TB-related technical enquiries received in Japan, 2017-2019.

SETTING: Japan, an intermediate TB burden country. OBJECTIVE: To review TB-related technical enquiries received at the Research Institute of Tuberculosis, Japan, from January 2017 to December 2019. DESIGN: This was a cohort study. RESULTS: A total of 2,197 enquiries were analysed. On average, 61.0 enquiries/month (range: 42-81) were received. The enquiry rates were highest for the Yamanashi (4.65/100,000 population) and Ishikawa (4.55) Prefectures, and lowest in the Yamagata (0.46) and Tochigi (0.56) Prefectures. The main organisations the enquirers belonged to were local governments (n = 1,585, 72.1%) and healthcare facilities (n = 307, 14.0%). The enquirers were medical doctors (n = 391, 17.8%), nurses (n = 1,207, 54.9%), other healthcare professionals (n = 57, 2.6%), the general public (n = 168, 7.6%) and others/unknown (n = 374, 17.0%). The most frequent enquiries were about TB diagnosis and treatment (n = 501, 22.8%), including laboratory diagnosis (n = 88, 4.0%), TB treatment in general (n = 93, 4.2%) and management of comorbidities (n = 86, 3.9%), followed by contact investigations (n = 385, 17.5%) and TB in foreigners (n = 344, 15.7%). CONCLUSION: As the most frequent enquiries were about diagnosis and treatment of TB, the health ministry of Japan should maintain a few specialised TB institutions with TB physicians to provide technical assistance.

LIEU: Le Japon, un pays à charge intermédiaire en matière de TB. OBJECTIF: Examiner les demandes de renseignements techniques liées à la TB reçues au Research Institute of Tuberculosis, au Japon, de janvier 2017 à décembre 2019. METHODE: Il s'agissait d'une étude de cohorte. RÉSULTATS: Au total, 2 197 demandes ont été analysées. En moyenne, 61,0 demandes de renseignements/mois (fourchette : 42­81) ont été reçues. Les taux de demande étaient les plus élevés dans les préfectures de Yamanashi (4,65/100 000 habitants) et d'Ishikawa (4,55), et les plus faibles dans les préfectures de Yamagata (0,46) et de Tochigi (0,56). Les principales organisations auxquelles appartiennent les enquêteurs sont les administrations locales (n = 1 585 ; 72,1%) et les établissements de santé (n = 307; 14,0%). Les enquêteurs étaient des médecins (n = 391 ; 17,8%), des infirmières (n = 1 207 ; 54,9%), d'autres professionnels de la santé (n = 57 ; 2,6%), le grand public (n = 168 ; 7,6%) et autres/inconnus (n = 374 ; 17,0%). Les demandes les plus fréquentes concernaient le diagnostic et le traitement de la TB (n = 501 ; 22,8%), y compris le diagnostic en laboratoire (n = 88 ; 4,0%), le traitement de la TB en général (n = 93 ; 4,2%) et la prise en charge des comorbidités (n = 86 ; 3,9%), suivis par les enquêtes sur les contacts (n = 385 ; 17,5%) et la TB chez les étrangers (n = 344 ; 15,7%). CONCLUSION: Comme les demandes de renseignements les plus fréquentes concernaient le diagnostic et le traitement de la TB, le ministère de la santé du Japon devrait maintenir quelques institutions spécialisées dans la TB avec des médecins spécialistes de la TB pour fournir une assistance technique.

Western Pacific Regional Green Light Committee: progress and way forward.

The Western Pacific Regional Green Light Committee (rGLC WPR) was established in 2011 to promote the rational scale-up of programmatic management of drug-resistant tuberculosis (PMDT). We reflect on its achievements, consider the challenges faced, and explore its potential future role. Achievements include the supervision and support of national PMDT action plans, increased local ownership, contextualized guidance, and a strong focus on regional capacity building, as well as a greater awareness of regional challenges. Future rGLC activities should include (1) advocacy for high-level political commitment; (2) monitoring, evaluation, and supervision; (3) technical support and contextualized guidance; and (4) training, capacity building, and operational research. Regional activities require close collaboration with both national and global efforts, and should be an important component of the new Global Drug-resistant TB Initiative.

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.

Development and validation of a tuberculosis prognostic score for smear-positive in-patients in Japan.

BACKGROUND: No scoring system has ever been used to estimate the prognosis of individual tuberculosis (TB) patients. OBJECTIVE: To develop and validate a tuberculosis prognostic score. METHODS: This retrospective cohort study conducted in Japan comprised the development (n = 179; mean age 65.9 ± 18.8 years) and validation (n = 244; mean age 64.3 ± 20.1 years) of a tuberculosis prognostic score among patients with newly diagnosed smear-positive non-multidrug-resistant pulmonary tuberculosis without human immunodeficiency virus infection. The score (raw score) was defined by modifying a logistic regression formula using known risk factors as independent variables and in-patient death as a dependent variable. RESULTS: The raw score was calculated as follows: age (years) + (oxygen requirement, 10 points) - 20 × albumin (g/dl) + (activity of daily living: independent, 0 point; semi-dependent, 5 points; totally dependent, 10 points). The raw scores were grouped into risk groups 1 (raw score < -30) to 5 (raw score ≥ 60) using 30-point intervals. Every increase in risk group was equivalent to a 7.3-fold increase in the odds ratio for in-hospital death (P < 0.001). The area under the receiver operating characteristics curve by risk group for in-patient death was 0.875 (P < 0.001). CONCLUSIONS: In this study we were able to develop and validate a tuberculosis prognostic score.

Epidemiological impact of mass tuberculosis screening: a 2-year follow-up after a national prevalence survey.

OBJECTIVE: To assess the epidemiological impact of mass tuberculosis (TB) screening in the community and the prognosis of bacteriologically negative individuals with abnormal findings on chest radiography (CXR). METHODS: A follow-up study consisting of two parts--a register match of notified TB cases with 22,160 participants in a national TB prevalence survey, and a repeat medical examination for the subjects of a prevalence survey with abnormal findings on CXR--was conducted 2 years after the prevalence survey in Cambodia. RESULTS: Thirty-four cases with new smear-positive TB were detected by register match, giving a standardised notification ratio of 0.38 (95%CI 0.27-0.52). An additional seven new smear-positive TB cases and 93 new smear-negative, culture-positive TB cases were detected by medical examination. The incidence rates of bacteriologically positive TB were 8.5% per year (95%CI 6.3-11.2) in cases with a CXR suggestive of active TB and 2.9% per year (95%CI 2.2-3.7) in those with a CXR with other abnormalities. CONCLUSIONS: Detection and treatment of smear-negative, culture-positive TB cases as well as smear-positive TB cases was associated with a rapid reduction in subsequent incidence of new smear-positive TB. Sputum culture-negative individuals with abnormal CXR findings are at a high risk of disease progression, and require follow-up and potentially preventive treatment.

Evaluation of a simple loop-mediated isothermal amplification test kit for the diagnosis of tuberculosis.

OBJECTIVE: A new loop-mediated isothermal amplification (LAMP) test kit, including a simple DNA extraction device for the detection of Mycobacterium tuberculosis complex, was developed for commercial use and evaluated for its usefulness in diagnosing tuberculosis (TB). DESIGN: The LAMP test was performed using untreated and N-acetyl-L-cysteine (NALC) NaOH-treated sputum specimen. The efficiency of the kit was compared with other conventional laboratory examinations, including other nucleic acid amplification (NAA) tests. RESULTS: The sensitivity of LAMP using raw sputum (direct LAMP) in smear- and culture-positive specimens was 98.2% (95%CI 94.9-99.4), while the sensitivity in smear-negative, culture-positive specimens was 55.6% (95%CI 43.4-68.0). The diagnostic sensitivity of direct LAMP for the diagnosis of individuals with TB was 88.2% (95%CI 81.4-92.7). The sensitivity values of direct LAMP were slightly, but not statistically significantly lower than those of Cobas Amplicor MTB and TRC Rapid MTB, while the sensitivity of the LAMP test using NALC-NaOH treated sputum was significantly lower than other NAA tests (P < 0.05) for smear-negative, culture-positive specimens. The new commercial version of the LAMP kit was easy to handle and yielded results within 1 h of receiving sputum specimens. CONCLUSIONS: This test is considered a promising diagnostic tool for TB, even for peripheral laboratories with limited equipment, such as those in developing countries.

Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the efficacy, safety and pharmacokinetics of pregabalin in treating neuropathic pain associated with diabetic peripheral neuropathy in Japanese patients. METHODS: A randomized, double-blind, placebo-controlled, multicentre 14 week clinical trial was conducted. Japanese patients with diabetic peripheral neuropathy (n = 317) were randomized to receive placebo or pregabalin at 300 or 600 mg/day. The primary efficacy measure was a change of mean pain score from baseline to end-point from patients' daily pain diaries. RESULTS: Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate. CONCLUSIONS: Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.

Risk of relapse and failure after retreatment with the Category II regimen in Nepal.

SETTING: Kathmandu Valley urban area, Nepal. OBJECTIVE: To study the probabilities of failure and relapse and of amplifying drug resistance to isoniazid (INH) and rifampicin (RMP) after the Category II retreatment regimen. DESIGN: Cohort study of smear-positive tuberculosis (TB) retreatment cases. RESULTS: Of 250 cases started on Category II retreatment, 209 were relapse cases; of these, 18 were INH-resistant RMP-susceptible, 18 were INH+RMP-resistant and nine were culture-negative. Of 19 return after interruption cases, two were INH-resistant RMP-susceptible and one was INH+RMP-resistant. Among 22 failures, no case was INH-resistant RMP-susceptible, six were INH+RMP-resistant and 14 were culture-negative. No INH-susceptible RMP-resistant cases were observed. Among 182 INH+RMP-susceptible cases, one failed and four relapsed during follow-up. Two of the five cases became INH+RMP-resistant and the remaining three remained susceptible. Among 20 INH-resistant RMP-susceptible cases, two failed and none relapsed. One of the two became INH+RMP-resistant and the other case remained INH-resistant RMP-susceptible. DISCUSSION: The proportion of resistance among retreatment cases in Kathmandu Valley was not high. The risk of relapse with amplification of RMP resistance among INH-resistant RMP-susceptible cases on the Category II retreatment regimen was 5% (1/20), and that among INH+RMP-susceptible cases was 1% (2/182).

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.

Estimation of incidence of tuberculosis infection in health-care workers using repeated interferon-gamma assays.

The aim was to estimate the incidence of Mycobacterium tuberculosis (Mtb) infection in health-care workers (HCWs) in Japan. We repeated cross-sectional surveys of HCWs with QuantiFERON-TB Gold (QFT-G) in 2003, 2005 and 2007 at a hospital with tuberculosis (TB) wards, and 311 HCWs who underwent QFT-G testing two or three times were included in the study. Five HCWs (1.8%) converted from negative to positive. Incidence of new TB infection was estimated to be 0.6/100 person-years by the CDC's definition. Thirteen positive persons (41%) reverted from positive to negative. Multivariable logistic regression analysis identified a significant association between QFT-G conversion and working in TB wards. The IFN-gamma levels of all but two subjects with reverting or converting QFT-G results were close to the test's cut-off. The incidence of Mtb infection in HCWs at our hospital was higher than that estimated for the general population in Japan. Criteria for defining QFT-G conversion and reversion need further investigation considering the high proportion of reversion, as the incidence of infection would have changed if we had applied other definitions.

Minimally invasive video-assisted thoracoscopic lobectomy for better clinical outcomes in peripheral T1NO lung cancer.

It is an unresolved issue whether various thoracotomies affect clinical outcomes. In addition, a wide variety of technical approaches of video-assisted thoracic surgery depend on the facility. We reviewed 152 consecutive patients with clinical T1N0M0 lung cancer that underwent three types of lobectomy with systematic mediastinal lymphadenectomy in a single institute: 46 conventional thoracotomies (OPEN), 50 anterolateral small thoracotomies mainly using the thoracoscope as a light guide (ASSIST), and 56 minimum thoracotomies in which only a thoracoscope view was used (PURE). Total discharge from the chest drainage tube, length of hospital stay, and post-thoracotomy pain were significantly less in PURE than in OPEN and ASSIST. The results of mediastinal lymphadenectomy were equivalent. The 3-year survival rates were also similar among the three groups. We conclude that good clinical outcomes, especially reduced post-thoracotomy pain, seemed to correlate with the lesser degree of destruction of the chest wall with the identical quality as an acceptable cancer operation in PURE.

Performance of an interferon-gamma release assay for diagnosing latent tuberculosis infection in children.

Newly developed interferon-gamma release assays have become commercially available to detect tuberculosis (TB) infection in adults. However, little is known about their performance in children. We compared test results between the QuantiFERON-TB Gold test (QFT) and tuberculin skin test (TST) in young children living with pulmonary TB patients in Cambodia. Of 195 children tested with both QFT and TST, the TST-positive rate of 24% was significantly higher than the QFT-positive rate of 17%. The agreement between the test results was considerable (kappa-coefficient 0.63). Positive rates increased from 6% to 32% for QFT and from 15% to 43% for TST, according to the sputum smear grades of the index cases. The presence of Bacille Calmette-Guérin (BCG) scars did not significantly affect the results of TST or QFT in a logistic regression analysis. In conclusion, QFT can be a substitute for TST in detecting latent TB infection in childhood contacts aged

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.

Development of acquired drug resistance in recurrent tuberculosis patients with various previous treatment outcomes.

SETTING: Chiang Rai province, Northern Thailand. OBJECTIVE: To study the probability of acquiring drug resistance to isoniazid (H) and rifampicin (R) on recurrence after treatment success, default and failure, among sputum smear-positive pulmonary tuberculosis (TB) patients treated with standardised short-course chemotherapy. DESIGN: Retrospective analysis of registration records of TB patients from May 1996 to December 2000 in Chiang Rai, where routine drug susceptibility testing (DST) is conducted for surveillance purposes. Patients registered twice or more were examined. RESULTS: Of 59 cases treated with HRZE/HR who underwent DST at the time of registration, 31 were fully susceptible to H and R at first registration, of whom four acquired drug resistance to H or R. Of 13 cases resistant to H or R at first registration, 11 became multidrug-resistant (MDR). The remaining 15 patients were original MDR cases. Among 28 MDR or H- or R-resistant cases, six reverted from resistant to susceptible. DISCUSSION: A high proportion of patients with H- or R-resistant TB became MDR after treatment with 2HRZE/HR. Using this regimen, MDR may increase in a population with a high prevalence of H or R resistance. We are unable to explain why some drug-resistant cases became drug-susceptible. Further investigation is necessary.

Current epidemiological trend of tuberculosis in Japan.

OBJECTIVE: To observe the recent epidemiological trend of tuberculosis and to determine the factors related to the deteriorating trend in incidence and mortality rates in Japan. DESIGN: Descriptive analyses of tuberculosis notification rates and mortality rates by age, sex, year and birth-cohort. RESULTS: The decline in the tuberculosis notification rate has started slowing down since around 1980. Among the cohorts born before 1950, the trend of notification rate by age has levelled off since around 1980. The reduction in the tuberculosis mortality rate has also recently begun to slow down, but later and to a lesser extent than that of the notification rate. Although deaths due to tuberculosis occur mostly among the elderly, the rate of decline in mortality among middle-aged males has slowed down recently. The trend in the mortality rate of birth-cohorts has recently shown an upward trend with age. CONCLUSION: A major cause of the current stagnation of the decline in notification rates is the increase in the elderly population with a high prevalence of tuberculosis infection in the past, who are more likely to develop the disease as they approach biological senescence. Other possible causes are a gradual shift of the tuberculosis problem to socio-economically deprived segments of the urban population, and behavioural changes causing delay in case-finding.

Change of migration time and separation window accompanied by field-enhanced sample stacking in capillary zone electrophoresis.

When field-enhanced sample stacking was used in capillary zone electrophoresis (CZE) analysis of cations, the decrease of migration time and the reduction of separation window was observed with increase of sample plug length. A simple equation expressing the migration velocity in the stacking process was derived to explain the above phenomenon. From experiments and theoretical consideration, we confirmed that this effect was caused by the higher potential gradient and larger eletroosmotic flow (EOF) mobility at the sample plug than those at the supporting electrolyte. A mathematical model appropriate for the computer simulation of such a system was studied considering the experimental results, and it was concluded that electroosmotic velocity (v(eof)) should be introduced to the equation of continuity as a constant.

Prevalence of drug-resistant tuberculosis in an HIV endemic area in northern Thailand.

SETTING: Chiang Rai Province in Northern Thailand, where human immunodeficiency virus (HIV) infection has been prevalent since the 1990s. OBJECTIVE: To observe the prevalence of drug-resistant tuberculosis (TB) and investigate the factors related to the level of drug resistance in an HIV endemic area. DESIGN: Population-based surveillance study covering the whole province. METHOD: Drug susceptibility testing was performed at the Thai Ministry of Public Health laboratory for all sputum smear-positive TB patients diagnosed in hospitals in Chiang Rai Province over a 25-month period in 1996-1998. Patient characteristics were obtained through interview by trained personnel. HIV testing was performed with informed consent. RESULTS: Among the 1077 incident patients without previous history of treatment, the proportion of patients with resistance to isoniazid was 13.2%, 10.8% to rifampicin, 15.6% to streptomycin, and 5.8% to ethambutol. Multidrug resistance (MDR), i.e., resistance to at least both isoniazid and rifampicin, was observed in 6.3%. Factors associated with primary MDR-TB were HIV positivity (OR 2.2, 95%CI 1.3-3.9), age <50 years (OR 2.0), and treatment in the provincial hospital (OR 2.3), compared to patients treated in the community and private hospitals. Stratified analysis shows a significantly high prevalence of primary MDR-TB among HIV-positive patients treated in the provincial hospital against HIV-negative patients or HIV-positive patients in other hospitals. CONCLUSION: The prevalence of primary MDR-TB in this area was high. It is necessary to strengthen TB control activities in order to reduce the burden of MDR-TB.

Standardization of capillary zone electropherograms obtained by using field enhanced sample stacking.

Migration times in a capillary zone electropherogram obtained by using the field enhanced sample stacking technique are strongly affected by the injected sample volume. That is, the migration times significantly decrease with the increase of the sample volume. To avoid inaccurate qualitative analysis due to the above phenomena, the time axis of the electropherograms was converted into an effective mobility axis using our conversion method taking account of the temperature increase in the separation tube and relaxation of the potential gradient of the separation field. After the conversion, accurate qualitative analysis was possible in spite of drastic change of the migration time, suggesting our conversion method could be successfully used for the standardization of electropherograms obtained even by using the stacking effect. The cause of the decrease of the migration time in the stacking process was briefly discussed.

New method for standardization of electropherograms obtained in capillary zone electrophoresis.

A new method for standardization of electropherograms obtained by capillary zone electrophoresis was proposed, where the migration time axis was replaced by the effective mobility axis. The mobility increase due to temperature increase by Joule heating and the relaxation effect of the potential gradient were eliminated successfully by introducing a temperature coefficient for mobility expression and a delay time, respectively. The precision of the mobility evaluated by the proposed conversion methods was evaluated for a model sample. By using the conversion method, almost the same electropherograms could be obtained even from the electropherograms originally obtained by using different hardware conditions.