hardship due to ongoing fears of exposure and threats to personal safety, along with societal measures enacted to curb disease transmission, have had broad psychosocial impact on patients and healthcare workers alike. These changes can significantly affect diagnosing and managing behavioral emergencies such as agitation in the emergency department. On behalf of the American Association for Emergency Psychiatry, we highlight unique considerations for patients with severe behavioral symptoms and staff members managing symptoms of agitation during COVID-19. Early detection and treatment of agitation, precautions to minimize staff hazards, coordination with security personnel and psychiatric services, and avoidance of coercive strategies that cause respiratory depression will help mitigate heightened risks to safety caused by this outbreak

A System Dynamics Evaluation Model: Implementation of Health Information Exchange for Public Health Reporting

The objective of this study is to evaluate complex dynamics involved in implementing electronic health information exchange for public health reporting at a state health department, and to identify policy implications to inform similar implementations. Qualitative data were collected over eight months from seven experts at NYS DOH who implemented web services and protocols for querying, receipt, and validation of electronic data supplied by regional health information organizations. Extensive project documentation also was collected. During group meetings experts described the implementation process and created reference modes and causal diagrams that the evaluation team used to build a preliminary model. System dynamics modeling techniques were applied iteratively to build causal loop diagrams representing the implementation. Validation of the diagrams was done iteratively by individual experts followed by group review online, and through confirmatory review of documents a! nd artifacts. Three casual loop diagrams captured well-recognized system dynamics: Sliding Goals, Project Rework, and Maturity of Resources. The findings were associated with specific policies that address funding, leadership, ensuring expertise, planning for rework, communication, and timeline management. This evaluation illustrates the value of a qualitative approach to system dynamics modeling. As a tool for strategic thought about complicated and intense processes, qualitative models can be produced with fewer resources than a full simulation, yet still provide insights that are timely and relevant. System dynamics techniques clarified endogenous and exogenous factors at play in a highly complex technology implementation, which may inform other states engaged in implementing HIE supported by federal HITECH legislatio

Governance and stakeholder perspectives of managed re-alignment: Adapting to sea level rise in the Inner Forth estuary, Scotland

With climate change, coastal areas are faced with unprecedented sea level rise and flooding, raising questions as to how societies will choose to adapt. One option is to strengthen existing sea walls to maintain current land uses; however, scientists, policy-makers and conservationists increasingly see the benefits of managed realignment, which is a nature-based coastal adaptation that involves the conversion of reclaimed farmland back to wetlands, allowing periodic local flooding in designated areas to reduce the risk of flooding downstream. We interviewed 16 local organisations, landowners and farmers and held workshops with 109 citizens living the Inner Forth estuary in eastern Scotland, to examine how managed realignment is supported by stakeholder attitudes and their engagement. Most of the farmers we interviewed prefer strengthened sea walls, to maintain their livelihoods and agricultural heritage. Citizens and local organisations were mainly supportive of managed realignment, because it provided wildlife and flood regulation benefits. However, we identified several barriers that could present obstacles to implementing managed realignment, for example, uncertainty whether it would support their principles of economic and rational decision-making. Our findings suggest that the local capacity to cope with rising sea levels is limited by lack of engagement with all relevant stakeholder groups, the limited scope of existing stakeholder partnerships and poor short-term funding prospects of landscape partnerships that would facilitate collaboration and discussion. We suggest that including citizens, landowners, farmers and industries would strengthen existing stakeholder deliberation and collaboration, and support the Inner Forth’s transition towards a more sustainable future shoreline

Inadequate Sedation During Therapeutic Paralysis: Use of Bispectral Index in Critically Ill Patients

Background: Patients receiving therapeutic paralysis may experience inadequate sedation due to intrinsic limitations of behavioral sedation assessment. Bispectral index (BISTM) provides an objective measure of sedation; however, the role of BISTM is not well defined in intensive care unit (ICU) patients on neuromuscular blocking agents (NMBA). Objective: The aim of this study was to delineate the relationship between BISTM and level of sedation for critically ill patients during therapeutic paralysis. Methods: This was a retrospective observational study conducted in ICU patients receiving continuous infusion NMBA and BISTM monitoring. The primary endpoint was the correlation of BISTM\60 during therapeutic paralysis with a Richmond Agitation Sedation Score (RASS) of -4 to -5 (i.e., deep or unarousable sedation) at the time of emergence from therapeutic paralysis. Results: Thirty-one patients were included in the analysis. Three of these patients (9.6 %) were inadequately sedated upon emergence from paralysis; that is, restless or agitated (RASS ?1 to ?2). We did not observe a correlation between BISTM and RASS upon emergence from paralysis (r = 0.27, p = 0.14). The sensitivity of BISTM\60 in predicting deep sedation (RASS -5 to -4) was 100 % (95 % confidence interval [CI] 0–100) with a positive predictive value of 35.7 %. The sensitivity and positive predictive value of BISTM\60 in predicting light sedation or deeper (RASS -5 to -2) was 92.9 % (95 %CI 83.3–100) and 92.9 %, respectively. Conclusion: These results suggest that 1 in 10 critically ill patients receiving therapeutic paralysis may be inadequately sedated. BISTM monitoring may serve as a useful adjunctive measure of sedation in critically ill patients receiving therapeutic paralysis

Inadequate Sedation During Therapeutic Paralysis: Use of Bispectral Index in Critically Ill Patients

Background Patients receiving therapeutic paralysis may experience inadequate sedation due to intrinsic limitations of behavioral sedation assessment. Bispectral index (BIS™) provides an objective measure of sedation; however, the role of BIS™ is not well defined in intensive care unit (ICU) patients on neuromuscular blocking agents (NMBA). Objective The aim of this study was to delineate the relationship between BIS™ and level of sedation for critically ill patients during therapeutic paralysis. Methods This was a retrospective observational study conducted in ICU patients receiving continuous infusion NMBA and BIS™ monitoring. The primary endpoint was the correlation of BIS™ \u3c 60 during therapeutic paralysis with a Richmond Agitation Sedation Score (RASS) of −4 to −5 (i.e., deep or unarousable sedation) at the time of emergence from therapeutic paralysis. Results Thirty-one patients were included in the analysis. Three of these patients (9.6 %) were inadequately sedated upon emergence from paralysis; that is, restless or agitated (RASS +1 to +2). We did not observe a correlation between BIS™ and RASS upon emergence from paralysis (r = 0.27, p = 0.14). The sensitivity of BIS™ \u3c 60 in predicting deep sedation (RASS −5 to −4) was 100 % (95 % confidence interval [CI] 0–100) with a positive predictive value of 35.7 %. The sensitivity and positive predictive value of BIS™ \u3c 60 in predicting light sedation or deeper (RASS −5 to −2) was 92.9 % (95 %CI 83.3–100) and 92.9 %, respectively. Conclusion These results suggest that 1 in 10 critically ill patients receiving therapeutic paralysis may be inadequately sedated. BIS™ monitoring may serve as a useful adjunctive measure of sedation in critically ill patients receiving therapeutic paralysis

Kinetics and Phenotype of Vaccine-Induced CD8+ T-Cell Responses to Toxoplasma gondii

Multiple studies have established that the ability of CD8+ T cells to act as cytolytic effectors and produce gamma interferon is important in mediating resistance to the intracellular parasite Toxoplasma gondii. To better understand the generation of the antigen-specific CD8+ T-cell responses induced by T. gondii, mice were immunized with replication-deficient parasites that express the model antigen ovalbumin (OVA). Class I tetramers specific for SIINFEKL were used to track the OVA-specific endogenous CD8+ T cells. The peak CD8+ T-cell response was found at day 10 postimmunization, after which the frequency and numbers of antigen-specific cells declined. Unexpectedly, replication-deficient parasites were found to induce antigen-specific cells with faster kinetics than replicating parasites. The generation of optimal numbers of antigen-specific CD8+ effector T cells was found to require CD4+ T-cell help. At 7 days following immunization, antigen-specific cells were found to be CD62Llow, KLRG1+, and CD127low, and they maintained this phenotype for more than 70 days. Antigen-specific CD8+ effector T cells in immunized mice exhibited potent perforin-dependent OVA-specific cytolytic activity in vivo. Perforin-dependent cytolysis appeared to be the major cytolytic mechanism; however, a perforin-independent pathway that was not mediated via Fas-FasL was also detected. This study provides further insight into vaccine-induced cytotoxic T-lymphocyte responses that correlate with protective immunity to T. gondii and identifies a critical role for CD4+ T cells in the generation of protective CD8+ T-cell responses

Affiliative Behavior, Ultrasonic Communication and Social Reward Are Influenced by Genetic Variation in Adolescent Mice

Social approach is crucial for establishing relationships among individuals. In rodents, social approach has been studied primarily within the context of behavioral phenomena related to sexual reproduction, such as mating, territory defense and parental care. However, many forms of social interaction occur before the onset of reproductive maturity, which suggests that some processes underlying social approach among juvenile animals are probably distinct from those in adults. We conducted a longitudinal study of social investigation (SI) in mice from two inbred strains to assess the extent to which genetic factors influence the motivation for young mice to approach one another. Early-adolescent C57BL/6J (B6) mice, tested 4–6 days after weaning, investigated former cage mates to a greater degree than BALB/cJ (BALB) mice, irrespective of the sex composition within an interacting pair. This strain difference was not due to variation in maternal care, the phenotypic characteristics of stimulus mice or sensitivity to the length of isolation prior to testing, nor was it attributable to a general difference in appetitive motivation. Ultrasonic vocalization (USV) production was positively correlated with the SI responses of mice from both strains. Interestingly, several USV characteristics segregated with the genetic background of young mice, including a higher average frequency and shorter duration for the USVs emitted by B6 mice. An assessment of conditioned place preference responses indicated that there was a strain-dependent difference in the rewarding nature of social contact. As adolescent mice aged, SI responses gradually became less sensitive to genetic background and more responsive to the particular sex of individuals within an interacting pair. We have thus identified a specific, genetic influence on the motivation of early-adolescent mice to approach one another. Consistent with classical theories of motivation, which propose a functional relationship between behavioral approach and reward, our findings indicate that reward is a proximal mechanism through which genetic factors affect social motivation during early adolescence

Controls of Litter Size—Do Conclusions Drawn from Institutional Research Herds Always Have Relevance to Commercial Swine Production?

Increasing litter size in pigs has been an ongoing concern of many producers because it has the greatest impact on profitability of the swine enterprise. To study the biology of conceptus growth and survival, many models have been used by researchers. It was determined that a major component in limiting litter size results from the impacts of limitations in uterine space (i.e. uterine capacity). Placental efficiency, which is the ratio of a fetus’s weight compared with that of its placenta, has been shown to impact litter size, and is heritable. Selection for breeding animals having a high placental efficiency at term, has been shown to increase litter size. Furthermore, although piglet weight was only slightly decreased in offspring of boars and gilts selected for increased placental efficiency, placental size was profoundly reduced. This reduction in placental size was coupled with an increase in vascularity, thus nutrient and oxygen uptake by the conceptus could be accomplished over a decreased surface area of attachment to the uterine wall. Reproductive data obtained to date have been gathered largely from university swine herds that may have little relevance to commercially used US pig breeds. In contrast to the constant evaluations of physiological changes associated with increased litter size at universities, swine seed stock producers have selected for many generations simply on increased litter size and have not bothered to evaluate the resulting physiological changes associated with increased fecundity. Therefore, it was the objective of this study to investigate the reproductive characteristics of a commercially relevant swine herd in Iowa (PIC Camborough Line) at selected gestational ages. Multiparous sows (ranging from 1 to 14 parities) were slaughtered on days 25, 36, and 44 of gestation, time periods corresponding to intervals which are before, during, and after the time when uterine capacity becomes limiting. At the laboratory, the uterine horns were measured and ovulation rate was determined. Conceptuses were removed and fetal and placental weights were determined. Uterine horn length and ovulation rate did not differ between the three gestational groups. Conceptus number decreased from 15.8 ± 0.6 on day 25 to 12.9 ± 0.5 and 12.1 ± 0.4 on day 36 and day 44 (litter size in this population averages ~11.5 liveborn piglets/litter). Conceptus survival to day 25 was 60.2 ± 0.1%, which then decreased to 50.1 ± 0.1% on day 36 and 46.3 ± 0.1% on day 44. There was a positive correlation between conceptus number and ovulation rate on day 25 but by day 36 this association was lost. Conceptus number was not associated with uterine length on day 25, but by day 36 there was a positive association that remained through day 44. On all three gestation days there was a negative association between conceptus number and placental weight, but no association between conceptus number and fetal weight was observed, indicating that larger litters are comprised of conceptuses having small placentae, but the same sized fetuses. These data indicate that, compared with commonly reported values for university herds (16-18 ovulations), ovulation rate in these mixed parity production animals is extremely high, whereas conceptus survival as estimated from the number of conceptuses divided by the number of ovulations was very low. Additionally, although conceptus number was related to the ovulation rate on day 25, by day 36 the limitations of uterine size began to reduce conceptus number irrespective of ovulation rate. These data suggest that ovulation rate is not a limiting factor in litter size in this line of commercially relevant pigs. In contrast, the higher than expected ovulation rate observed in these pigs resulted in significant embryo losses and early uterine crowding. The consequences of this early conceptus crowding may have detrimental impacts on prenatal and postnatal growth rate and survival