Ensuring continuous TB treatment across Asian borders.

BACKGROUND: Mid-treatment cross-border migration of patients with TB increases the risk of treatment interruption. OBJECTIVE: To establish a cross-border referral process for patients with TB in Japan, and enhance their access to health facilities and treatment outcomes. DESIGN: This prospective cohort study describes and assesses the process of foreign-born patients with TB who returned to their home countries during treatment, focusing on their access to healthcare facilities and treatment outcomes. RESULTS: We enrolled 135 foreign-born patients with TB, and confirmed that 112 (83.0%) were referred to and accessed healthcare facilities after returning to their home countries. Of 102 patients due to complete treatment as of July 2023, 87 (85.3%) completed their treatment. We did not identify significant differences in the treatment success rate among patient characteristics, except between the patients with confirmed access to a healthcare facility and those without (P < 0.001). We confirmed that 49/87 (56.3%) patients had completed treatment with official data. CONCLUSION: The access and treatment success rates of the cross-bordered patients with TB from Japan were >80%; however, we should further improve this proportion by confirming the treatment outcomes with official data.

CONTEXTE: La migration transfrontalière en milieu de traitement des patients atteints de TB augmente le risque d'interruption du traitement. OBJECTIF: Etablir un processus d'orientation transfrontalière pour les patients atteints de TB au Japon et à améliorer leur accès aux établissements de santé et les résultats de leur traitement. CONCEPTION: Cette étude de cohorte prospective décrit et évalue le processus des patients atteints de TB et nés à l'étranger qui sont retournés dans leur pays d'origine pendant le traitement, en se concentrant sur leur accès aux établissements de santé et sur les résultats du traitement. RÉSULTATS: Nous avons recruté 135 patients atteints de TB et nés à l'étranger et confirmé que 112 (83,0%) ont été orientés vers des établissements de santé et y ont accédé après leur retour dans leur pays d'origine. Des 102 patients qui devaient terminer leur traitement en juillet 2023, 87 (85,3%) l'ont terminé. Nous n'avons pas identifié de différences significatives dans le taux de réussite du traitement en fonction des caractéristiques des patients, sauf entre les patients ayant un accès confirmé à un établissement de santé et ceux qui n'en ont pas (P < 0,001). Nous avons confirmé que 49 (56,3%) des 87 patients avaient terminé leur traitement à l'aide des données officielles. CONCLUSION: Les taux d'accès et de réussite du traitement des patients transfrontaliers atteints de TB en provenance du Japon étaient >85% ; cependant, nous devrions encore améliorer cette proportion en confirmant les résultats du traitement à l'aide de données officielles.

A cost-effectiveness study of tuberculosis and latent tuberculosis infection screening in prisons in Japan.

BACKGROUND: Prison inmates are considered a high-risk population for tuberculosis (TB) in Japan. However, they are currently only screened for active TB using chest X-ray (CXR) as part of an annual health check.OBJECTIVE: To evaluate the cost-effectiveness of screening for latent TB infection (LTBI) using interferon-gamma release assay (IGRA) on entry into prison institutions.METHOD: We developed a transmission model of TB, taking into consideration the TB and LTBI epidemiology among inmates in Japan. Using a decision tree, we compared and evaluated no screening, screening using CXR, and IGRA screening for LTBI with CXR upon entry for a hypothetical cohort of 10 000 persons, aged ≥20 years; active TB cases prevented was the health outcome.RESULTS: It was estimated that 314 active TB cases would occur in the absence of any screening policy. IGRA with CXR screening averted 176 cases, while just one case of active TB was averted with CXR only screening. The incremental cost-effectiveness ratio per active TB case prevented was respectively US$2672 and US$43 984 for IGRA + CXR screening and CXR only screening.CONCLUSION: Screening with IGRA should be considered as the most cost-effective screening policy for prison inmates.

Trends of tuberculosis rates before and after the declaration as a public health emergency in Japan, 1992-2006.

SETTING: Over the period 1992 to 2006, Japan had tuberculosis (TB) notification rates of about 40 to 20 per 100 000 population. In 1999, the Minister of Health and Welfare of Japan declared a public health emergency based on the resurgence of TB.OBJECTIVE: To compare the trends of TB notification rates before and after the declaration.DESIGN: This is an ecological study on the trends of TB notification rates. The trends per year in TB notification rates were compared before (1992-1997) and after (2001-2006) the emergency declaration.RESULTS: The trends in the notification rates for all types of TB and sputum smear-positive TB (SSP-TB) decreased from -3.3% (95% confidence interval [CI] -4.6 to -1.9) and 0.94% (95%CI -0.33 to 2.2), respectively, per year before the declaration to -5.8% (95%CI -6.3 to -5.3) and -3.3% (95%CI -2.4 to -4.2), respectively, per year after the declaration with statistical significance. Trends in notification rates for both all types of TB and SSP-TB statistically significantly decreased after the declaration in Fukuoka, Osaka and Saitama Prefectures.CONCLUSION: The declaration of TB as a public health emergency in Japan in 1999 had a positive impact on TB control in Japan and thus TB epidemiology.

Using surveillance data to simulate the impact of a hypothetical pre-entry tuberculosis screening programme in Japan.

BACKGROUND: Despite a growing burden of foreign-born tuberculosis (TB) patients, Japan does not currently practise pre-entry tuberculosis (TB) screening among foreign-born entrants. OBJECTIVE: To evaluate the impact of a hypothetical pre-entry TB screening programme among new foreign-born entrants into Japan. METHOD: Using publicly available sources, we estimated 1) the number of prevalent TB cases, defined as bacteriologically or clinically confirmed cases among new foreign-born entrants into Japan in 2015, and 2) the yield from a hypothetical pre-entry TB screening programme under three scenarios: Scenario A, in which screening would be required of all applicants intending to stay for 3 months; Scenario B, screening among applicants for visas for settlement purposes; and Scenario C, screening among student and technical intern visa applicants. RESULTS: The numbers of prevalent TB cases under Scenarios A, B and C were respectively 492, 54 and 248 out of a total of 328 791, 21 554 and 182 879 applicants, respectively 276, 29 and 137 of whom would be detected via the pre-entry screening programme, giving an yield of respectively 83.9, 134.5 and 74.9 per 100 000 screened under each scenario. CONCLUSION: The yield was the highest under Scenario B; however, the impact was greatest under Scenario A, in that it detected the greatest number of patients and thus contributed the most in reducing the burden of foreign-born TB cases in Japan.

Evaluation of tuberculosis contact investigations in Japan.

SETTING: Although monitoring and evaluation using standardised indicators is an important aspect of tuberculosis (TB) contact investigation, no attempts have been made to systematically evaluate contact investigations in Japan. OBJECTIVE: To evaluate TB contact investigations conducted in public health centres (PHCs) by estimating the scores of selected indicators. DESIGN: A cross-sectional study was conducted in 2012 to estimate six selected indicator scores for contact tracing, contact evaluation and contact treatment at 11 PHCs using the TB registry and relevant contact investigation records of all forms of newly notified active TB cases. Indicator scores were compared across PHCs using median and interquartile range (IQR). RESULTS: A total of 2527 contacts of 313 index TB cases were identified; of these, 1874 were evaluated using the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Of 187 contacts who were TST/IGRA-positive, 15 were diagnosed with active TB. Consistently higher medians and lower IQRs were obtained for indicators of contact tracing and contact evaluation than those of contact treatment. CONCLUSION: Our study is the first to evaluate the performance of TB contact investigations in Japan using standardised indicators; the study indicated performance gaps, especially in the treatment for latent tuberculous infection among contacts.

Evaluating the impact of health resource reconstruction on improving spatial accessibility of tuberculosis care.

SETTING: In Japan, a decline in tuberculosis (TB) notification rates and shortening of duration of hospitalisation have led to a drastic decrease in the number of hospital beds for TB patients (TB beds), causing severe undersupply in certain regions. OBJECTIVE: To assess the current status of spatial access to TB beds in Japan and evaluate the potential impact of health resource reconstruction in mitigating undersupply of TB beds. DESIGN: A cross-sectional study was conducted whereby a two-step floating catchment area (2SFCA) method was used to calculate an 'accessibility score' to evaluate spatial accessibility of TB beds in the regions classified by four levels of urbanisation. The impact of introducing 'potential TB beds' was assessed via the changes in the proportion of undersupplied regions and TB patients notified from undersupplied regions. RESULTS: Undersupplied regions were characterised by 'very low', 'low' and 'moderate' level of urbanisation. By introducing 'potential TB beds', the proportion of both undersupplied regions and TB patients could be significantly reduced, especially in less urbanised regions. CONCLUSION: Our results may be used to guide future decision-making over resource allocation of TB care in Japan. The 2SFCA method may be applied to other countries using appropriate demand and supply variables.

Can social network analysis assist in the prioritisation of contacts in a tuberculosis contact investigation?

OBJECTIVES: To evaluate the effectiveness of social network analysis (SNA) in prioritising contacts in a tuberculosis (TB) contact investigation. METHOD: We reviewed and analysed patient and contact investigation data from a large outbreak that occurred in Tokyo, Japan, between 2010 and 2012. Relevant data were extracted to create a social matrix, which was then analysed using SNA software to visualise the network and calculate SNA metrics (degree and betweenness) for all patients and contacts. Statistical analyses were conducted to examine whether degree and betweenness centrality scores could prioritise contacts for in-depth investigation by calculating the odds of latent tuberculous infection (LTBI) being diagnosed among contacts with high scores compared to those with low scores. RESULTS: The data on a total of 8 patients and 376 contacts, of whom 56 were diagnosed with LTBI, were analysed. Centrality scores did not show a statistically significant association with the risk of contacts being diagnosed with LTBI. However, contacts with high betweenness scores were more likely to be diagnosed with LTBI than contacts with lower scores (OR 2.88, 95%CI 1.31-5.83, P = 0.007). CONCLUSION: Our results showed the potential of a betweenness score in prioritising contacts during TB contact investigation.

Overview of the tuberculosis burden in prison institutions in Japan, 2000-2012.

BACKGROUND: Although prison inmates in Japan are considered a high-risk group for tuberculosis (TB), little is known about the overall TB burden in prisons. OBJECTIVE: To estimate the incidence and epidemiological characteristics of TB among inmates in Japan, and to perform an ecological analysis to identify an association between socio-economic factors and TB incidence in prisons. METHOD: Using the annual reports on correctional statistics, we calculated TB incidence among inmates between 2000 and 2012. Multivariate analysis was conducted with selected socio-economic variables to examine their impact on overall and age-specific incidence. RESULTS: The average TB incidence between 2000 and 2012 among inmates was 255.0 per 100,000 population. The proportion of foreigners among new inmates was the best predictor of overall TB incidence, as well as of incidence among inmates aged 20-29 and 30-39 years. The proportion of those working in the construction industry before being arrested was the best predictor of incidence among those aged 40-49 and 50-59 years. CONCLUSION: TB incidence among inmates was approximately 11 times higher than in the general population. A more detailed analysis of patient information is needed to identify specific risk groups within the incarcerated population and improve case finding.

Permanent employment or public assistance may increase tuberculosis survival among working-age patients in Japan.

OBJECTIVES: To measure the effect of employment and health insurance status on the survival of working age tuberculosis (TB) patients in Japan. METHODS: Retrospective cohort analysis of new smear-positive pulmonary TB patients aged 15-59 years registered in the Japanese national TB surveillance system between 2007 and 2010. We performed univariate and multivariate Cox proportional hazard model analysis. The survival curves for employment and health insurance status were calculated using Kaplan-Meier analysis. RESULTS: Of 9097 patients studied, 267 (2.9%) died of TB within 12 months. After adjustment with a multivariate model, employment and health insurance status were independently associated with increased risk of TB death: unemployment (HR 2.80, 95%CI 2.11-3.72), absence of insurance (HR 1.48, 95%CI 1.02-2.15). The analysis of survival curves indicated that those with public assistance had almost the same survival rate as insured patients in the unemployed group. Permanent workers (employed >30 days) had the highest survival rates, followed by casual workers (employed <30 days) and the unemployed in the insured group. CONCLUSION: Patients with permanent jobs had better survival rates than unemployed patients and casual workers. Despite being unemployed, receiving public assistance could improve survival. Health measures are required for the unemployed and casual workers.

Minocycline selectively inhibits M1 polarization of microglia.

Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1(G93A) mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1(G93A) mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

Factors associated with declining numbers of chronic tuberculosis excretors in Japan.

SETTING: Japan's National Tuberculosis Programme (NTP). OBJECTIVES: To determine and assess the chronological change of chronic excretors. DESIGN: We compared two groups of chronic excretors (continuous excretion of TB bacilli in the last 2 years) classified by time of registration; the first group was registered from 1991 to 1997, and the second from 1998 to 2004. The epidemiological situation and the NTP were also compared. RESULT: There were 481 cases in the first group, comprising 0.17% of registered cases, and 159 cases in the second group, comprising 0.06%. Stratified analysis by treatment regimen and TB category confirmed a decrease in the ratio of chronic excretors in all sub-groups. Human factors such as non-adherence, no drug susceptibility testing (DST) on initiation of treatment and inadequate modification of treatment in new sputum smear-positive cases were more frequent in the first group than in the second (37.0% vs. 28.9%, 19.5% vs. 10.7%, 36.8% vs. 19.5%, P < 0.05). Other known risk factors, such as interruption due to side effects and complication of diabetes and/or alcoholism, were similarly distributed. CONCLUSION: The decline in chronic excretors has been associated with the DOTS strategy, baseline DST and appropriate modification of treatment regimen in new sputum smear-positive cases.

Use of the QuantiFERON-TB Gold test for screening tuberculosis contacts and predicting active disease.

OBJECTIVE: To evaluate the performance of the QuantiFERON(R)-TB Gold (QFT-G) test for screening tuberculosis (TB) contacts and estimating their risk of progressing to active TB disease. METHODS: Data on clinical progression to active disease were collected from public health centres 2 years after close contacts of TB cases had been QFT-G-tested. RESULTS: Among 3102 contacts observed, 419 were QFT-G-positive, and isoniazid (INH) treatment was initiated in 323. Twenty (4.8%) of these 419 developed TB disease. Among 2683 QFT-G-negative persons, 19 were diagnosed with TB (0.7%) during the average follow-up period of 1.6 years. The estimated sensitivity of QFT-G in detecting contacts who would progress to active TB was 51%, or 64% allowing for the effects of INH treatment. Among the QFT-G-negative contacts, all those who developed TB disease were contacts of highly infectious cases. Large-scale tuberculin skin testing was not available. CONCLUSIONS: TB incidence among QFT-G-positive contacts was higher than among QFT-G-negative contacts, but the number of TB cases among QFT-G-negative contacts is non-negligible, especially among contacts of highly infectious cases.

Molecular epidemiology of Mycobacterium tuberculosis in an urban area in Japan, 2002-2006.

SETTING: Shinjuku City, Tokyo, Japan. OBJECTIVE: To evaluate the status of transmission of Mycobacterium tuberculosis in Shinjuku City to allocate resources efficiently and effectively for a successful tuberculosis (TB) control programme. DESIGN: Observational descriptive study combining the genotype data of M. tuberculosis with TB patient profiles. RESULTS: The genotype clustering rate was significantly higher in males (adjusted odds ratio [aOR] 1.94, 95%CI 1.04-3.65, P = 0.038), patients aged <40 years (aOR 2.09, 95%CI 1.17-3.71, P = 0.012) and the homeless (aOR 2.72, 95%CI 1.42-5.20, P = 0.002), and was lower for the foreign-born (aOR 0.21, 95%CI 0.06-0.76, P = 0.017). Among 45 genotype clusters containing 152 TB patients, 26 clusters containing 102 patients (67.1%) were composed of a mix of homeless and non-homeless patients. One of the mixed clusters included an 8-month-old infant born in Japan. CONCLUSION: The study revealed that M. tuberculosis transmission occurred more frequently among the homeless than in non-homeless persons. However, transmission by casual contact between the homeless and the general population was also shown to occur.

Waning of the specific interferon-gamma response after years of tuberculosis infection.

HYPOTHESIS: Memory T-cell responses to specific antigens wane over time in subjects with tuberculosis (TB) infection. SETTING: Accumulated evidence indicates that QuantiFERON-TB Gold (QFT-G), a specific whole-blood interferon-gamma (IFN-gamma) based assay, can detect recent TB infections with superior sensitivity and specificity. OBJECTIVE: We applied this technique to the adult population of a Japanese community to determine its epidemiological usefulness. METHOD: A total of 1559 subjects attending periodic health screening volunteered to participate in the study. RESULTS: The QFT-G positive rates were 3.1% for those aged 40-49 years, 5.9% for those aged 50-59 and 9.8% for those aged 60-69. The expected infection prevalence estimated by the authors from a series of studies was 11.1%, 29.6% and 53.1% for those aged 40-49, 50-59 and 60-69 years, respectively. This wide gap between the expected and observed positivity suggests that the IFN-gamma response waned substantially with time after infection. Those with X-rays suggestive of old TB lesions exhibited positivity rates well below 100%. CONCLUSION: The specific IFN-gamma response may wane considerably with time after infection. Longitudinal studies are required to investigate long-term dynamics of cell-mediated immunity in infected donors.

Trends of delays in tuberculosis case finding in Japan and associated factors.

SETTING: Nationwide tuberculosis (TB) registry in Japan, 1987-2002. OBJECTIVE: To clarify the trends of patient's delay (PD), doctor's delay (DD) and total delay (TD), their relation and factors associated with the delays. DESIGN: Longitudinal study on trends in delays. Among patients with symptomatic smear-positive pulmonary TB, those with long PD (> or =2 months), DD (> or =1 month) and TD (> or =3 months) were analysed. RESULTS: Long PD rates increased until around 1997, whereas long DD rates decreased markedly from 1995 to 1999. Long TD rates increased until 1997, and decreased slightly thereafter. Men aged 30-59 years had higher rates of long PD, and the long PD rates increased through the 16-year observation period. Day labourers receiving or applying for welfare benefit had the highest rate of long TD, 46.5% during 1995-2002. Teachers and medical doctors showed the greatest increase in long TD rates through the period. CONCLUSION: Long TD was influenced more by PD than DD, and showed an upward trend. However, the long TD rate has declined slightly owing to the recent reduction in long DD. The reduction in DD since 1995 occurred immediately after the introduction of new technology in bacteriological examinations.

Hyper-production of an isomalto-dextranase of an Arthrobacter sp. by a proteases-deficient Bacillus subtilis: sequencing, properties, and crystallization of the recombinant enzyme.

Arthrobacter globiformis T6 is unique in that it produces an enzyme yielding only isomaltose from dextran. In the present study, the organism was re-identified and its classification as a new species of the genus Arthrobacter, A. dextranlyticum, was proposed. The high G+C gene (66.8 mol%) for the isomalto-dextranase was sequenced. The deduced amino acid sequence, with a calculated molecular mass of 65,993 Da (603 amino acids), was confirmed by nanoscale capillary liquid chromatography coupled to tandem mass spectrometry, which covered 71.1% of the amino acid residues of the entire sequence. The enzyme was grouped into glycoside hydrolase family 27, and the C-terminal domain has homology to carbohydrate-binding module family 6. Hyper-exoproduction of the recombinant enzyme was achieved at a level corresponding to approximately 4.6 g l(-1) of culture broth when proteases-deficient Bacillus subtilis cells were used as the host. The purified enzyme (65.5 kDa) had an optimal pH and temperature for activity of 3.5 and 60 degrees C, respectively. It was crystallized using the sitting-drop vapor-diffusion method at 293 K.

A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma.

The incidence of bone metastasis was around 13% in 404 patients with hepatocellular carcinoma (HCC) who underwent treatment at the National Kyushu Cancer Center between 1988-97, which is a high value among various cancers. This is, in part, due to the prolonged survival time of HCC patients in recent years. Serum vascular endothelial growth factor (VEGF) levels were significantly elevated in HCC patients with bone metastases as compared to those in patients with liver cirrhosis/chronic hepatitis and HCC patients without bone metastasis. VEGF was positively stained in both the primary lesion and bone metastasis of HCC by immunohistochemistry. In the process of bone metastasis, an increase in bone resorption is a crucial step prior to invasion of the bone. VEGF, the most important angiogenic factor, has been shown to stimulate bone resorption through its effects on osteoclasts. Thus, HCC cells reach the bone marrow space, and then secrete VEGF which facilitates osteolytic bone metastasis. VEGF may also facilitate tumor growth in the bone by acting as an angiogenic factor once invasion of the bone is complete. This might be another reason for the high incidence of bone metastasis in HCC.