Age-period-cohort analysis on tuberculosis cases in Japan, 1953-2022.

Background: Age-period-cohort (APC) analysis has been employed to differentiate long-term trends in the incidences of communicable diseases, including tuberculosis (TB), into the effects of age, birth year, and calendar period. However, no such study was hitherto conducted for Japan, which has 70 years of surveillance data. Therefore, we conducted APC analysis for TB in Japan. Methods: The national TB data for 1953-2022 were analyzed using the log-transformed linear model of APC analysis. Results: Annual age-and sex-standardized notification rates of TB peaked at 599.0 per 100 000 population in 1955 and fell by 99% to 4.5 in 2022. Adjusting for the effects of the birth cohort and period, the relative age-effect risk of TB peaked at 20-29 years and went down toward 60-69 years. Regarding the birth cohort effect, the TB risk showed a turning point in approximately 1913 for the central years of birth. Another change appeared in 1963 when the decline of the risk slightly stagnated; then, it started declining again at a rate as fast as in 1923-1953. Period effects showed a hump in the late 1950s and early 1960s, then sharply declined to the late 1970s, and reached a near plateau level until 2022. Conclusion: Our results highlight the continuing peak in TB disease risk for young adults and sharp decrease in disease risk in the 1960s and 70s. The introduction of anti-TB drugs in the 1950s and early 1970s had the most important impact on the epidemiology of TB in Japan.

Epidemiology of the koch phenomenon of infants after bacillus calmette-Guerin vaccination by interferon-γ release assay status, Japan, 2013-2019.

Background: The epidemiology of infants who exhibited the Koch-like phenomenon after Bacillus Calmette-Guérin vaccination and who subsequently tested positive in interferon-γ release assay (IGRA) was compared to that of those who tested negative. The reports of pediatricians on the phenomenon to the health authorities of Japan were retrieved and analyzed. Methods: In 2013-2019, 790 infants with such events were reported with IGRA test results available, of whom 81 (10.3%) tested positive and 709 (89.7%) negative. Results: The infants who were IGRA positive did not show an increasing trend (P = 0.06, P = 0.60), whereas those who were IGRA negative showed a significantly increasing trend (P = 0.42, P = 0.0002). The infants who were IGRA positive did not exhibit seasonality, whereas those who were IGRA negative had a higher number of cases in winter than in summer. The rates of infants who were IGRA positive per 10 million live births showed a significant correlation with the tuberculosis (TB) notification rates by prefecture (P = 0.41, P = 0.004), whereas those who were IGRA negative did not (P = 0.04, P = 0.78). Conclusion: The IGRA-positive infants were distributed quite differently from those who were IGRA negative and appeared more likely to be infected with TB. Reports of pediatricians on the Koch-like phenomenon should continuously be collected as the reports reflect a risk of TB infection including TB outbreaks among infants in Japan. The reports should include IGRA test results as IGRA is more specific than tuberculin skin testing. Infants with IGRA-positive results should be followed up for 2-3 years to determine their final outcomes.

Analysis of a tuberculosis outbreak in an office: Hokkaido, Japan, 2019-2020.

Background: In August 2018, a male worker (Pt1) in an office was diagnosed with smear-positive pulmonary tuberculosis (TB). This study aims to characterize the cases found in the TB outbreak in the office. Methods: The risks of TB disease or infection were compared among the staff members by seating locations. Results: A total of 116 current and ex-staff members were investigated, among whom 13 patients with active TB, including Pt1, and 20 with latent TB infection were found by the end of 2020. One-third of the seating groups located at one end of the office that Pt1 belonged to had the highest risk of TB disease (30.8%, 95% confidence interval [CI]: 14.3%-51.8%) and infection (61.5%, 95% CI: 40.6%-79.8%) with a high relative risk of TB infection (6.2, 95% CI: 2.0-18.8) compared to another one-third of the seating groups at the other end of the office that had the lowest risk of active TB (0%, 95% CI: 0%-11.6%) and TB infection (10.0%, 95% CI: 2.1%-26.5%). Conclusion: The seating groups that Pt1 belonged to had the highest risk of TB disease and infection because the staff members in the groups were exposed to the air containing TB bacilli from Pt1. Local health offices should initiate active case finding using chest X-rays as soon as they are notified of a sputum smear-positive TB case if the delay of the diagnosis is longer than three months.

Multidrug-Resistant Tuberculosis Outbreak among Immigrants in Tokyo, Japan, 2019-2021.

In mid-September 2019, a teenage Chinese male student and part-time waiter in Tokyo was diagnosed with multidrug-resistant (MDR) sputum smear-positive pulmonary tuberculosis (TB). This study describes the outbreak investigation of his friends and colleagues at the restaurant. We investigated 6 friends and 15 colleagues; 5 friends and 13 colleagues underwent interferon-γ release assay (IGRA). Of these, 3 friends (60.0%) and 4 colleagues (30.8%) were IGRA-positive. Each of the friends and colleagues was found to have MDR-TB (20% and 7.7%, respectively). Challenges during the investigation were the unavailability of regimens for latent TB infection (LTBI) for contacts with MDR-TB, budgetary constraints concerning implementing computed tomography (CT) scans for the contacts, frequent address changes of foreign-born patients and contacts, investigation during the coronavirus disease pandemic, and variations of alphabetical expression of the names of the patients and contacts, particularly for those from China. It is recommended that the national government officially adopt prophylaxis regimens for LTBI with MDR-TB, address the budgetary constraints regarding CT scans, and deploy liaison officers for coordinating investigations involving many foreign-born patients and contacts scattered in multiple municipalities. The names of foreign-born persons could more accurately be identified using both the alphabet and Chinese characters.

Turnaround times of the sputum sample courier system at tuberculosis treatment centers in Lusaka, Zambia, 2021.

Background: Health facilities which do not have capacity to diagnose tuberculosis (TB) depend on other facilities. This involves the courier of specimen such as sputum to diagnostic centers. This study was aimed at determining the turnaround time of sputum examinations for TB patients involving a courier system between the treatment and diagnostic centers. Methods: The study tracked the sputum samples between TB treatment and diagnostic centers. Sputum samples for both diagnosis and follow-up reasons were purposely and serially tracked from the time they were sent to the laboratory to the time results were received at the treatment centers. Results: Of the 65 sputum samples tracked at Chazanga, results were available for 49 (75.4%), 6 (9.2%) were unaccounted for, 4 (6.2%) were rejected by the laboratory, 4 (6.2%) had "error" results, and 2 (3.1%) were declared "missing" because it took more than a month to return the results. The turnaround time ranged from 2 days to 18 days with an average of 5.8 days (95% confidence interval [CI]: 4.5-7.1 days). At Kaunda Square, of the 49 samples tracked, results were available for 44 (89.8%), 2 (4.1%) were unaccounted for, 2 (4.1%) were rejected, and 1 (2.0%) was declared "missing." The turnaround time ranged from 2 to 25 days with an average of 6.3 days (95% CI: 5.3-7.4 days). Conclusion: The turnaround times of sputum examinations of the two treatment centers were long. The courier system should be closely monitored to determine if it is performing well because the system is still necessary for facilities without laboratories.

Removal of chlorophyll and pheophorbide from Chlorella pyrenoidosa by supercritical fluid extraction: potential of protein resource.

This study tried to quantitatively clarify the usefulness of supercritical fluid extraction for removal of chlorophyll and pheophorbide from Chlorella pyrenoidosa. C. pyrenoidosa powder was subjected to supercritical fluid extraction, and chlorophyll a and pheophorbide a in its extracted fractions were measured by HPLC-UV. Chlorophyll a and pheophorbide a in residue after supercritical fluid extraction became below of detection limit.

A diffused community tuberculosis outbreak that could be detected earlier using surveillance data, Japan, 2012-2014.

Background: Early detection of an outbreak is a role of disease surveillance systems; however, tuberculosis (TB) surveillance systems were underutilized to detect the outbreaks. In mid-2015, a local health office of central Japan noticed the number of TB cases of city in 2012-2014 were well above the expected numbers. This study was conducted to determine whether and when a community TB outbreak could be detected and characterize the cases using the national surveillance data. Method: The surveillance data of the A city and surrounding areas were retrospectively reviewed and analyzed for 2006-2018. Results: The TB notification rates of the A city from 2012 to 2014 were 28.0 (95% confidence interval [CI]: 20.3-38.4), 26.0 (95%CI: 18.6-36.0), 28.2 (95%CI: 20.3-38.4) per 100,000 population, respectively, higher than that of the entire prefecture (13.6, 13.0, 13.3, respectively). Similarly, in the neighboring B city, the rates of 2012 and 2014 were 51.0 (95%CI: 27.2-87.2) and 51.2 (95%CI: 27.3-87.5), respectively, higher than that of its parent prefecture (13.4 and 12.7, respectively). By the end of July 2012 (A city) or August 2012 (B city), the accumulated numbers of TB cases exceeded the previous annual TB cases. The average TB notification rates of A and B cities for 2012-2014 were higher than the surrounding areas. Conclusion: A community TB outbreak without well-defined setting could be detected by monitoring TB surveillance data.

A multidrug-resistant tuberculosis outbreak in a language school: Tokyo, Japan, 2019-2020.

Background: Japan has successfully reduced the burden of tuberculosis (TB) in the past seven decades; however, there are still some issues in eliminating TB. Its presence in immigrants, particularly multidrug-resistant (MDR) TB, is one of them. In mid-September 2019, a teenage Chinese male student in a morning class of a Japanese language school in Tokyo, Japan, was diagnosed with sputum smear-positive pulmonary MDR-TB. Method: The outbreak cases were analyzed in a cohort study. Results: We investigated 138 students and 18 teachers, of whom 81 (51.9%) were male, 115 (73.7%) were aged from 20 to 29 years, and 124 (76.9%) were from China. Four other students in the same classroom and another in a different classroom from the index patient in the morning classes were also diagnosed with MDR-TB disease by the end of November 2020. In addition, 31 cases of latent TB infection (LTBI) were detected among the students and teachers. Students in the same classroom had the highest risk of TB infection (78.9%, 95% confidence interval [CI]: 54.4%-93.9%) with a relative risk of 8.6 (95% CI: 3.9-19.0), followed by students in the other classrooms of the morning classes (25.9%, 95% CI: 15.0%-39.7%) with a relative risk of 2.8 (95% CI: 1.2-6.8), compared with the afternoon class students (9.2%, 95% CI: 3.5-19.0) who had minimal contact with the index patient. Conclusion: National TB programs should adopt prophylaxis regimens for MDR-TB LTBI cases and provide prophylaxis to them, particularly if related to an outbreak. The Japanese government should screen immigrants for TB, particularly those from TB-endemic areas.

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome.

BACKGROUND: SCN5A-related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX). OBJECTIVE: We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects. METHODS: Target panel sequencing was performed. Wild-type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24-36 hr, whole-cell sodium currents (INa ) were recorded using patch-clamp techniques. RESULTS: The proband was 29-year-old male who experienced cardiopulmonary arrest. Later, his 36-year-old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G-INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady-state activation (SSA) was shifted to depolarizing potentials compared with WT-INa (V1/2 -WT: -39.1 ± 0.8 mV, W374G: -30.9 ± 1.1 mV, p < .01). Incubation of W374G-transfected cells with MEX (W374G-MEX) increased INa density, but it was still reduced compared with WT-INa (W374G-MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G-MEX-INa was comparable to W374G-INa (V1/2 -W374G-MEX: -31.6 ± 0.7 mV, P = NS). CONCLUSIONS: Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.

Positivity of interferon-gamma release assay among foreign-born individuals, Tokyo, Japan, 2015-2017.

Background: The aim of this study is to analyze interferon-gamma release assay (IGRA) data of foreign-born individuals in Japan derived from tuberculosis (TB) contact investigations. Methods: A contact with a TB patient was considered to have occurred when an individual had contact with a TB patient for more than 8 h indoors. This is a retrospective cohort study, and all the TB contacts tested with IGRA during the contact investigations conducted by the Shinjuku city Health Office from 2015 through 2017 were enrolled. Results: A total of 880 foreign-born contacts were investigated. The IGRA positivity of the contacts from China and Viet Nam were both 5.1% (95% confidence intervals [CIs]: 3.2%-7.8% and 2.4%-9.5%, respectively), whereas that from Nepal and Myanmar were 24.4% (95% CI: 16.0%-34.6%) and 23.3% (95% CI: 9.9%-42.3%), respectively. Multiple logistic regression analysis showed that the risk factors were smear status of the index patient (1+: adjusted odds ratio [aOR]: 6.2, 95% CI: 1.2-30.5, smear status 3+: aOR: 14.3, 95% CI: 1.7-118.2), age of the contact (aOR: 1.1, 95% CI: 1.0-1.1 for 1 year increment), and being born in Nepal (aOR: 5.6, 95% CI: 2.8-11.2) and Myanmar (aOR: 4.3, 95% CI: 1.4-13.0), compared with China as reference. Conclusions: In contact investigations involving foreign-born individuals, local health offices should carefully consider the composition of the TB contacts and expand the focus of the investigation, if deemed necessary.

The annual risk of tuberculosis infection in newly hired researchers and healthcare workers using interferon-gamma release assay in Japan.

The tuberculosis (TB) notification rate in Japan is gradually decreasing but has not yet achieved "pre-elimination," defined by the World Health Organization. To effectively tackle, control, and eliminate TB, estimating and monitoring the annual risk of TB infection (ARI) using tuberculin skin testing (TST) to understand the dynamics of TB epidemiology are significantly important. However, studies estimating ARIs using TST are few considering that Bacillus Calmette-Guérin vaccination coverage is high in Japan. This was a single-center, cross-sectional study conducted between January 2011 and December 2018 in Tokyo area where interferon-gamma release assays (IGRAs) were performed in newly hired researchers of Keio University School of Medicine and healthcare workers of Keio University Hospital to determine TB infection. We estimated the prevalence of TB infection and ARI based on their IGRA results. Among the 3908 subjects, 83 (2.124%) had positive IGRA results. Multiple logistic regression analysis revealed that age was a significant risk factor for positive IGRA result (adjusted odds ratio, 1.046). The ARIs were 0.049%-0.156% between 1986 and 2004, midyears of TB infection, but have not significantly decreased over approximately two decades. To decrease the risk of TB infection, advanced strategies to control and eliminate TB in Tokyo area are significantly required.

An enterohaemorrhagic Escherichia coli outbreak spread through the environment at an institute for people with intellectual disabilities in Japan in 2005.

OBJECTIVE: An enterohaemorrhagic Escherichia coli (EHEC) outbreak at an institute with multiple facilities for children and adults with intellectual disabilities was investigated to characterize the cases and identify risk factors for infection. METHODS: A case was defined as a resident, a staff member or a visitor at the institute from 16 May through 30 June 2005 testing positive for type 2 Vero toxin-producing EHEC O157:H7 (confirmed case) or exhibiting bloody diarrhoea for two or more days (probable case). We collected and analysed demographic, clinical, laboratory and individual behaviour data to identify possible risk factors for infection and infection routes. RESULTS: We recorded 58 confirmed cases, of which 13 were symptomatic. One probable case was also found. The median age of the patients was 37 years (range: 6-59 years). Thirty-six patients (61%) were male. Thirteen patients (93%) had diarrhoea and six (43%) had abdominal pain. Two developed haemolytic-uraemic syndrome but recovered. All the patients were treated with antibiotics and tested negative after treatment. Some residents had problems with personal hygiene. The residents of one of the facilities who cleaned a particular restroom had 18.0 times higher odds of being infected with EHEC (95% confidence interval: 4.0-102.4) than those who did not. DISCUSSION: The source of the outbreak could not be identified; however, the infection may have spread through environmental sources contaminated with EHEC. We recommend that institutional settings, particularly those that accommodate people with intellectual disabilities, clean restrooms as often as possible to reduce possible infection from contact with infected surfaces.

Referral and treatment outcomes of tuberculosis patients who crossed the border from Japan to the philippines.

Background: The referral and treatment outcomes of tuberculosis (TB) patients referred from Japan to the Philippines have not yet been systematically reported. This study aimed to describe the cross-border referral process for TB patients referred from Japan to the Philippines. Methods: This is a retrospective descriptive review of the referral process between the two countries. The data on the pathways of Filipino patients with TB or latent TB infection initially treated in Japan from 2009 to mid-2018 were summarized. We calculated the proportion of the referred-and-accessed and that of the successfully treated in the health facilities in the Philippines. The Chi-square test or Fisher's exact test was applied to test significant differences between categorical data. Results: Among the 36 Filipino TB patients referred, 83.3% (30 patients) were successful in accessing any of the health facilities. Among these, 28 patients confirmed that they had started TB treatment in the Philippines. Age groups (P = 0.17), gender (P = 0.76), planned place of residence (P = 0.44), bacteriological results (P = 0.81), and TB patient types (P = 0.96) did not show any significant differences in the referred-and-access rate. The treatment success rate among the 23 TB patients (excluding five patients who were still receiving treatment as of writing) was 91.3%. However, only three out of five multidrug-resistant TB patients successfully started treatment. Conclusions: The current cross-border TB patient referral mechanism between Japan and the Philippines indicated successful results. However, it needs to be enhanced by strengthening the mechanism to track referral outcomes systemically.

A tuberculosis contact investigation involving a large number of contacts tested with interferon-gamma release assay at a nursing school: Kanagawa, Japan, 2012.

In May 2012, a teacher of a nursing school with about 300 staff members and students in Japan was diagnosed with sputum smear-positive pulmonary tuberculosis (TB), leading to an investigation involving nearly 300 contacts. We describe the contacts' closeness to the index TB patient and the likelihood of TB infection and disease. A case of TB was defined as an individual with positive bacteriological tests or by a physician diagnosis of TB. A latent TB infection (LTBI) case was defined as an individual who had a positive interferon-gamma release assay (IGRA). A total of 283 persons screened with IGRA were analysed. Eight persons (2.8%, 95% confidence interval [CI]: 1.2-5.4) tested positive by IGRA; one student who had intermediate (less than 10 hours) contact with the index patient was found to have pulmonary TB by chest X-ray. The positivity in IGRA among staff members with very close contact with the index patient (4 of 21, 19%, 95% CI: 5.4-42%) with a statistically significant relative risk of 17 (95% CI: 2.0-140) was high compared with that of the intermediate contacts (1 of 88, 1.1% [95% CI: 0.028-6.2]). There was a statistically significant trend in the risk of TB infection and closeness with the index patient among the staff members and students (P < 0.00022). In congregate settings such as schools, the scope of contact investigation may have to be expanded to detect a TB case among those who had brief contact with the index patient.

Estimating Latent Tuberculosis Infection Using Interferon-γ Release Assay, Japan.

We estimated the latent tuberculosis infection (LTBI) rate for foreign-born students at Keio University, Tokyo, Japan, using an interferon-γ release assay. The LTBI rate for students from countries with estimated tuberculosis incidence >100 cases/100,000 persons was high (10.0%). Universities should screen for LTBI in students from countries with high tuberculosis incidence.

Risk of tuberculosis infection among health care workers and nursing students in Japan.

It is important to evaluate the risk of tuberculosis (TB) infection among health care workers (HCWs) and nursing students in Japan to propose the optimal countermeasure against new TB infection for them. To estimate the annual incidence of TB infection in HCWs at a Japanese university hospital without TB wards and in nursing students at a Japanese university using interferon-gamma release assay (IGRA). Serial IGRAs were prospectively conducted on the HCWs between August 2010 and December 2015. For nursing students, two IGRA tests were conducted before commencement of clinical training and at employment as nurses between April 2007 and December 2015. A total of 328 HCWs and 298 nursing students were followed for 670.15 and 1212.80 person-years, respectively. Assuming IGRA-positive conversions were all attributable to true infection, the incidence of TB infection in HCWs and nursing students was 0.149/100 and 0.0825/100 person-years, respectively. At a Japanese university hospital without TB wards and a Japanese university, the annual incidence of TB infection among HCWs and nursing students estimated from serial IGRA results was low, but continued vigilance for the prevention of TB infection is essential.

Risk of tuberculosis among air passengers estimated by interferon gamma release assay: survey of contact investigations, Japan, 2012 to 2015.

Although the World Health Organization recommends contact investigations around air travel-associated sputum smear-positive tuberculosis (TB) patients, evidence suggests that the information thus obtained may have overestimated the risk of TB infection because it involved some contacts born in countries with high TB burden who were likely to have been infected with TB in the past, or because tuberculin skin tests were used, which are less specific than the interferon gamma release assay (IGRA) particularly in areas where Bacillus Calmette-Guérin (BCG) vaccination coverage is high. We conducted a questionnaire survey on air travel-associated TB contact investigations in local health offices of Japan from 2012 to 2015, focusing on IGRA positivity. Among 651 air travel-associated TB contacts, average positivity was 3.8% (95% confidence interval (CI): 2.5-5.6) with a statistically significant increasing trend with older age (p < 0.0094). Positivity among 0-34 year-old contacts was 1.0% (95% CI: 0.12-3.5%), suggesting their risk of TB infection is as small as among Japanese young adults with low risk of TB infection (positivity: 0.85-0.90%). Limiting the contact investigation to fewer passengers (within two seats surrounding the index case, rather than two rows) seems reasonable in the case of aircraft with many seats per row.

Extraction of nobiletin from Citrus Unshiu peels by supercritical fluid and its CRE-mediated transcriptional activity.

BACKGROUND: Polymethoxyflavone (PMF) is one of bioactive compounds in Citrus Unshiu and included mainly in the peels rather than the fruits, seeds and leaves. HYPOTHESIS/PURPOSE: Supercritical CO2 extraction is one candidate for selective extraction of polymethoxyflavone and in this study, supercritical CO2 extraction with/without ethanol entrainer from Citrus Unshiu peels was examined at a temperature of 333K and a pressure of 30MPa. METHODS: CRE (cyclic AMP response element)-mediated transcriptional assay was examined by using the extracts from supercritical fluid extraction. RESULTS: The results showed that extracts including nobiletin increased with increasing ethanol concentration in supercritical CO2 and the elapsed extraction time. Extracts at ethanol concentration of 5 mol% showed high CRE-mediated transcription activity. This can be caused by activity of the extract including nobiletin in addition to the other methoxylated flavonoid species such as tangeretin. Extracts at ethanol concentration of 50% showed the highest CRE-mediated transcription activity, which can be attributed to flavonoid glycoside such as hesperidin. From our investigations, flavonoid glycoside can be one of promoters of CRE-mediated transcription activity.

Nutrient recycle from defatted microalgae (Aurantiochytrium) with hydrothermal treatment for microalgae cultivation.

Defatted heterotrophic microalgae (Aurantiochytrium limacinum SR21) was treated with high temperature water (175-350°C, 10-90min) to obtain nitrogen and phosphorous nutrients as a water soluble fraction (WS). Yields of nitrogen and phosphorous recovered in WS varied from 38 to 100% and from 57 to 99%, respectively. Maximum yields of nitrogen containing compounds in WS were proteins (43%), amino acids (12%) and ammonia (60%) at treatment temperatures of 175, 250 and 350°C, respectively. Maximum yield of phosphorous in WS was 99% at a treatment temperature of 250°C. Cultivation experiments of microalgae (A. limacinum SR21) using WS obtained at 200 and 250°C showed positive growth. Water soluble fractions from hydrothermal treatment of defatted microalgae are effective nitrogen and phosphorous nutrient sources for microalgae cultivation.