What women want and why. Women's preferences for induction of labour or expectant management in late-term pregnancy.

BACKGROUND: Both induction of labour at 41 weeks and expectant management until 42 weeks are common management strategies in low-risk pregnancy since there is no consensus on the optimal timing of induction in late-term pregnancy for the prevention of adverse outcomes. Our aim was to explore maternal preference for either strategy and the influence on quality of life and maternal anxiety on this preference. METHODS: Obstetrical low-risk women with an uncomplicated pregnancy were eligible when they reached a gestational age of 41 weeks. They were asked to fill in questionnaires on quality of life (EQ6D) and anxiety (STAI-state). Reasons of women's preferences for either induction or expectant management were explored in a semi-structured questionnaire containing open ended questions. RESULTS: Of 782 invited women 604 (77.2%) responded. Induction at 41 weeks was preferred by 44.7% (270/604) women, 42.1% (254/604) preferred expectant management until 42 weeks, while 12.2% (74/604) of women did not have a preference. Women preferring induction reported significantly more problems regarding quality of life and were more anxious than women preferring expectant management (p<0.001). Main reasons for preferring induction of labour were: "safe feeling" (41.2%), "pregnancy taking too long" (35.4%) and "knowing what to expect" (18.6%). For women preferring expectant management, the main reason was "wish to give birth as natural as possible" (80.3%). CONCLUSION: Women's preference for induction of labour or a policy of expectant management in late-term pregnancy is influenced by anxiety, quality of life problems (induction), the presence of a wish for natural birth (expectant management), and a variety of additional reasons. This variation in preferences and motivations suggests that there is room for shared decision making in the management of late-term pregnancy.

Microencephaly in fetal piglets following in utero inoculation of Zika virus.

Zika virus (ZIKV) is a mosquito-borne flavivirus that became associated with microcephaly in newborns and Guillain-Barré syndrome in adults after its emergence in the Pacific and the Americas in 2015. Newly developed rodent and nonhuman primate models have already revealed important insights into ZIKV-induced neuropathology. Nonhuman primates are phylogenetically closely related to humans and are therefore preferred human surrogates in ZIKV research. However, the use of nonhuman primates, particularly during gestation, raises ethical issues. Considering that pigs also share many anatomical and physiological features with humans, this species may be an attractive alternative human surrogate for ZIKV research. Here, we inoculated 20 porcine fetuses in utero and assessed the effect of ZIKV on brain development 4 weeks later. All inoculated fetuses presented mild to severe neuropathology, characterized by a depletion of neurons in the cerebral cortex. In most cases, neuronal depletion was confined to specific cerebral lobes without affecting brain size, whereas in severe cases a more generalized depletion resulted in microencephaly. Although the virus was widespread in the sows' placenta at the time of necropsy only low levels of viral RNA were detected in fetal brain samples, thereby preventing the identification of primary target cells. Our findings suggest that pigs can be used to study ZIKV-induced neurodevelopmental defects as currently observed in human neonates, varying from stunted brain growth to localized cortical neuronal depletion in the absence of major macroscopic abnormalities.

[A postpartum woman with toxic shock syndrome: group A streptococcal infection, a much feared postpartum complication.] / Een kraamvrouw met toxische-shocksyndroom.

BACKGROUND: The development of toxic shock syndrome (TSS) after an invasive group A streptococcal (GAS) infection in the postpartum period is a much feared complication. The mortality rate of TSS with necrotizing fasciitis is 30 to 50%. CASE DESCRIPTION: We present the case of a woman with atypical pelvic pain which was the first symptom of toxic shock syndrome as a consequence of a GAS infection. Clinical deterioration necessitated a hysterectomy. Also a fasciotomy was performed as consequence of lower extremity compartment syndrome. After this, multiple debridement operations were necessary, followed by split skin grafts. CONCLUSION: This case illustrates the extremely serious complications of GAS infection. In some cases aggressive surgical intervention is necessary, in addition to an optimal antibiotic treatment regime. Ideally, the treatment of a GAS-induced TSS should be managed by a multidisciplinary medical team.

Preliminary Evaluation of a Bunyavirus Vector for Cancer Immunotherapy.

Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8(+) T cells in vitro and that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cells in vivo. These results suggest that the NSR system holds promise for cancer immunotherapy.

Evaluation of nonspreading Rift Valley fever virus as a vaccine vector using influenza virus hemagglutinin as a model antigen.

Virus replicon particles are capable of infection, genome replication and gene expression, but are unable to produce progeny virions, rendering their use inherently safe. By virtue of this unique combination of features, replicon particles hold great promise for vaccine applications. We previously developed replicon particles of Rift Valley fever virus (RVFV) and demonstrated their high efficacy as a RVFV vaccine in the natural target species. We have now investigated the feasibility of using this nonspreading RVFV (NSR) as a vaccine vector using influenza virus hemagglutinin as a model antigen. NSR particles were designed to express either the full-length hemagglutinin of influenza A virus H1N1 (NSR-HA) or the respective soluble ectodomain (NSR-sHA). The efficacies of the two NSR vector vaccines, applied via either the intramuscular or the intranasal route, were evaluated. A single vaccination with NSR-HA protected all mice from a lethal challenge dose, while vaccination with NSR-sHA was not protective. Interestingly, whereas intramuscular vaccination elicited superior systemic immune responses, intranasal vaccination provided optimal clinical protection.

Comparative efficacy of two next-generation Rift Valley fever vaccines.

Rift Valley fever virus (RVFV) is a re-emerging zoonotic bunyavirus of the genus Phlebovirus. A natural isolate containing a large attenuating deletion in the small (S) genome segment previously yielded a highly effective vaccine virus, named Clone 13. The deletion in the S segment abrogates expression of the NSs protein, which is the major virulence factor of the virus. To develop a vaccine of even higher safety, a virus named R566 was created by natural laboratory reassortment. The R566 virus combines the S segment of the Clone 13 virus with additional attenuating mutations on the other two genome segments M and L, derived from the previously created MP-12 vaccine virus. To achieve the same objective, a nonspreading RVFV (NSR-Gn) was created by reverse-genetics, which not only lacks the NSs gene but also the complete M genome segment. We have now compared the vaccine efficacies of these two next-generation vaccines and included the Clone 13 vaccine as a control for optimal efficacy. Groups of eight lambs were vaccinated once and challenged three weeks later. All mock-vaccinated lambs developed high fever and viremia and three lambs did not survive the infection. As expected, lambs vaccinated with Clone 13 were protected from viremia and clinical signs. Two lambs vaccinated with R566 developed mild fever after challenge infection, which was associated with low levels of viral RNA in the blood, whereas vaccination with the NSR-Gn vaccine completely prevented viremia and clinical signs.

Vertical transmission of Rift Valley fever virus without detectable maternal viremia.

Rift Valley fever virus (RVFV) is a zoonotic bunyavirus that causes abortions in domesticated ruminants. Sheep breeds exotic to endemic areas are reportedly the most susceptible to RVFV infection. Within the scope of a risk assessment program of The Netherlands, we investigated the susceptibility of a native breed of gestating sheep to RVFV infection. Ewes were infected experimentally during the first, second, or third trimester of gestation. Mortality was high among ewes that developed viremia. Four of 11 inoculated ewes, however, did not develop detectable viremia nor clinical signs and did not seroconvert for immunoglobulin G (IgG) or IgM antibodies. Surprisingly, these ewes were found to contain viral RNA in maternal and fetal organs, and the presence of live virus in fetal organs was demonstrated by virus isolation. We demonstrate that RVFV can be transmitted vertically in the absence of detectable maternal viremia.

Acid-activated structural reorganization of the Rift Valley fever virus Gc fusion protein.

The entry of the enveloped Rift Valley fever virus (RVFV) into its host cell is mediated by the viral glycoproteins Gn and Gc. We investigated the RVFV entry process and, in particular, its pH-dependent activation mechanism using our recently developed nonspreading-RVFV-particle system. Entry of the virus into the host cell was efficiently inhibited by lysosomotropic agents that prevent endosomal acidification and by compounds that interfere with dynamin- and clathrin-dependent endocytosis. Exposure of plasma membrane-bound virions to an acidic pH (

Heparan sulfate facilitates Rift Valley fever virus entry into the cell.

Rift Valley fever virus (RVFV), an emerging arthropod-borne pathogen, has a broad host and cell tropism. Here we report that the glycosaminoglycan heparan sulfate, abundantly present on the surface of most animal cells, is required for efficient entry of RVFV. Entry was significantly reduced by preincubating the virus inoculum with highly sulfated heparin, by enzymatic removal of heparan sulfate from cells and in cells genetically deficient in heparan sulfate synthesis.

Efficacy of three candidate Rift Valley fever vaccines in sheep.

Rift Valley fever virus (RVFV) is a mosquito-transmitted Bunyavirus that causes high morbidity and mortality among ruminants and humans. The virus is endemic to the African continent and the Arabian Peninsula and continues to spread into new areas. The explosive nature of RVF outbreaks requires that vaccines provide swift protection after a single vaccination. We recently developed several candidate vaccines and here report their efficacy in lambs within three weeks after a single vaccination. The first vaccine comprises the purified ectodomain of the Gn structural glycoprotein formulated in a water-in-oil adjuvant. The second vaccine is based on a Newcastle disease virus-based vector that produces both RVFV structural glycoproteins Gn and Gc. The third vaccine comprises a recently developed nonspreading RVFV. The latter two vaccines were administered without adjuvant. The inactivated whole virus-based vaccine produced by Onderstepoort Biological Products was used as a positive control. Five out of six mock-vaccinated lambs developed high viremia and fever and one lamb succumbed to the challenge infection. A single vaccination with each vaccine resulted in a neutralizing antibody response within three weeks after vaccination and protected lambs from viremia, pyrexia and mortality.

Protective efficacy of a Classical swine fever virus C-strain deletion mutant and ability to differentiate infected from vaccinated animals.

Classical swine fever (CSF) continues to be the most economically damaging pig disease in the world. The disease can be effectively controlled by vaccination with the live C-strain vaccine. This vaccine, however, does not enable the serological differentiation between infected and vaccinated animals (DIVA) and its use can therefore impose severe trade restrictions. CSF-specific diagnostic ELISAs detect antibodies directed against the conserved and immunodominant A domain of the E2 structural glycoprotein. We previously reported the production of a C-strain virus in which the immunodominant TAVSPTTLR epitope of the A domain is stably mutated with the aim to render the virus suitable as a DIVA vaccine. We here report that a single vaccination with this vaccine virus protected pigs from a lethal challenge dose of the highly virulent Brescia strain. Analysis of the sera, however, demonstrated that a commercially available E2 ELISA was unsuitable as an accompanying DIVA test.

Rift Valley fever virus immunity provided by a paramyxovirus vaccine vector.

Rift Valley fever virus (RVFV) causes recurrent large outbreaks among humans and livestock. Although the virus is currently confined to the African continent and the Arabian Peninsula, there is a growing concern for RVFV incursions into countries with immunologically naïve populations. The RVFV structural glycoproteins Gn and Gc are preferred targets in the development of subunit vaccines that can be used to control future outbreaks. We here report the production of Gn and Gc by a recombinant vaccine strain of the avian paramyxovirus Newcastle disease virus (NDV) and demonstrate that intramuscular vaccination with this experimental NDV-based vector vaccine provides complete protection in mice. We also demonstrate that a single intramuscular vaccination of lambs, the main target species of RVFV, is sufficient to elicit a neutralizing antibody response.

Rift Valley fever virus subunit vaccines confer complete protection against a lethal virus challenge.

Rift Valley fever virus (RVFV) is an emerging mosquito-borne virus causing significant morbidity and mortality in livestock and humans. Rift Valley fever is endemic in Africa, but also outside this continent outbreaks have been reported. Here we report the evaluation of two vaccine candidates based on the viral Gn and Gc envelope glycoproteins, both produced in a Drosophila insect cell expression system. Virus-like particles (VLPs) were generated by merely expressing the Gn and Gc glycoproteins. In addition, a soluble form of the Gn ectodomain was expressed and affinity-purified from the insect cell culture supernatant. Both vaccine candidates fully protected mice from a lethal challenge with RVFV. Importantly, absence of the nucleocapsid protein in either vaccine candidate facilitates the differentiation between infected and vaccinated animals using a commercial recombinant nucleocapsid protein-based indirect ELISA.

Intramuscular inoculation of calves with an experimental Newcastle disease virus-based vector vaccine elicits neutralizing antibodies against Rift Valley fever virus.

In the past decade, the use of Newcastle disease virus (NDV) as a vaccine vector for the prevention of economically important livestock diseases as well as for human diseases has been extensively explored. In this study, we have constructed a recombinant NDV vaccine virus, named NDFL-Gn, that produces the Rift Valley fever virus (RVFV) Gn glycoprotein. Calves were immunized via either the intranasal route or the intramuscular route. Delivery via the intranasal route elicited no detectable antibody responses, whereas delivery via the intramuscular route elicited antibodies against both NDV and the Gn protein. The RVFV-neutralizing activity of the antisera from intramuscularly vaccinated calves was demonstrated, suggesting that NDV is a promising vaccine vector for the prevention of RVF in calves.

Rational design of a classical swine fever C-strain vaccine virus that enables the differentiation between infected and vaccinated animals.

The C-strain of the classical swine fever virus (CSFV) is considered the gold standard vaccine for the control of CSF. This vaccine, however, does not enable the serological differentiation between infected and vaccinated animals (DIVA). Consequently, its use can impose severe trade restrictions. The immunodominant and evolutionarily conserved A-domain of the E2 structural glycoprotein is an important target in CSFV-specific ELISAs. With the ultimate aim to render the C-strain suitable as a DIVA vaccine, mutations were introduced that were expected to dampen the immunogenicity of the A-domain. In the first of two approaches, the feasibility of shielding the A-domain by N-linked glycans was evaluated, whereas in the second approach C-strain mutants were created with targeted deletions in the A-domain. Analysis of the antibody responses elicited in rabbits suggested that shielding of the A-domain by an N-linked glycan had a minor effect on the immune response against the A-domain, whereas a targeted deletion of only a single amino acid severely dampened this response. C-strain mutants with larger deletions were highly debilitated and incapable of sustained growth in vitro. By providing the viruses with the opportunity to increase their fitness by mutation, a mutant was rescued that found a way to compensate for the imposed fitness cost. Most of the identified mutations occurred in several independently evolved viruses, demonstrating parallel evolution. By virtue of this compensatory evolution, a well replicating and genetically stable C-strain mutant was produced that can be serologically differentiated from wildtype CSFV. The findings provide the molecular basis for the development of a novel, genetically stable, live attenuated CSF DIVA vaccine.