Exploring the genetic diversity of the Japanese population: Insights from a large-scale whole genome sequencing analysis.

The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.

Risk for Prison-to-Community Tuberculosis Transmission, Thailand, 2017-2020.

To determine contributions of previously incarcerated persons to tuberculosis (TB) transmission in the community, we performed a healthcare facility-based cohort study of TB patients in Thailand during 2017-2020. We used whole-genome sequencing of Mycobacterium tuberculosis isolates from patients to identify genotypic clusters and assess the association between previous incarceration and TB transmission in the community. We identified 4 large genotype clusters (>10 TB patients/cluster); 28% (14/50) of the patients in those clusters were formerly incarcerated. Formerly incarcerated TB patients were more likely than nonincarcerated patients to be included in large clusters. TB patients within the large genotype clusters were geographically dispersed throughout Chiang Rai Province. Community TB transmission in the community was associated with the presence of formerly incarcerated individuals in Thailand. To reduce the risk for prison-to-community transmission, we recommend TB screening at the time of entry and exit from prisons and follow-up screening in the community.

SARS-CoV-2 Variants and Age-Dependent Infection Rates among Household and Nonhousehold Contacts.

To determine the effects of age and variants of concern on transmission of SARS-CoV-2, we analyzed infection rates among close contacts over 4 periods in Toyama Prefecture, Japan. Among household contacts, odds of infection were 6.2 times higher during the period of the Omicron variant than during previous periods, particularly among children and adolescents.

Familial Clusters of Coronavirus Disease in 10 Prefectures, Japan, February-May 2020.

The overall coronavirus disease secondary attack rate (SAR) in family members was 19.0% in 10 prefectures of Japan during February 22-May 31, 2020. The SAR was lower for primary cases diagnosed early, within 2 days after symptom onset. The SAR of asymptomatic primary cases was 11.8%.

Clusters of Coronavirus Disease in Communities, Japan, January-April 2020.

We analyzed 3,184 cases of coronavirus disease in Japan and identified 61 case-clusters in healthcare and other care facilities, restaurants and bars, workplaces, and music events. We also identified 22 probable primary case-patients for the clusters; most were 20-39 years of age and presymptomatic or asymptomatic at virus transmission.

Predicting the risk of pulmonary tuberculosis based on the neutrophil-to-lymphocyte ratio at TB screening in HIV-infected individuals.

BACKGROUND: The neutrophil to lymphocyte ratio (NL ratio) has been reported to be a predictive biomarker of tuberculosis (TB). We assessed the association between the NL ratio and the incidence of active TB cases within 1 year after TB screening among HIV-infected individuals in Thailand. METHODS: A day care center that supports HIV-infected individuals in northernmost Thailand performed TB screening and follow-up visits. We compared the baseline characteristics between the TB screening positive group and the TB screening negative group. The threshold value of NL ratio was determined by cubic-spline curves and NL ratios were categorized as high or low NL ratio. We assessed the association between NL ratio and progression to active TB within 1-year using the Cox-proportional hazard model. RESULTS: Of the 1064 HIV-infected individuals who screened negative for TB at baseline, 5.6% (N = 60) eventually developed TB and 26 died after TB diagnosis. A high NL ratio was associated with a higher risk of TB (adjusted hazard ratio (aHR) 2.19, 95% CI: 1.23-3.90), after adjusting for age, sex, ethnicity, CD4 counts, and other risk factors. A high NL ratio in HIV-infected individuals with normal chest X-ray predicted TB development risk. In particular, a high NL ratio with TB symptoms could predict the highest risk of TB development (aHR 2.58, 95%CI: 1.07-6.23). CONCLUSIONS: Our results showed that high NL ratio increased the risk of TB. NL ratio combined with TB symptoms could increase the accuracy of TB screening among HIV-infected individuals.

The large contribution of twins to neonatal and post-neonatal mortality in The Gambia, a 5-year prospective study.

BACKGROUND: A high twinning rate and an increased risk of mortality among twins contribute to the high burden of infant mortality in Africa. This study examined the contribution of twins to neonatal and post-neonatal mortality in The Gambia, and evaluated factors that contribute to the excess mortality among twins. METHODS: We analysed data from the Basse Health and Demographic Surveillance System (BHDSS) collected from January 2009 to December 2013. Demographic and epidemiological variables were assessed for their association with mortality in different age groups. RESULTS: We included 32,436 singletons and 1083 twins in the analysis (twining rate 16.7/1000 deliveries). Twins represented 11.8 % of all neonatal deaths and 7.8 % of post-neonatal deaths. Mortality among twins was higher than in singletons [adjusted odds ratio (AOR) 4.33 (95 % CI: 3.09, 6.06) in the neonatal period and 2.61 (95 % CI: 1.85, 3.68) in the post-neonatal period]. Post-neonatal mortality among twins increased in girls (P for interaction = 0.064), being born during the dry season (P for interaction = 0.030) and lacking access to clean water (P for interaction = 0.042). CONCLUSION: Mortality among twins makes a significant contribution to the high burden of neonatal and post-neonatal mortality in The Gambia and preventive interventions targeting twins should be prioritized.

Protection of the third-dose and fourth-dose mRNA vaccines against SARS-CoV-2 Omicron subvariant: a systematic review and meta-analysis.

OBJECTIVES: The rapid spread of the SARS-CoV-2 Omicron variant has raised concerns regarding waning vaccine-induced immunity and durability. We evaluated protection of the third-dose and fourth-dose mRNA vaccines against SARS-CoV-2 Omicron subvariant and its sublineages. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases and other resources (PubMed, Embase, CENTRAL, MEDLINE, CINAHL PLUS, APA PsycINFO, Web of Science, Scopus, ScienceDirect, MedRxiv and bioRxiv) were searched until December 2022. STUDY ELIGIBILITY CRITERIA: We included studies that assessed the effectiveness of mRNA vaccine booster doses against SARS-CoV-2 infection and severe COVID-19 outcomes caused by the subvariant. DATA EXTRACTION AND SYNTHESIS: Estimates of vaccine effectiveness (VE) at different time points after the third-dose and fourth-dose vaccination were extracted. Random-effects meta-analysis was used to compare VE of the third dose versus the primary series, no vaccination and the fourth dose at different time points. The certainty of the evidence was assessed by Grading of Recommendations, Assessments, Development and Evaluation approach. RESULTS: This review included 50 studies. The third-dose VE, compared with the primary series, against SARS-CoV-2 infection was 48.86% (95% CI 44.90% to 52.82%, low certainty) at ≥14 days, and gradually decreased to 38.01% (95% CI 13.90% to 62.13%, very low certainty) at ≥90 days after the third-dose vaccination. The fourth-dose VE peaked at 14-30 days (56.70% (95% CI 50.36% to 63.04%), moderate certainty), then quickly declined at 61-90 days (22% (95% CI 6.40% to 37.60%), low certainty). Compared with no vaccination, the third-dose VE was 75.84% (95% CI 40.56% to 111.12%, low certainty) against BA.1 infection, and 70.41% (95% CI 49.94% to 90.88%, low certainty) against BA.2 infection at ≥7 days after the third-dose vaccination. The third-dose VE against hospitalisation remained stable over time and maintained 79.30% (95% CI 58.65% to 99.94%, moderate certainty) at 91-120 days. The fourth-dose VE up to 60 days was 67.54% (95% CI 59.76% to 75.33%, moderate certainty) for hospitalisation and 77.88% (95% CI 72.55% to 83.21%, moderate certainty) for death. CONCLUSION: The boosters provided substantial protection against severe COVID-19 outcomes for at least 6 months, although the duration of protection remains uncertain, suggesting the need for a booster dose within 6 months of the third-dose or fourth-dose vaccination. However, the certainty of evidence in our VE estimates varied from very low to moderate, indicating significant heterogeneity among studies that should be considered when interpreting the findings for public health policies. PROSPERO REGISTRATION NUMBER: CRD42023376698.

Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease.

The genetics underlying tuberculosis (TB) pathophysiology are poorly understood. Human genome-wide association studies have failed so far to reveal reproducible susceptibility loci, attributed in part to the influence of the underlying Mycobacterium tuberculosis (Mtb) bacterial genotype on the outcome of the infection. Several studies have found associations of human genetic polymorphisms with Mtb phylo-lineages, but studies analysing genome-genome interactions are needed. By implementing a phylogenetic tree-based Mtb-to-human analysis for 714 TB patients from Thailand, we identify eight putative genetic interaction points (P < 5 × 10-8) including human loci DAP and RIMS3, both linked to the IFNγ cytokine and host immune system, as well as FSTL5, previously associated with susceptibility to TB. Many of the corresponding Mtb markers are lineage specific. The genome-to-genome analysis reveals a complex interactome picture, supports host-pathogen adaptation and co-evolution in TB, and has potential applications to large-scale studies across many TB endemic populations matched for host-pathogen genomic diversity.

Characteristics and Treatment Outcomes among Migrants with Pulmonary Tuberculosis: A Retrospective Cohort Study in Japan, 2009-2018.

This study aimed to describe characteristics and treatment outcomes of overseas-born pulmonary tuberculosis (PTB) patients in Japan, and identify the factors associated with "treatment non-success". We conducted a retrospective analysis of overseas-born patients with drug-susceptible PTB using cohort data of PTB cases newly registered in the Japan tuberculosis (TB) surveillance system between 2009 and 2018. Overall, 9151 overseas-born PTB cases were included in this study, and 70.3% were aged 34 years old or younger. "Students of high school and higher" (28.6%) and "regular workers other than service related sectors" (28.5%) accounted for over half of the study population, and they have continued to increase. Overall, the treatment success rate was 67.1%. Transferred-out constituted the largest proportion (14.8%) among the treatment non-success rate (32.9%). Multiple logistic regression analysis revealed patients whose health insurance type was "others and unknown", including the uninsured (adjusted OR (AOR) = 3.43: 95% Confidence Intervals (CI) 2.57-4.58), those diagnosed as TB within "one year" (AOR = 2.61, 95% CI 1.97-3.46) and "1-5 years" (AOR = 2.44, 95% CI 1.88-3.17) of arrival in Japan, and males (AOR = 1.34, 95% CI 1.16-1.54), which were the main factors associated with treatment non-success. These findings imply that Japan needs to develop TB control activities considering the increasing trends of overseas-born PTB patients, the majority of whom are young and highly mobile. There is a need to pay greater attention to overseas-born PTB patients diagnosed within a short duration after entering Japan, who may be socially and economically disadvantaged for their treatment completion.

Secondary transmission of SARS-CoV-2 during the first two waves in Japan: Demographic characteristics and overdispersion.

OBJECTIVES: Super-spreading events caused by overdispersed secondary transmission are crucial in the transmission of COVID-19. However, the exact level of overdispersion, demographics, and other factors associated with secondary transmission remain elusive. In this study, we aimed to elucidate the frequency and patterns of secondary transmission of SARS-CoV-2 in Japan. METHODS: We analyzed 16,471 cases between January 2020 and August 2020. We generated the number of secondary cases distribution and estimated the dispersion parameter (k) by fitting the negative binomial distribution in each phase. The frequencies of the secondary transmission were compared by demographic and clinical characteristics, calculating the odds ratio using logistic regression models. RESULTS: We observed that 76.7% of the primary cases did not generate secondary cases with an estimated dispersion parameter k of 0.23. The demographic patterns of primary-secondary cases differed between phases, with 20-69 years being the predominant age group. There were higher proportions of secondary transmissions among older individuals, symptomatic patients, and patients with 2 days or more between onset and confirmation. CONCLUSIONS: The study showed the estimation of the frequency of secondary transmission of SARS-CoV-2 and the characteristics of people who generated the secondary transmission.

Epidemiological Factors Associated with COVID-19 Clusters in Medical and Social Welfare Facilities.

The characteristics of coronavirus disease 2019 (COVID-19) clusters in medical and social welfare facilities and the factors associated with cluster size are still not yet fully understood. We reviewed COVID-19 cases in Japan identified from January 15 to April 30, 2020 and analyzed the factors associated with cluster size in medical and social welfare facilities. In this study, COVID-19 clusters were identified in 56 medical and 34 social welfare facilities. The number of cases in those facilities peaked after the peak of the general population. The duration of occurrence of new cases in clusters was positively correlated with the number of cases in both types of facilities (rho = 0.44, P < 0.001; and rho = 0.69, P < 0.001, respectively). However, the number of days between the first case in a prefecture and the onset of clusters was negatively correlated with the number of cases only in clusters in social welfare facilities (rho = - 0.4, P = 0.004). Our results suggest that COVID-19 cases in those facilities were prevalent in the latter phase of the disease's community transmission, although the underlying mechanisms for such a trend could differ between medical and social welfare facilities.

Integration of publicly available case-based data for real-time coronavirus disease 2019 risk assessment, Japan.

In response to the outbreak of coronavirus disease 2019 (COVID-19) in Japan, a national COVID-19 cluster taskforce (comprising governmental and nongovernmental experts) was established to support the country's Ministry of Health, Labour and Welfare in conducting daily risk assessment. The assessment was carried out using established infectious disease surveillance systems; however, in the initial stages of the pandemic these were not sufficient for real-time risk assessment owing to limited accessibility, delay in data entry and inadequate case information. Also, local governments were publishing anonymized data on confirmed COVID-19 cases on their official web sites as daily press releases. We developed a unique database for nationwide real-time risk assessment that included these case lists from local government web sites and integrated all case data into a standardized format. The database was updated daily and checked systematically to ensure comprehensiveness and quality. Between 15 January 2020 and 15 June 2021, 776 459 cases were logged in the database, allowing for analysis of real-time risk from the pandemic. This semi-automated database was used in daily risk assessments, and to evaluate and update control measures to prevent community transmission of COVID-19 in Japan. The data were reported almost every week to the Japanese Government Advisory Panel on COVID-19 for public health responses.

Behavioral factors associated with SARS-CoV-2 infection in Japan.

BACKGROUND: The relative burden of COVID-19 has been less severe in Japan. One reason for this may be the uniquely strict restrictions imposed upon bars/restaurants. To assess if this approach was appropriately targeting high-risk individuals, we examined behavioral factors associated with SARS-CoV-2 infection in the community. METHODS: This multicenter case-control study involved individuals receiving SARS-CoV-2 testing in June-August 2021. Behavioral exposures in the past 2 weeks were collected via questionnaire. SARS-CoV-2 PCR-positive individuals were cases, while PCR-negative individuals were controls. RESULTS: The analysis included 778 individuals (266 [34.2%] positives; median age [interquartile range] 33 [27-43] years). Attending three or more social gatherings was associated with SARS-CoV-2 infection (adjusted odds ratio [aOR] 2.00 [95% CI 1.31-3.05]). Attending gatherings with alcohol (aOR 2.29 [1.53-3.42]), at bars/restaurants (aOR 1.55 [1.04-2.30]), outdoors/at parks (aOR 2.87 [1.01-8.13]), at night (aOR 2.07 [1.40-3.04]), five or more people (aOR 1.81 [1.00-3.30]), 2 hours or longer (aOR 1.76 [1.14-2.71]), not wearing a mask during gatherings (aOR 4.18 [2.29-7.64]), and cloth mask use (aOR 1.77 [1.11-2.83]) were associated with infection. Going to karaoke (aOR 2.53 [1.25-5.09]) and to a gym (aOR 1.87 [1.11-3.16]) were also associated with infection. Factors not associated with infection included visiting a cafe with others, ordering takeout, using food delivery services, eating out by oneself, and work/school/travel-related exposures including teleworking. CONCLUSIONS: We identified multiple behavioral factors associated with SARS-CoV-2 infection, many of which were in line with the policy/risk communication implemented in Japan. Rapid assessment of risk factors can inform decision making.

Epidemiology of Coronavirus Disease 2019 in Japan: Descriptive Findings and Lessons Learned through Surveillance during the First Three Waves.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has caused unprecedented global morbidity and mortality. Japan has faced three epidemic "waves" of COVID-19 from early 2020 through early 2021. Here we narratively review the three waves in Japan, describe the key epidemiologic features of COVID-19, and discuss lessons learned. METHODS: We assessed publicly available surveillance data, routine surveillance reports, and other relevant sources-multiple indicators were monitored to improve interpretation of surveillance data. Weekly trends for each wave were described based on the number of case notifications; number of tests performed; proportion of those tests that were positive for the novel coronavirus; the prevalent number of COVID-19 hospitalizations (total hospitalizations and those categorized as severe); and number of COVID-19 deaths. For each indicator and wave, we recorded the first calendar week to show an increase over two consecutive previous weeks, along with the peak week. RESULTS: The spring wave was characterized by detection of cases imported from China, followed by notifications of sporadic cases without travel history, clusters, and mild/asymptomatic cases. The summer wave saw a large increase in notifications and a younger age distribution, but in the context of increased testing with lower test positivity. The winter wave brought considerable morbidity and mortality, surpassing the cumulative case counts and fatalities from the earlier waves, with high peak values. Overall, relative to the first wave, the burden of severe outcomes was lower in the second and higher in the third wave, but varied by prefecture. In all three waves, severe outcomes peaked after notification counts and test positivity peaked; severe outcomes were also consistently skewed toward the elderly. CONCLUSIONS: Important lessons were learned from each wave and across waves-some aspects remained constant, while others changed over time. In order to rapidly detect an increase in incidence, continuous, timely, and sensitive surveillance-using multiple information sources with careful interpretations-will be key in COVID-19 control.

Stillbirths, Neonatal Morbidity, and Mortality in Health-Facility Deliveries in Urban Gambia.

Background: The Gambia Demographic and Health Survey 2013 data showed that up to 63% of deliveries in the country occur in health facilities. Despite such a high rate, there are few facility-based studies on delivery outcomes in the country. This analysis ancillary to a randomized control trial describes occurrence of poor pregnancy outcomes in a cohort of women and their infants delivering in a government health facility in urban Gambia. Methods: Using clinical information obtained during the trial, we calculated rates of poor pregnancy outcomes including stillbirths, hospitalization and neonatal deaths. Logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) in the risk factors analysis. Results: Between April 2013 and 2014, 829 mothers delivered 843 babies, including 13 stillbirths [15.4 (7.1-23.8)] per 1,000 births. Among 830 live born infants, 7.6% (n = 63) required hospitalization during the 8-week follow-up period. Most of these hospitalizations (74.6%) occurred during the early neonatal period (<7 days of life). Severe clinical infections (i.e., sepsis, meningitis and pneumonia) (n = 27) were the most common diagnoses, followed by birth asphyxia (n = 13), major congenital malformations (n = 10), jaundice (n = 6) and low birth weight (n = 5). There were sixteen neonatal deaths, most of which also occurred during the early neonatal period. Overall, neonatal mortality rate (NMR) and perinatal mortality rate (PMR) were 19.3 (CI: 9.9-28.7) per 1,000 live births and 26.1 (CI: 15.3-36.9) per 1,000 total births, respectively. Severe clinical infections and birth asphyxia accounted for 37 and 31% of neonatal deaths, respectively. The risk of hospitalization was higher among neonates with severe congenital malformations, low birth weight, twin deliveries, and those born by cesarean section. Risk of mortality was higher among neonates with severe congenital malformations and twin deliveries. Conclusion: Neonatal hospitalization and deaths in our cohort were high. Although vertical interventions may reduce specific causes of morbidity and mortality, data indicate the need for a holistic approach to significantly improve the rates of poor pregnancy outcomes. Critically, a focus on decreasing the high rate of stillbirths is warranted. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01800942.

Roles of Children and Adolescents in COVID-19 Transmission in the Community: A Retrospective Analysis of Nationwide Data in Japan.

Background: Roles of children and adolescents in spreading coronavirus disease 2019 (COVID-19) in the community is not fully understood. Methods: We analyzed the data of 7,758 children and adolescents with COVID-19 and characteristics of secondary transmission generated by these cases using case information published by local governments. Ratio of pediatric and adolescent cases generating secondary transmission was calculated for various social settings. Results: The incidence of COVID-19 was 24.8 cases per 105 population aged between 0 and 9 years, and 59.2 among those aged between 10 and 19 years, which was lower than that among individuals of all age groups (79.6 per 105 population) between January 15 and October 31, 2020. The proportion of cases generating secondary cases was 8.3% among infants and young children in nursery schools and kindergartens, 16% among children and adolescents attending primary schools, 34% among those attending junior high schools, 43% among those attending high schools, 31% among those attending professional training colleges, and 24% in those attending universities. Households were the most common setting for secondary transmission. Conclusion: The risk of generating secondary cases might be limited among pediatric and adolescent cases with COVID-19, especially in settings outside households. Effectiveness of traditional mitigation measures (e.g., school closures) to suppress COVID-19 transmissions should be carefully evaluated.

High tuberculosis burden among HIV-infected populations in Thailand due to a low-sensitivity tuberculin skin test.

The current Thai guideline recommends that among people living with HIV, isoniazid preventive therapy (IPT) should be given to those with a positive tuberculin skin test (TST). We conducted a case-control study, nested within a cohort study, in Chiang Rai Province in Thailand to determine the role of TST in predicting the development of active tuberculosis (TB) within the following 2 years. Comparison between participants with CD4+ counts <50cells/mm3 to those with CD4+ ≥200cells/mm3 revealed that TST results were less sensitive (7.7% vs 50.0%) and had a lower negative predictive value (73.1% vs 97.3%) in those with a CD4+ count <50cells/mm3. In people with HIV, using a positive TST result as a criterion for initiating IPT inadvertently decreases the benefits of IPT, especially among those with low CD4+ counts.

Risk factors associated with large clusters of tuberculosis patients determined by whole-genome sequencing in a high-tuberculosis-burden country.

Whole-genome sequencing (WGS) analysis has great discriminative power for detecting similar molecular fingerprints of suspected tuberculosis (TB) clusters. The proportion of TB cases within clusters and the associated risk factors are important epidemiological parameters guiding appropriate outbreak control strategies in endemic settings. We conducted a hospital-based TB case-cohort study between 2003 and 2011 in the northernmost province of Thailand. We identified TB clusters by Mycobacterium tuberculosis WGS and analysed the risks of TB clustering and the characteristics of large clusters compared with small clusters. Among 1146 TB isolates, we identified 77 clusters with 251 isolates defined by a 5-single-nucleotide variant (SNV) cutoff and 112 clusters with 431 isolates defined by a 12-SNV cutoff. Twelve large clusters with 6 isolates or more in each cluster were identified by a 12-SNV cutoff. Sublineage 2.2.1 (both Ancestral and Modern) strains and imprisonment were independently associated with large clusters. Furthermore, although large clusters of Lineage 2.2.1/Ancestral strains included a high number of prisoners, Lineage 2.2.1/Modern strain clusters were only associated with treatment failures and drug resistance. Heterogeneity among lineage strains was observed with respect to large-cluster characteristics. Patients with an increased TB-transmission tendency should be priority targets for contact investigations and outbreak interventions to prevent ongoing transmission.

Author Correction: Exposure to paternal tobacco smoking increased child hospitalization for lower respiratory infections but not for other diseases in Vietnam.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.