Using Regular High-Quality Serosurveys to Identify and Close National Immunity Gaps-Measles and Rubella Elimination in Japan.

In Japan, periodic measles outbreaks occurred mainly among young children under the routine immunization program with one dose of the measles-containing vaccine (MCV). A second dose of MCV was introduced in 2006. During a nationwide measles resurgence in 2007-2008, the most affected age group was teenagers. The national serological surveillance for vaccine-preventable diseases made it clear that there was a measles immunity gap among teenagers who had not received a second dose of MCV. To fill this immunity gap, nationwide non-selective supplementary immunization activities (SIAs) were carried out as a five-year program from April 2008 to March 2013 by providing an opportunity to be vaccinated with the measles and rubella vaccine during the first year of junior high school (12-13 years old) and the last year of high school (17-18 years old). The SIA was conducted with the strong involvement of local governments in charge of vaccination delivery and collaboration between the health and education sectors. Japan was verified as achieving measles elimination in 2015 and this has been sustained to date. The challenge of rubella elimination following a similar strategy of a serological diagnosis of an immunity gap and targeted vaccination is also discussed.

The Role of Wild Boar as Host of Japanese Encephalitis Virus in the Absence of Domestic Pigs.

Pigs are the most common amplifying hosts of the Japanese encephalitis virus (JEV). In 2016, four residents on Tsushima Island who did not own pig farms were diagnosed with JE. Therefore, a serosurvey was conducted to estimate the risk and seroprevalence of JEV after the outbreak. Sera collected from 560 Tsushima Island residents between January and September 2017 were tested for neutralizing antibodies against JEV strains JaGAr01 (genotype 3) and Muar (genotype 5). Sera collected from six wild boars between June and July 2022 were tested. The seroprevalence rates of neutralizing antibodies against JaGAr01 and Muar were 38.8% and 24.6%, respectively. High anti-JEV neutralizing antibody titers of ≥320 were identified in 16 residents, including 3 younger than 6 years with prior JEV vaccination, 2 in their 40s, and 11 older than 70. However, no anti-JEV-specific IgM was detected. Residents who engaged in outdoor activities had higher anti-JEV antibody titers. Sera from wild boars were negative for JEV RNA, but four of six samples contained neutralizing antibodies against JEV. Therefore, JEV transmission continues on Tsushima Island, even in the absence of pig farms, and wild boars might serve as the amplifying hosts.

Fatal SARS-CoV-2 Infection among Children, Japan, January-September 20221.

To determine the characteristics of pediatric patients 0-19 years of age who died after onset of SARS-CoV-2 infection in Japan during January 1-September 30, 2022, we reviewed multiple sources. We identified 62 cases, collected detailed information from medical records and death certificates, and conducted interviews, resulting in 53 patients with detailed information for our study. Among 46 patients with internal causes of death (i.e., not external causes such as trauma), 15% were <1 year of age, 59% had no underlying disease, and 88% eligible for vaccination were unvaccinated. Nonrespiratory symptoms were more common than respiratory symptoms. Out-of-hospital cardiac arrest affected 46% of patients, and time from symptom onset to death was <7 days for 77%. Main suspected causes of death were central nervous system abnormalities (35%) and cardiac abnormalities (20%). We recommend careful follow-up of pediatric patients after SARS-CoV-2 infection during the first week after symptom onset, regardless of underlying diseases.

Adverse Event Following Immunization Monitoring System in Japan.

Although immunization is essential for maintaining public health, adverse events following immunization (AEFI) occur at a certain rate. Therefore, it is extremely important to conduct postimmunization safety monitoring and relief systems to ensure the safe implementation of immunizations for the public. This article summarizes the monitoring system of AEFI and the unique compensation system (so-called relief system) in Japan. In addition, current problems and issues on the AEFI monitoring and relief system will be specified, and immunization-related systems planned to be built in the future in Japan will be introduced.

Analysis of Suspected Measles Cases with Discrepant Measles-Specific IgM and rRT-PCR Test Results, Japan.

We investigated clinically suspected measles cases that had discrepant real-time reverse transcription PCR (rRT-PCR) and measles-specific IgM test results to determine diagnoses. We performed rRT-PCR and measles-specific IgM testing on samples from 541 suspected measles cases. Of the 24 IgM-positive and rRT-PCR--negative cases, 20 were among children who received a measles-containing vaccine within the previous 6 months; most had low IgG relative avidity indexes (RAIs). The other 4 cases were among adults who had an unknown previous measles history, unknown vaccination status, and high RAIs. We detected viral nucleic acid for viruses other than measles in 15 (62.5%) of the 24 cases with discrepant rRT-PCR and IgM test results. Measles vaccination, measles history, and contact history should be considered in suspected measles cases with discrepant rRT-PCR and IgM test results. If in doubt, measles IgG avidity and PCR testing for other febrile exanthematous viruses can help confirm or refute the diagnosis.

Enhanced measures, including PCR-based screening and syndromic surveillance for nosocomial outbreaks of the COVID-19 Omicron variant, using descriptive epidemiology and whole-genome sequencing in a Japanese tertiary care hospital.

INTRODUCTION: In this study, we aimed to analyze the effectiveness of enhanced preventive measures against nosocomial COVID-19 Omicron outbreaks based on those encountered. METHODS: We introduced PCR-based screening and syndromic surveillance, in addition to standard and transmission-based precautions, during a COVID-19 outbreak in three wards of Kagoshima University Hospital, a Japanese tertiary care hospital, in February 2022, amid the Omicron variant endemic. Furthermore, we analyzed the descriptive epidemiology and whole-genome sequencing (WGS) of positive SARS-CoV-2 PCR samples from this outbreak. RESULTS: PCR-based screening tests were conducted following the identification of three cases through syndromic surveillance. As a result, 30 individuals tested positive for SARS-CoV-2, including 13 inpatients, five attendant family members, and 12 healthcare workers across the three wards. Notably, no new infections were observed within eight days following the implementation of preventive measures. Among the SARS-CoV-2 genomes analyzed (n = 16; 53.3%), all strains were identified as belonged to BA.1.1 variant. Detailed analysis of descriptive and molecular epidemiology, incorporating single-nucleotide polymorphism analysis of WGS and clarification of transmission links, considering two potential entry routes to the hospital. CONCLUSIONS: Introduction of additional preventive measures, including PCR-based screening and syndromic surveillance, in addition to WGS and descriptive epidemiology, is useful for the early intervention of nosocomial outbreaks and for revealing the transmission route of the COVID-19 Omicron variant.

Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer.

BACKGROUND: Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms. METHODS: From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1). RESULTS: Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice. CONCLUSIONS: Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.

SARS-CoV-2 Infection in Wrestlers after International Tournaments, April 2021.

Epidemiologic and genomic investigation of SARS-CoV-2 infections in members of Japan's national wrestling team after participation in international tournaments in 2021 revealed multiple lineages of SARS-CoV-2 not reported in Japan. The attack rate among wrestlers was high. Results suggest possible transmission during matches. We recommend early case detection and response practices.

Differences of clinical features and outcomes between male and female elderly patients in gastric cancer.

Although the average life span differs between males and females, little is known about differences in clinical features and short and long-term outcomes between elderly male and female gastric cancer patients. This study was designed to clarify these issues to identify the possibility for sex-based treatment strategies in elderly gastric cancer patients. This study included 295 consecutive elderly gastric cancer patients (75 years or older) who underwent curative gastrectomy between 1997 and 2016. We defined postoperative complications as Clavien-Dindo classification grade II or higher. Comorbidities were present in 67% of all patients. Males tended to have more comorbidities than females (P = 0.077). Male patients had significantly more upper gastric cancers (P = 0.001), a higher incidence of postoperative complications (P = 0.045), and poorer prognoses than females (P = 0.003). Multivariate analysis revealed that being male was an independent risk factor for postoperative complications (Odds ratio 2.5, P = 0.045) and a poor prognostic factor (Hazard ratio 1.81, P = 0.008). Patients who underwent limited surgery without postoperative complications tended to have a better prognosis than patients receiving standard surgery with postoperative complications (3-year overall survival: 78% vs. 55%, P = 0.156). Male was an independent risk factor for postoperative complications and an independent poor prognostic factor in elderly gastric cancer patients. To avoid postoperative complications, the limited surgery might be justified for high-risk elderly male patients.

Emergence of ciprofloxacin- and penicillin-resistant Neisseria meningitidis isolates in Japan between 2003 and 2020 and its genetic features.

Although we previously reported that some meningococcal isolates in Japan were resistant to penicillin (PCG) and ciprofloxacin (CIP), the antibiotic susceptibilities of Neisseria meningitidis isolates obtained in Japan remained unclear. In the present study, 290 N. meningitidis isolates in Japan between 2003 and 2020 were examined for the sensitivities to eight antibiotics (azithromycin, ceftriaxone, ciprofloxacin, chloramphenicol, meropenem, minocycline, penicillin, and rifampicin). All isolates were susceptible to chloramphenicol, ceftriaxone, meropenem, minocycline, and rifampicin while two were resistant to azithromycin. Penicillin- and ciprofloxacin-resistant and -intermediate isolates (PCGR, CIPR, PCGI and CIPI, respectively) were also identified. Based on our previous findings from whole genome sequence analysis, approximately 40% of PCGI were associated with ST-11026 and cc2057 meningococci, both of which were unique to Japan. Moreover, the majority of ST-11026 meningococci were CIPR or CIPI. Sensitivities to PCG and CIP were closely associated with genetic features, which indicated that, at least for Japanese meningococcal isolates, PCGR/I or CIPI/R would be less likely to be horizontally conferred from other neisserial genomes by transferring of the genes responsible (penA and gyrA genes, respectively), but rather that ancestral N. meningitidis strains conferring PCGR/I or CIPI/R phenotypes clonally disseminated in Japan.

Full genome-based characterization of an Asian G3P[6] human rotavirus strain found in a diarrheic child in Japan: Evidence for porcine-to-human zoonotic transmission.

Human rotavirus strains having the unconventional G3P[6] genotype have been sporadically detected in diarrheic patients in different parts of the world. However, the full genomes of only three human G3P[6] strains from Asian countries (China, Indonesia, and Vietnam) have been sequenced and characterized, and thus the exact origin and evolution of G3P[6] strains in Asia remain to be elucidated. Here, we sequenced and characterized the full genome of a G3P[6] strain (RVA/Human-wt/JPN/SO1199/2020/G3P[6]) found in a stool sample from a 3-month-old infant admitted with acute gastroenteritis in Japan. On full genomic analysis, strain SO1199 was revealed to have a unique Wa-like genogroup configuration: G3-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1. VP6 genotype I5 and NSP1 genotype A8 are commonly found in porcine rotavirus strains. Furthermore, phylogenetic analysis demonstrated that all 11 genes of strain SO1199 were closely related to those of porcine and/or porcine-like human rotaviruses and thus appeared to be of porcine origin. Thus, strain SO1199 was shown to possess a porcine-like genomic backbone and thus is likely to be the result of interspecies transmission of a porcine rotavirus strain. Of note is that all 11 genes of strain SO1199 were phylogenetically located in clusters, distinct from those of the previously identified porcine-like human G3P[6] strains from around the world including Asia, suggesting the occurrence of independent porcine-to-human zoonotic transmission events. To our knowledge, this is the first report on full genome-based characterization of a human G3P[6] strain that has emerged in Japan. Our findings revealed the diversity of unconventional human G3P[6] strains in Asia, and provide important insights into the origin and evolution of G3P[6] strains.

Mumps vaccine hesitancy: Current evidence and an evidence-based campaign in Japan.

BACKGROUND: Mumps is still endemic in Japan because mumps vaccination is voluntary. In this study, we investigated associations of parental socioeconomic status, family structure, and knowledge/belief about mumps and mumps vaccine with parental decision to vaccinate their children. We also evaluated effectiveness of a campaign based on survey results. METHODS: We conducted a cross-sectional survey of parents with children aged 1-6 years attending preschools or kindergartens in Tokamachi City, Japan. We assessed the association of parental factors with their decision to vaccinate their children using multivariable logistic regression analyses. We designed a campaign based on the survey results, and compared the number of annual vaccinations at Tokamachi Hospital per the child population aged 1-6 years in Tokamachi City before and after the campaign using a trend test. RESULTS: In total, 1391 of 1617 (86%) eligible parents completed the survey. Among these parents, 229 (16%) vaccinated their children. In multivariable analyses, higher parental education [odds ratio (OR) = 2.21; 95% CI, 1.59-3.08; P < 0.001], greater knowledge about mumps and the mumps vaccine (OR = 1.88; 95% CI, 1.60-2.21; P < 0.001), and living without grandparents (OR = 1.44; 95% CI, 1.05-1.99; P = 0.024) were significantly associated with parental decision to vaccinate their children. The number of annual vaccinations per the child population significantly increased following the campaign (P < 0.001). CONCLUSION: Our study showed several sociodemographic factors significantly associated with mumps vaccination. Further research is needed to examine the relevance of our findings to the uptake of other voluntary vaccines among children.

Obesity paradox as a new insight from postoperative complications in gastric cancer.

The obesity paradox is reported to exist in various diseases. However, obesity is a pivotal issue in gastric cancer (GC) patients because of the surgical difficulty related to postoperative abdominal infectious complications (PAIC). This study clarified the existence of the obesity paradox in GC. Between 1997 and 2015, 1536 consecutive patients underwent curative gastrectomy. Of all patients, 18.6% (285/1536) were obese and tended to have a better prognosis (P = 0.073). In patients without PAIC, obesity was a significant prognostic factor for 5-year overall survival (P = 0.017). PAIC was an independent poor prognostic factor in both obese and non-obese patients (P < 0.001; hazard ratio [HR] 4.22 and 1.82). In pStage II-III patients, there was a large and significant prognostic difference between non-PAIC and PAIC obese patients (P = 0.006; 5-year overall survival: 69.7% vs. 43.8%) related to the higher incidence of peritoneal recurrence in PAIC obese patients (P = 0.035; 31% vs. 10%). Whereas, there was a small prognostic difference between non-PAIC and PAIC non-obese patients (P = 0.102; 5-year overall survival: 56.5% vs. 51.9%). Although the obesity paradox is present in GC, PAIC had a more negative prognostic impact through peritoneal recurrence in obese GC patients.

Plasma miR-1254 as a predictive biomarker of chemosensitivity and a target of nucleic acid therapy in esophageal cancer.

This study investigated novel tumor suppressor microRNAs (miRNAs) that decrease in plasma and predict chemosensitivity to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC) and revealed their usefulness as novel therapeutic agents. We selected four miRNA candidates (miR-323, 345, 409, and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to NAC and an NCBI database review. Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P = 0.0021, area under the receiver-operating characteristic curve 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P = 0.0710) and were an independent factor predicting a higher response to chemotherapy (P = 0.0022, odds ratio 7.86) and better prognosis (P = 0.0235, hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to cisplatin in mice. Plasma miR-1254 might be a useful biomarker for predicting responses to NAC, and the restoration of plasma miR-1254 levels might improve chemosensitivity in ESCC.

Phylogeny of Shrew- and Mole-Borne Hantaviruses in Poland and Ukraine.

Earlier, we demonstrated the co-circulation of genetically distinct non-rodent-borne hantaviruses, including Boginia virus (BOGV) in the Eurasian water shrew (Neomys fodiens), Seewis virus (SWSV) in the Eurasian common shrew (Sorex araneus) and Nova virus (NVAV) in the European mole (Talpa europaea), in central Poland. To further investigate the phylogeny of hantaviruses harbored by soricid and talpid reservoir hosts, we analyzed RNAlater®-preserved lung tissues from 320 shrews and 26 moles, both captured during 1990-2017 across Poland, and 10 European moles from Ukraine for hantavirus RNA through RT-PCR and DNA sequencing. SWSV and Altai virus (ALTV) were detected in Sorex araneus and Sorex minutus in Boginia and the Bialowieza Forest, respectively, and NVAV was detected in Talpa europaea in Huta Dlutowska, Poland, and in Lviv, Ukraine. Phylogenetic analyses using maximum-likelihood and Bayesian methods showed geography-specific lineages of SWSV in Poland and elsewhere in Eurasia and of NVAV in Poland and Ukraine. The ATLV strain in Sorex minutus from the Bialowieza Forest on the Polish-Belarusian border was distantly related to the ATLV strain previously reported in Sorex minutus from Chmiel in southeastern Poland. Overall, the gene phylogenies found support long-standing host-specific adaptation.

Evaluating prognostic value and stage migration effects using a positive lymph node ratio in adenocarcinoma of the esophagogastric junction.

BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide. Lymph node metastasis is an important clinical issue in AEG patients. This study investigated the usefulness of a positive lymph node ratio (PLNR) to stratify prognosis and evaluate stage migration. METHODS: We retrospectively analysed 117 consecutive AEG patients (Siewert type I or II) who received a lymphadenectomy between 2000 and 2016. RESULTS: A PLNR cut-off value of 0.1 most effectively stratified patient prognosis into two groups (P < 0.001). Also, prognosis could be clearly stratified into four groups: PLNR = 0, 0 < PLNR < 0.1, 0.1 ≤ PLNR < 0.2, and 0.2 ≤ PLNR (P < 0.001, 5-year survival rates (88.6%, 61.1%, 34.3%, 10.7%)). A PLNR ≥ 0.1 significantly correlated with tumour diameter ≥ 4 cm (P < 0.001), tumour depth (P < 0.001), greater pathological N-status (P < 0.001), greater pathological Stage (P < 0.001), and oesophageal invasion length ≥ 2 cm (P = 0.002). A PLNR ≥ 0.1 was a poor independent prognostic factor (hazard ratio 6.47, P < 0.001). The PLNR could stratify prognosis if at least 11 lymph nodes were retrieved. A 0.2 PLNR cut-off value discriminated a stage migration effect in pN3 and pStage IV (P = 0.041, P = 0.015) patients; PLNR ≥ 0.2 might potentially diagnose a worse prognosis and need meticulous follow-up post-surgery. CONCLUSION: Using PLNR, we can evaluate the prognosis and detect higher malignant cases who need meticulous treatments and follow-up in the same pStage.

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

BACKGROUND: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. METHODS: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. RESULTS: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). CONCLUSIONS: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

An Introduction to the Japanese Immunization Program: Past, Present, and Future Perspectives.

In Japan, immunization is regulated by the Immunization Law, enacted shortly after World War II ended. It has been subsequently revised in response to social changes; however, after public health conditions improved, adverse events following immunization have received more public attention than the effectiveness of vaccination. This kind of public opinion had a major impact on the immunization program, leading to a so-called "vaccine gap" around a decade ago, that is, the less availability of vaccines for routine vaccination as compared with other countries. However, in recent years, several vaccines have been approved and are being routinely administered with the same schedule as in other countries. National immunization programs are influenced by various factors, such as cultures, customs, habits and ideas. This paper summarizes the status of immunization schedule and practices in Japan, process of policymaking, and possible future issues.

Genomic characterization of Japanese meningococcal strains isolated over a 17-year period between 2003 and 2020 in Japan.

While invasive meningococcal disease (IMD) is a major public concern worldwide, IMD is categorized as a rare infectious disease in Japan and, thus, its causative agents and epidemiology have not yet been characterized in detail. In the present study, we used molecular methods to epidemiologically characterize 291 meningococcal strains isolated in Japan over a 17-year period between 2003 and 2020 by whole genome sequencing (WGS). Serogroup Y meningococci (MenY) were the most abundant, followed by B (MenB) and then C and W among meningococci from IMD patients, while non-groupable as well as MenY and MenB were the most abundant among isolates from healthy carriers. Sequence type (ST) defined by multilocus sequence typing (MLST) showed that ST-1655 and ST-23 belonging to clonal complex (cc) 23 were dominant among Japanese IMD isolates, while ST-11026 (cc32) unique to Japan as well as ST-23 were dominant among Japanese non-IMD isolates. Phylogenetic analyses of ST by MLST revealed that Japanese isolates were classified with 12 ccs, including recently reported cc2057. Phylogenic analyses by WGS showed that isolates of ST-11026 and of ST-1655 were genetically close, whereas ST-23 isolates appeared to be diverse. Moreover, comparisons with other cc11 isolates isolated worldwide indicated that some Japanese cc11 isolates were genetically close to those isolated in Europe and China. An in silico analysis suggested that 14.3 and 44.2% of Japanese MenB were cross-reactive with 4CMenB and rLP2086 MenB vaccines, respectively. The results in the present study revealed that some epidemiological features were unique to Japan.