Zika virus infection at mid-gestation results in fetal cerebral cortical injury and fetal death in the olive baboon.

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5-7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs.

Translational Model of Zika Virus Disease in Baboons.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus with devastating outcomes seen recently in the Americas due to the association of maternal ZIKV infection with fetal microcephaly and other fetal malformations not previously associated with flavivirus infections. Here, we have developed the olive baboon (Papio anubis) as a nonhuman primate (NHP) translational model for the study of ZIKV pathogenesis and associated disease outcomes to contrast and compare with humans and other major NHPs, such as macaques. Following subcutaneous inoculation of adult male and nonpregnant female baboons, viremia was detected at 3 and 4 days postinfection (dpi) with the concordant presentation of a visible rash and conjunctivitis, similar to human ZIKV infection. Furthermore, virus was detected in the mucosa and cerebrospinal fluid. A robust ZIKV-specific IgM and IgG antibody response was also observed in all the animals. These data show striking similarity between humans and the olive baboon following infection with ZIKV, suggesting our model is a suitable translational NHP model to study ZIKV pathogenesis and potential therapeutics.IMPORTANCE ZIKV was first identified in 1947 in a sentinel rhesus monkey in Uganda and subsequently spread to Southeast Asia. Until 2007, only a small number of cases were reported, and ZIKV infection was relatively minor until the South Pacific and Brazilian outbreaks, where more severe outcomes were reported. Here, we present the baboon as a nonhuman primate model for contrast and comparison with other published animal models of ZIKV, such as the mouse and macaque species. Baboons breed year round and are not currently a primary nonhuman primate species used in biomedical research, making them more readily available for studies other than human immunodeficiency virus studies, which many macaque species are designated for. This, taken together with the similarities baboons have with humans, such as immunology, reproduction, genetics, and size, makes the baboon an attractive NHP model for ZIKV studies in comparison to other nonhuman primates.

Prescribing Bioidentical Menopausal Hormone Therapy: A Survey of Physician Views and Practices.

BACKGROUND: It is estimated that 1-2.5 million U.S. women use compounded bioidentical menopausal hormone therapy (MHT). However, the proportion of American physicians prescribing compounded bioidentical hormones remains unknown. This study aims to evaluate obstetrician-gynecologists' (OB/GYNs) and family medicine physicians' decisions reflected in prescribing practices of MHT in Kansas, and level of agreement with the American College of Obstetricians and Gynecologists (ACOG) recommendations. METHODS: An Internet-based 38-item survey was electronically disseminated to OB/GYNs and family medicine physicians identified through the Kansas State Board of Healing Arts licensure list. RESULTS: Out of 1349 physicians contacted, 164 (12.2%) responded to the survey. There were 128 (9.5%) responses included in the final analysis. In the past year, 96.1% (123/128) of respondents prescribed conventional MHT, 93.0% (119/128) prescribed Food and Drug Administration (FDA)-approved bioidentical MHT, and 66.1% (84/127) prescribed compounded bioidentical MHT. Of factors influencing MHT-prescribing practices, FDA regulation was not important to 16.7% (21/126) of physicians, whereas customization was important to 68.5% (87/127). There was a significant difference between specialties, 37.7% of OB/GYNs compared with 56.9% of family medicine physicians, regarding the ACOG statement that "patients should be counseled that conventional MHT is more appropriate than compounded preparations" (p = 0.031). Respondents disagreed with ACOG regarding the statements that "the practice of compounding makes it difficult to identify the active agent responsible for various effects" (41.0% of OB/GYNs and 34.8% of family medicine physicians) and "the practice of custom blending commercially available drug products lacks both a strong biological rationale and medical evidence for effectiveness" (36.1% of OB/GYNs and 37.9% of family medicine physicians). CONCLUSIONS: Prescribing practices for MHT vary between specialties. This study identifies a meaningful level of disagreement with ACOG recommendations regarding prescription of compounded rather than FDA-approved MHT. Further research is needed to better understand this level of discordance.

Impact of Zika virus for infertility specialists: current literature, guidelines, and resources.

In the past 2 years, Zika virus has emerged from obscurity onto the world stage-traversing and transcending clinical specialties, basic science disciplines, and public health efforts. The spread of Zika virus has serious implications for the specialty of reproductive endocrinology and infertility. Our patients, practices, and labs-worldwide and specifically in the USA-have been impacted by this teratogenic, sexually transmitted, largely asymptomatic virus. While the World Health Organization's Public Emergency of International Concern designation has lapsed as major epidemics have subsided and understanding of risks is in part clarified, the acute and long-term threat to pregnant patients is not over. The risk of wider spread in the USA is not insignificant, the subtler and long-ranging consequences beyond microcephaly are not fully known, large geographic areas of risk still contain naïve populations, and whether Zika will continue to be an intermittent risk in endemic areas is uncertain. Staying up to date with the burgeoning research on Zika virus is an important objective for the infertility specialist. Here, we review in detail the most relevant recent developments, discuss applicable guidelines, and propose strategies for contributing to a reduction in the risk and burden of Zika virus.