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The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04–0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Human T-cell leukemia virus type 2 (HTLV-2) is non-endemic in Japan unlike the related HTLV type 1. Previously, although HTLV-2-seropositivity was identified via western blotting in one male blood donor in Japan, there have been no reports of HTLV-2 provirus detection by nucleic acid testing. In this report, one Japanese pregnant woman was clinically diagnosed as being HTLV-2-infected with a line immunoassay for specific antibodies after primary testing through prenatal screening in Japan. In genomic DNA of her peripheral blood mononuclear cells, HTLV-2 proviral genome was detected by nucleic acid testing (three methods) with quantitative polymerase chain reaction. The full-genome sequence of this strain was successfully determined. The identified virus was interestingly characterized as a presumed progenitor of subtypes a and c by recombination region and phylogenetic tree analyses. In conclusion, the present infection is, to our knowledge, the first case of molecularly identified and genetically characterized HTLV-2 infection found via prenatal screening in non-endemic Japan.

In Japan, indigenous tick-borne phleboviruses (TBPVs) and their associated diseases first became evident in 2013 by reported human cases of severe fever with thrombocytopenia syndrome (SFTS). In this study, we report a novel member of the genus Phlebovirus designated as Kabuto Mountain virus (KAMV), which was isolated from the ixodid tick Haemaphysalis flava in Hyogo, Japan. A complete viral genome sequencing and phylogenetic analyses showed that KAMV is a novel member of TBPVs, which is closely related to the Uukuniemi and Kaisodi group viruses. However, unlike the Uukuniemi group viruses, the 165-nt intergenic region (IGR) in the KAMV S segment was highly C-rich in the genomic sense and not predicted to form a secondary structure, which are rather similar to those of the Kaisodi group viruses and most mosquito/sandfly-borne phleboviruses. Furthermore, the NSs protein of KAMV was highly divergent from those of other TBPVs. These results provided further insights into the genetic diversity and evolutionary relationships of TBPVs. KAMV could infect and replicate in some rodent and primate cell lines. We evaluated the infectivity and pathogenicity of KAMV in suckling mice, where we obtained a virulent strain after two passages via intracerebral inoculation. This is the first report showing the existence of a previously unrecognized TBPV in Japan, other than the SFTS virus.

The genus Thogotovirus, as represented by Thogoto virus and Dhori virus, comprises a group of arthropod-borne viruses, most members of which are transmitted by ticks. Here we report the genetic and biological characterization of a new thogotovirus, designated Oz virus (OZV), isolated from the hard tick Amblyomma testudinarium in Ehime, Japan. OZV efficiently replicated and induced a cytopathic effect in Vero cells, from which enveloped pleomorphic virus particles were formed by budding. OZV could also replicate in BHK-21 and DH82 cells and caused high mortality in suckling mice after intracerebral inoculation. Phylogenetic analyses of six viral proteins indicated that OZV is clustered with Dhori and related viruses, and is most closely related in glycoprotein (GP) and matrix protein (M) sequences to Bourbon virus, a human-pathogenic thogotovirus discovered recently in the United States. Our findings emphasize the need for understanding the geographic distribution and ecology of OZV and related viruses and for reevaluation of the medical and public health importance of thogotoviruses.

During the course of tick-borne virus surveillance in Japan, three independent isolates of probably the same virus were obtained from three geographically distant populations of the hard tick Haemaphysalis flava. Genome analyses of the three isolates demonstrated that they were closely related but distinct strains of a novel virus, designated Tarumizu tick virus (TarTV), which has a genome of 12 double-stranded RNA segments. The development of the virus-induced cytopathic effects on BHK cells significantly varied according to virus strains. Ten out of 12 segments of TarTV appeared to encode putative orthologs or functional equivalents of viral proteins of Colorado tick fever virus (CTFV) and Eyach virus, suggesting that TarTV is the third member of the genus Coltivirus in the family Reoviridae. This was supported by the facts that the 5'- and 3'-terminal consensus sequences of coltivirus genomes were found also in TarTV genome, and segment 9 of TarTV had sequence and structural features that may mediate a stop codon read-through as observed in that of CTFV. However, segment 7 and 10 of TarTV had no significant sequence similarities to any other proteins of known coltiviruses. Electron microscopic analysis demonstrated that TarTV particle had a non-enveloped bilayer icosahedral structure, and viral inclusion bodies were formed in infected cells. TarTV could infect and replicate in several mammalian cell lines tested, but show no clinical symptoms in intracerebrally inoculated mice. Taken together, our findings provide new insights into genetic diversity and evolution of the genus Coltivirus.

Middle East respiratory syndrome-coronavirus (MERS-CoV) is an emerging virus that causes severe disease with fatal outcomes; however, there are currently no approved vaccines or specific treatments against MERS-CoV. Here, we developed a novel bivalent vaccine against MERS-CoV and rabies virus (RV) using the replication-incompetent P-gene-deficient RV (RVΔP), which has been previously established as a promising and safe viral vector. MERS-CoV spike glycoprotein comprises S1 and S2 subunits, with the S1 subunit being a primary target of neutralizing antibodies. Recombinant RVΔP, which expresses S1 fused with transmembrane and cytoplasmic domains together with 14 amino acids from the ectodomains of the RV-glycoprotein (RV-G), was developed using a reverse genetics method and named RVΔP-MERS/S1. Following generation of RVΔP-MERS/S1 and RVΔP, our analysis revealed that they shared similar growth properties, with the expression of S1 in RVΔP-MERS/S1-infected cells confirmed by immunofluorescence and western blot, and the immunogenicity and pathogenicity evaluated using mouse infection experiments. We observed no rabies-associated signs or symptoms in mice inoculated with RVΔP-MERS/S1. Moreover, virus-specific neutralizing antibodies against both MERS-CoV and RV were induced in mice inoculated intraperitoneally with RVΔP-MERS/S1. These findings indicate that RVΔP-MERS/S1 is a promising and safe bivalent-vaccine candidate against both MERS-CoV and RV.

Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days.

Objective To evaluate the efficacy of double vaccination with the 2009 pandemic influenza A (H1N1) vaccine during pregnancy. Methods A study of the 2009 H1N1 vaccine was conducted in 128 pregnant women, who were between 8 and 32 weeks of gestation in October 2009, to monitor the immune response to vaccination and the change in antibody positivity rate and to assess the immune response. Furthermore, the study aimed to assess the changes in these parameters after the first and second vaccination, monitor the maintenance of antibody titers in maternal blood, assess antibody transfer to umbilical cord blood, and evaluate the vaccine. Results The antibody positivity rate increased from 7.2% before vaccination to 89.5% after the second vaccination. The vaccine was efficacious, producing a sufficient immune response in 90% of patients, regardless of the stage of gestation. The antibody titers were maintained until delivery, and were higher in umbilical cord blood at delivery than in maternal blood. Although the second vaccination increased the antibody titers in 27% of patients, and the antibody titers in maternal and umbilical cord blood at delivery tended to be higher in the double vaccination group than in the single, the differences were not statistically significant. Conclusion Single vaccination induces sufficient immune response and transfer of immunity to the fetus in pregnant women with no pre-existing antibodies. Level of evidence III.

Among the tick-borne orbiviruses (genus Orbivirus, family Reoviridae), 36 serotypes are currently classified within a single virus species, Great Island virus. In this study, we report the first characterization of a tick-borne orbivirus isolated from the tick Ixodes turdus in Japan, which we identified as a new member of the species Great Island virus. The virus isolate, designated Muko virus (MUV), replicated and induced cytopathic effects in BHK-21, Vero E6, and CCL-141 cells and caused high mortality in suckling mice after intracerebral inoculation. Full genome sequence analysis showed that MUV shared the greatest phylogenetic similarity with Tribec virus in terms of the amino acid sequences of all viral proteins except for outer capsid protein 1 (OC1; VP4 of MUV). Analysis of genome segment 9 in MUV detected an uninterrupted open reading frame that overlaps with VP6 (Hel), which putatively encodes a molecular and functional equivalent of NS4 from Great Island virus. Our study provides new insights into the geographic distribution, genetic diversity, and evolutionary history of the members of the species Great Island virus.

Increased morbidity and mortality in pregnant women were reported following three major historical influenza pandemics. To prevent influenza infection during pregnancy, the Centers for Disease Control (CDC) and the American College of Obstetricians and Gynecologists (ACOG) recommend that all pregnant women and those intending to get pregnant during the influenza season be vaccinated. In 2004, they advised expanding vaccination guidelines from the second and third trimester to all three trimesters. We evaluated the safety of influenza vaccination during pregnancy in 182 subjects from 2007-2009. No adverse events were seen in pregnancy or fetal medical condition regardless of the pregnancy stage at which vaccine was administered.

The etiology of inflammatory bowel disease is multifactorial and appears to combine both genetic and environmental factors. We experienced here a rare occurrence of woman monozygotic twins with ulcerative colitis (UC). A 45-year-old woman (the elder monozygotic twin) was admitted to our hospital because of bloody diarrhea occurring over 10 times per day, abdominal pain and fever. She was diagnosed as UC at the age of 22, and repeated the relapse and remission. She was diagnosed as relapse of UC and total colitis type. Her younger monozygotic twin sister also suffered from UC at the age of 22. Human leukocyte antigen was examined serologically with DNA type in both patients. DRB1*1502, which was previously shown to be dominant in Japanese patients with UC, was not observed in this case. Although the concordance in monozygotic twin in UC is reported to be 6.3-18.8%, the concordant case like this is relatively rare. We report this rare case of UC and the previously reported cases are also discussed.

Sjogren's syndrome can cause many organic changes, but is rarely accompanied by pleuritis. We report a 65-year-old patient with primary Sjogren's syndrome who developed bilateral pleuritis with moderately large effusions. He was diagnosed as having Sjogren's syndrome, based on xerophthalmia, xerostomia, positive results for anti-Sjogren's syndrome (anti-SS-A/SS-B) antibodies, the Schirmer test and biopsy findings in the minor salivary glands. The pleural fluid was lymphocyte rich and contained high levels of anti-SS-A/SS-B antibodies. There was no evidence of infection, malignancy or other collagen diseases which cause pleuritis. We conclude that this case adds to the eight previously published reports of primary Sjogren's syndrome complicated by pleural effusion.