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OBJECTIVE: To describe tuberculosis (TB) characteristics in the adolescent 10–19 years age group that is often underrepresented in surveillance and studies despite the high global TB burden estimated for this group.SETTING AND DESIGN: We use the case-based data reported to the European Surveillance System (TESSy) from European Union (EU)/European Economic Area (EEA) countries between 2007 and 2016 to describe notification rates, TB characteristics and treatment outcomes among adolescent TB cases. We also compare TB characteristics in young adolescents (10–14 years) and older adolescents (15–19 years).RESULTS: For the period 2007 to 2016, 705 826 TB cases were reported to TESSy by 29 EU/EEA countries, 38 054 (5.4%) of which were adolescents. The overall EU/EEA notification rate among adolescents was 6.9 per 100 000 population, 3.5 among young adolescents and 10.1 among older adolescents. The two adolescent groups had differences regarding sex distribution, site of disease, sputum smear microscopy positivity, laboratory confirmation and treatment outcome.CONCLUSION: Younger and older adolescents should be analysed as separate groups when studying and reporting TB, particularly to inform better targeting of TB prevention and care interventions in the future, in order to improve outcomes.

Background Tuberculosis (TB) remains a serious public health threat worldwide. Theoretically ultimate resolution of whole genome sequencing (WGS) for Mycobacterium tuberculosis complex (MTBC) strain classification makes this technology very attractive for epidemiological investigations. Objectives To summarize the evidence available in peer-reviewed publications on the role and place of WGS in detection of TB transmission. Sources A total of 69 peer-reviewed publications identified in Pubmed database. Content Evidence from >30 publications suggests that a cut-off value of fewer than six single nucleotide polymorphisms between strains efficiently excludes cases that are not the result of recent transmission and could be used for the identification of drug-sensitive isolates involved in direct human-to-human TB transmission. Sensitivity of WGS to identify epidemiologically linked isolates is high, reaching 100% in eight studies with specificity (17%–95%) highly dependent on the settings. Drug resistance and specific phylogenetic lineages may be associated with accelerated mutation rates affecting genetic distances. WGS can be potentially used to distinguish between true relapses and re-infections but in high-incidence low-diversity settings this would require consideration of epidemiological links and minority alleles. Data from four studies looking into within-host diversity highlight a need for developing criteria for acceptance or rejection of WGS relatedness results depending on the proportion of minority alleles. Implications WGS will potentially allow for more targeted public health actions preventing unnecessary investigations of false clusters. Consensus on standardization of raw data quality control processing criteria, analytical pipelines and reporting language is yet to be reached.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug‐resistant TB (XDR‐TB) (n = 11), pre‐XDR‐TB (n = 29) and drug‐susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient‐centred approaches.

Background The proportion of tuberculosis (TB) cases in the European Union/European Free Trade Association (EU/EFTA) that occur in migrants is increasing. Extrapulmonary TB poses challenges in diagnosis and treatment and causes serious morbidity and mortality. To date, there has been no in-depth exploration of extrapulmonary TB in migrants across Europe. Methods We analysed 22 years of data from the European Centre for Disease Prevention and Control's European Surveillance System (TESSy) for 32 EU/EFTA countries between 1995 and 2017. We investigated whether the proportion of TB cases that were extrapulmonary varied between migrants and non-migrants, and whether this varied by a) country/region of origin, b) reporting country/region, and c) site of disease. Results 1,270,896 TB cases were included in the analysis, comprising 326,987 (25.7%) migrants, and 943,909 (74.3%) non-migrants. The proportion of TB that is extrapulmonary is significantly higher in migrants than in non-migrants: 45.2% (n = 147,814) of cases in migrants were extrapulmonary, compared to 21.7% (n = 204,613) in non-migrants (χ2=6.7x104, p Conclusions Among TB cases in the EU/EFTA, extrapulmonary disease is significantly more common in migrants than non-migrants, which has clinical and policy implications for patient detection and management. There is a need to improve clinical awareness of extrapulmonary TB, integrate detection of extrapulmonary TB into latent TB infection screening programmes, and harmonise data collection on migrant status in health systems. Key messages Migrants in the EU/EFTA are disproportionately affected by extrapulmonary TB compared to non-migrants. This has clinical and policy implications for diagnosis, screening, and data collection.

SETTING: Implementation of novel diagnostic assays in tuberculosis (TB) laboratory diagnosis requires effective management of time and resources. OBJECTIVE: To further develop and assess at multiple centres a time-and-motion (T&M) tool as an objective means for recording the actual time spent on running laboratory assays. DESIGN: Multicentre prospective study conducted in six European Union (EU) reference TB laboratories. RESULTS: A total of 1060 specimens were tested using four laboratory assays. The number of specimens per batch varied from one to 60; a total of 64 recordings were performed. Theoretical hands-on times per specimen (TTPS) in h:min:s for Xpert® MTB/RIF, mycobacterial interspersed repetitive unit-variable number of tandem repeats genotyping, Ziehl-Neelsen staining and manual fluorescence microscopy were respectively 00:33:02 ± 00:12:32, 00:13:34 ± 00:03:11, 00:09:54 ± 00:00:53 and 00:06:23 ± 00:01:36. Variations between laboratories were predominantly linked to the time spent on reporting and administrative procedures. Processing specimens in batches could help save time in highly automated assays (e.g., line-probe) (TTPS 00:14:00 vs. 00:09:45 for batches comprising 7 and 31 specimens, respectively). CONCLUSIONS: The T&M tool can be considered a universal and objective methodology contributing to workload assessment in TB diagnostic laboratories. Comparison of workload between laboratories could help laboratory managers justify their resource and personnel needs for the implementation of novel, time-saving, cost-effective technologies, as well as identify areas for improvement.

Background Pillar 3 of the End TB Strategy calls for the promotion of research and innovation at the country level to facilitate improved implementation of existing and novel interventions to end tuberculosis (TB). In an era of increasing cross-border migration, there is a specific need to integrate migration-related issues into national TB research agendas. The objective of the present review is to provide a conceptual framework to guide countries in the development and operationalization of a migrant-inclusive TB research agenda. Methods We conducted a literature review, complemented by expert opinion and the previous articles in this State of the Art series, to identify important themes central to migration-related TB. We categorized these themes into a framework for a migration-inclusive global TB research agenda across a comprehensive spectrum of research. We developed this conceptual framework taking into account: 1) the biomedical, social and structural determinants of TB; 2) the epidemiologic impact of the migration pathway; and 3) the feasibility of various types of research based on a country's capacity. Discussion The conceptual framework presented here is based on the key principle that migrants are not inherently different from other populations in terms of susceptibility to known TB determinants, but that they often have exacerbated or additional risks related to their country of origin and the migration process, which must be accounted for in developing comprehensive TB prevention and care strategies. A migrant-inclusive research agenda should systematically consider this wider context to have the highest impact.

Extensively drug-resistant (XDR) tuberculosis (TB) poses a threat to public health due to its complicated, expensive and often unsuccessful treatment. A cluster of three XDR TB cases was detected among foreign medical students of a Romanian university. The contact investigations included tuberculin skin testing or interferon gamma release assay, chest X-ray, sputum smear microscopy, culture, drug susceptibility testing, genotyping and whole-genome sequencing (WGS), and were addressed to students, personnel of the university, family members or other close contacts of the cases. These investigations increased the total number of cases to seven. All confirmed cases shared a very similar WGS profile. Two more cases were epidemiologically linked, but no laboratory confirmation exists. Despite all the efforts done, the source of the outbreak was not identified, but the transmission was controlled. The investigation was conducted by a team including epidemiologists and microbiologists from five countries (Finland, Israel, Romania, Sweden and the UK) and from the European Centre for Disease Prevention and Control. Our report shows how countries can collaborate to control the spread of XDR TB by exchanging information about cases and their contacts to enable identification of additional cases and transmission and to perform the source investigation.

A cluster of multidrug-resistant tuberculosis (MDR-TB) among migrants is described by Walker et al. in their manuscript accepted for publication in Lancet Infectious Diseases. As most European countries have entry screening for tuberculosis (active case finding) for certain categories of migrants, we evaluated whether cases were identified by entry screening and if not, why not. Our assessment shows that 27 of 36 (75%) patients were screened for TB. Of these, 13 (50%) were diagnosed as a result of the screening. Most patients were eventually diagnosed with MDR-TB within months of entry in the country. We conclude that systematic screening of migrants at entry can identify tuberculosis but only captures active TB at entry and thus access for migrants to the health system in the host countries should be ensured to allow early detection and treatment of cases and avoid further spread.

As tuberculosis (TB) rates continue to decline in native populations in most low TB incidence countries, the proportion of TB patients born outside their country of residence ('foreign-born') increases. Some low-incidence countries have experienced a substantial increase in TB rates related to recent increases in the number of asylum seekers and other migrants from TB-endemic countries. However, average TB rates among the foreign-born in low-incidence countries declined moderately in 2009-2015. TB in foreign-born individuals is commonly the result of reactivation of latent infection with Mycobacterium tuberculosis acquired outside the host country. Transmission is generally low in low-incidence countries, and transmission from migrants to the native population is often modest. Variations in levels and trends in TB notifications among the foreign-born are likely explained by differences and fluctuations in the number and profile of migrants, as well as by variations in TB control, health and social policies in the host countries. To optimise TB care and prevention in migrants from endemic to low-incidence countries, we propose a framework for identifying possible TB care and prevention interventions before, during and after migration. Universal access to high-quality care along the entire migration pathway is critical. Screening for active TB and latent tuberculous infection should be tailored to the TB epidemiology, adapted to the needs of specific migrant groups and linked to treatment. Ultimately, the long-term TB elimination goal can be reached only if global health and socio-economic inequalities are dramatically reduced. Low-incidence countries, most of which are among the wealthiest nations, need to contribute through international assistance.

To estimate trends in tuberculosis (TB) notification rates by geographical origin, we retrieved surveillance data from 2010 to 2015 for 29 European Union and European Economic Area countries. The TB notification rate decreased at an annual rate of 5.3%. The decrease in notification rate was higher in native residents (7.0%) than in those of foreign origin (3.7%). Targeted screening and facilitated access to care and treatment could help prevent and control TB in migrants.

Tuberculosis (TB) infection control (IC) is key in controlling TB transmission in health facilities in Lithuania. This article presents a project that aimed at supporting health care facilities in Lithuania in implementing TB-IC. The project consisted of 1) facility TB-IC assessments, 2) development of facility TB-IC plans, 3) TB-IC training and 4) site visits. We assessed the impact of these activities through a self-assessment questionnaire. The project resulted in limited improvements. Most progress was seen in administrative and managerial activities. Possible reasons for the limited improvements are challenges with funding and the lack of supportive legislation and a national TB-IC plan.La lutte contre l'infection tuberculeuse (TB-IC) est la clé du contrôle de la transmission de la TB dans les structures de santé de Lituanie. Cet article présente un projet qui a visé à soutenir les structures de soins de santé de Lituanie dans la mise en œuvre de la TB-IC. Le projet a consisté en : 1) l'évaluation des structures de TB-IC, 2) l'élaboration de plans pour ces structures de TB-IC, 3) la formation à la TB-IC et 4) visites de sites. Nous avons évalué l'impact de ces activités par un questionnaire d'autoévaluation. Le projet a abouti à des améliorations limitées. Les progrès les plus importants ont été vus dans les activités d'administration et de gestion. Les raisons possibles de ces améliorations limitées sont des problèmes relatifs au financement et au manque de soutien légal, ainsi qu'à l'absence d'un plan national de TB-IC.El control de la infección tuberculosa (TB-IC) constituye una medida fundamental en el control de la transmisión de la TB en los establecimientos de salud en Lituania. En el presente artículo se describe un proyecto encaminado a prestar apoyo a los establecimientos sanitarios en la ejecución de las normas de la TB-IC. El proyecto comportaba las siguientes medidas: 1) la evaluación del TB-IC en las instituciones; 2) la elaboración de planes de TB-IC en los establecimientos; 3) la capacitación en esta esfera; y 4) las visitas a los centros. Se examinó la repercusión de estas intervenciones mediante un cuestionario de autoevaluación. Con el proyecto se alcanzaron mejoras de un alcance limitado. La mayor parte del progreso se observó en las actividades administrativas y de gestión. Entre las posibles razones de este resultado modesto se cuentan las dificultades de financiamiento, la falta de una legislación de apoyo y de un plan nacional de TB-IC.

The period of economic transition has had severe consequences for health and health systems in Ukraine. The tuberculosis (TB) situation illustrates this. The strategy recommended by the World Health Organization (WHO) for TB, directly observed treatment short-course (DOTS), has the potential to provide real improvements in TB services, forming the basis of the response to the growing epidemic. In 2002, Ukraine, financially supported by USAID and the European Community (EC), began to introduce DOTS through pilot projects in Mariupol and Kyiv City. The aim of this study is to assess the feasibility, effectiveness, health service cost, patient cost, and the cost-effectiveness of these pilots, in order to inform the national scale-up of DOTS. The study finds that DOTS is feasible and has the potential to be both effective and cost-effective in Ukraine. Following this study, Ukraine adopted DOTS as a national TB control strategy in 2005. However, the pilots also found that there are several evidence-related concerns and perverse economic incentives to both providers and patients that will need to be addressed if national scale-up is to be successful. These include concerns related to the treatment of MDR-TB, economic benefits to some patients to remain hospitalized, and payments to providers and health facilities that support current practices. These will need to be addressed if Ukraine is to develop an effective response to its emerging TB epidemic.

The targets for tuberculosis control, framed within the United Nations' Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence surveys are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infection in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.

Currently, schistosomiasis control in Mali is mainly based on treatment with praziquantel (PZQ). The policy is to ensure (1). the treatment, every 3 years, of school-age children in all areas where the prevalence of haematuria (an indicator of Schistosoma haematobium infection) in this age-group is30%, and (2). the sound management of all patients presenting with haematuria or (bloody) diarrhoea (an indicator of S. mansoni infection) at health centres. In the present study, the application of case management was evaluated by visiting 60 healthcare facilities in four geographical areas and interviewing the health-workers at these facilities. The presence of S. haematobium and S. mansoni was reported in the coverage areas of 83% and 37%, respectively, of the healthcare facilities investigated. Health-worker knowledge of the main symptoms of schistosome infection was good and patients exhibiting symptoms attributable to schistosome infection were very likely to receive adequate treatment, particularly (at a frequency of about 80%) when they presented with haematuria. At health-centre level, patients were often directly treated with PZQ, whereas health-workers in district hospitals and private clinics requested a diagnostic test prior to any treatment. PZQ was available in most healthcare facilities but not in the private clinics. The mean cost of treatment of a patient with S. haematobium infection (euro; 2.30) was very similar to the corresponding cost for S. mansoni infection (euro; 2.37). The cost of the PZQ represented approximately 50% of the total costs borne by the patients when presenting at health centres. Patients with the symptoms of S. haematobium infection in Mali can expect adequate diagnosis and treatment in agreement with the recommendations of the World Health Organization. Patients presenting with symptoms related to S. mansoni infection are, however, less likely to be correctly diagnosed. The relatively high costs of treatment and the infrequency with which cases of schistosomiasis seek healthcare necessitate policy decisions, to ensure an affordable and more attractive, clinical system of case management.

Worldwide resistance to antituberculosis drugs is jeopardising the control and eventually the elimination of tuberculosis (TB). Patients who are infected by Mycobacterium tuberculosis resistant to antituberculosis drugs, especially to both isoniazid and rifampicin and thus having multidrug-resistant (MDR) TB, need more complicated treatment that lasts longer and consists of a large number of drugs and frequently leads to side effects. In the European Union and European Economic Area (EU/EEA), treatment outcome results for all types of drug resistance were below the target of 85% set by the European Centre for Disease Prevention and Control (ECDC), for new pulmonary culture-positive cases and with 34% the reported treatment success rate of MDR-TB cases was substantially below the target of 70% [1, 2]. Of TB cases diagnosed with MDR-TB in 2009 in the EU/EEA, almost two-thirds died during treatment, failed their treatment or defaulted from treatment. This failure to ensure adequate MDR-TB treatment not only puts patients’ lives at risk but also paves the way for XDR TB, and further transmission of the disease. Analysis of the worldwide data for TB from 2007 to 2010, showed proportions of MDR-TB of 3.4% in new TB cases and 19.8% in those previously treated [3]. The proportions of TB cases with MDR-TB are similar in the EU/EEA with 2.6% of the new culture-confirmed TB cases diagnosed with MDR-TB and 18.8% of previously treated culture-confirmed TB cases [2]. In this issue of Eurosurveillance and in the 13 March issue, studies on surveillance of drug-resistant TB, including molecular surveillance, are published. These studies show that drug-resistant TB occurs in diverse settings in Europe and that there is ongoing transmission of drug-resistant TB also in countries with a low TB incidence.

The European Union and European Economic Area (EU/EEA) tuberculosis (TB) surveillance system collects detailed information on resistance to TB drugs. Using this information, we provide an overview of the current TB drug resistance situation and trends in the EU/EEA by performing a descriptive analysis, including analysis of treatment outcomes, of the TB cases reported between January 2007 and December 2012. The percentages of TB cases with different drug resistance patterns have been stable with about 90% of the new laboratory-confirmed cases pan-susceptible, 6% monodrug-resistant, 2% polydrug-resistant, 2% multidrug drug-resistant (MDR) TB - excluding extensively drug-resistant (XDR) TB -, and 0.2% XDR-TB. In previously treated laboratory-confirmed TB cases, the percentage with MDR-TB excluding XDR-TB declined until 2010 to 16% and remained stable thereafter. During the study period, the percentages of cases with monodrug- and polydrug-resistant TB remained constant at about 8% and 2% whereas the percentage of XDR-TB cases increased slightly to 2.6%. Treatment outcome results for all cases have been stable with overall 77.9% of the pan-susceptible cases, 69.6% of the monoresistant cases, 68.2% of the polyresistant cases, 32.2% of the MDR-TB cases (excluding XDR-TB), and 19.1% of the XDR-TB cases treated successfully. The treatment success rate target for new pulmonary culture-positive MDR-TB cases of 70% has not been reached. In addition, drug resistance surveillance can be improved by more complete reporting of drug susceptibility results and treatment outcome. .

Contains fulltext : 137468.pdf (Publisher’s version ) (Open Access) The European Centre for Disease Prevention and Control (ECDC) initiated a project on the molecular surveillance of multi- and extensively drug-resistant tuberculosis (MDR-/XDR-TB) transmission in the European Union (EU) in the period from 2009 to 2011. In total, 2,092 variable number of tandem repeat (VNTR) patterns of MDR-/XDR-TB Mycobacterium tuberculosis isolates were collected, originating from 24 different countries in the period 2003 to 2011. Of the collected VNTR patterns, 45% (n=941) could be assigned to one of the 79 European multiple-country molecular fingerprint clusters and 50% of those (n=470) belonged to one extremely large cluster caused by Beijing strains of one genotype. We conclude that international transmission of MDR-/XDR-TB plays an important role in the EU, especially in the eastern part, and is significantly related to the spread of one strain or clone of the Beijing genotype. Implementation of international cluster investigation in EU countries should reveal underlying factors of transmission, and show how TB control can be improved regarding case finding, contact tracing, infection control and treatment in order to prevent further spread of MDR-/XDR-TB in the EU.

AIMS To determine the prevalence of anaemia among HIV-positive and -negative drug users, estimate the incidence of anaemia among HIV-positive drug users and study risk factors for prevalent anaemia with emphasis on HIV infection, gender and drug use behaviour. DESIGN, SETTING AND PARTICIPANTS Cross-sectional study among HIV-positive and HIV-negative drug users (n = 360) and a longitudinal study among HIV-positive drug users (n = 175, 860 visits) participating in a cohort study of drug users in Amsterdam. MEASUREMENTS Self-reported data on socio-demographics, drug use behaviour and zidovudine and protease inhibitor therapy on regular cohort visits. Laboratory determinations of haemoglobin concentration, CD4(+)-cell counts and HIV-1 RNA. FINDINGS The prevalence of anaemia was 21.1% among participating drug users according to the WHO definition. The incidence of anaemia in HIV-positive individuals was 33.0/100 person-years. The main risk factor for anaemia was high frequency of injecting drugs. A Quetelet body mass index < or = 20 and female gender were also positively and significantly related to anaemia in the cross-sectional study. In the longitudinal study among HIV-positive drug users progression of HIV infection indicated by low CD4(+)-cell count and AIDS diagnosis were predictive of anaemia. CONCLUSION The results indicate that drug users in the Amsterdam cohort study have a high prevalence of anaemia, which can be explained mainly by high frequency of injecting drugs and HIV infection progression. Reduction or cessation of injecting drug use should reduce anaemia.

As part of development of a continuous process for D-malate production, the stability of maleate hydratase in permeabilized Pseudomonas pseudoalcaligenes was characterized as a function of relevant process conditions. In a system where D-malate is produced from a Ca-maleate suspension, these conditions were temperature, D-malate2-, Ca2+, and biocatalyst concentration. The decrease of maleate-hydratase activity with time was described by first-order irreversible inactivation. The first-order inactivation rate constant increased with temperature between 20°C and 35°C and decreased with D-malate2- concentration between 0 and 50 mM; the temperature dependency increased with D-malate2- concentration. Although seemingly even more attractive with respect to biocatalyst stability, the effects of temperatures below 20°C and D-malate2- concentrations exceeding 50 mM were not determined, as biocatalyst activity at these temperatures is extremely low and the D-malate2- concentration will not exceed 50 mM due to the l...

Actinobacillus sp. 130Z fermented glucose to the major products succinate, acetate, and formate. Ethanol was formed as a minor fermentation product. Under CO2-limiting conditions, less succinate and more ethanol were formed. The fermentation product ratio remained constant at pH values from 6.0 to 7.4. More succinate was produced when hydrogen was present in the gas phase. Actinobacillus sp. 130Z grew at the expense of fumarate and l-malate reduction, with hydrogen as an electron donor. Other substrates such as more-reduced carbohydrates (e.g., d-sorbitol) resulted in higher succinate and/or ethanol production. Actinobacillus sp. 130Z contained the key enzymes involved in the Embden-Meyerhof-Parnas and the pentose-phosphate pathways and contained high levels of phosphoenolpyruvate (PEP) carboxykinase, malate dehydrogenase, fumarase, fumarate reductase, pyruvate kinase, pyruvate formate-lyase, phosphotransacetylase, acetate kinase, malic enzyme, and oxaloacetate decarboxylase. The levels of PEP carboxykinase, malate dehydrogenase, and fumarase were significantly higher in Actinobacillus sp. 130Z than in Escherichia coli K-12 and accounted for the differences in succinate production. Key enzymes in end product formation in Actinobacillus sp. 130Z were regulated by the energy substrates.

Tuberculosis (TB) is decreasing in the European Union/European Economic Area (EU/EEA), but remains a significant public health problem. Although pulmonary TB accounts for the majority of the cases and is the main transmissible form of the disease, extrapulmonary TB also contributes to the burden of disease and does not receive specific attention in international control strategies. We performed a descriptive analysis to assess the burden and trends of extrapulmonary TB in EU/EEA countries. During 2002–11, 167,652 cases of extrapulmonary TB were reported by the 30 Member States. Extrapulmonary TB accounted for 19.3% of all notified cases, ranging from 5.8% to 44.4% among the Member States. Overall, TB notification rates decreased in 2002–11 due to a decrease in pulmonary TB. Notification rates of extrapulmonary TB remained stable at 3.4 per 100,000 in 2002 and 3.2 per 100,000 in 2011. Thus the proportion of extrapulmonary TB increased from 16.4% in 2002 to 22.4% in 2011. Of all extrapulmonary TB cases reported during 2002–11, 37.9% were foreign-born or citizens of another country, 33.7% were culture-confirmed, and the overall treatment success was 81.4%. A significant percentage of notified TB cases are extrapulmonary, and in contrast to pulmonary TB, extrapulmonary TB rates are not decreasing.

Tuberculosis (TB) is decreasing in the European Union/European Economic Area (EU/EEA), but remains a significant public health problem. Although pulmonary TB accounts for the majority of the cases and is the main transmissible form of the disease, extrapulmonary TB also contributes to the burden of disease and does not receive specific attention in international control strategies. We performed a descriptive analysis to assess the burden and trends of extrapulmonary TB in EU/EEA countries. During 2002–11, 167,652 cases of extrapulmonary TB were reported by the 30 Member States. Extrapulmonary TB accounted for 19.3% of all notified cases, ranging from 5.8% to 44.4% among the Member States. Overall, TB notification rates decreased in 2002–11 due to a decrease in pulmonary TB. Notification rates of extrapulmonary TB remained stable at 3.4 per 100,000 in 2002 and 3.2 per 100,000 in 2011. Thus the proportion of extrapulmonary TB increased from 16.4% in 2002 to 22.4% in 2011. Of all extrapulmonary TB cases reported during 2002–11, 37.9% were foreign-born or citizens of another country, 33.7% were culture-confirmed, and the overall treatment success was 81.4%. A significant percentage of notified TB cases are extrapulmonary, and in contrast to pulmonary TB, extrapulmonary TB rates are not decreasing.

Research into the nature and extent of cognitive dysfunction in patients suffering from bipolar disorder has increased greatly over the last 10 years because the dysfunction is known to persist even if the mood symptoms are in remission and can influence a patient’s psychosocial functioning.To provide an overview of 1) the nature and extent of cognitive dysfunction in bipolar patients; 2) clinically relevant factors such as illness characteristics, comorbidity and psychotropic/psychoactive drugs and 3) the consequences of cognitive dysfunction.We searched the literature in PubMed using the following search terms: bipolar disorder, neuropsychological, cognitive functioning, cognition, functional outcome, determinants, psychotropic/psychoactive drugs.Attentional deficits, memory lapses and aberrant executive functioning occur in both manic and depressive episodes, and may persist even in absence of mood symptoms. The precise cause of cognitive dysfunction is unknown. Persistent cognitive dysfunction frequently interferes with daily functioning.Since the treatment of bipolar patients is nowadays directed towards complete recovery rather than symptomatic remission, it is important to take into account the possibility that these patients are also suffering from cognitive dysfunction.

Background Existing international guidelines provide different recommendations for the management of contacts of multidrug-resistant tuberculosis (MDR-TB) patients. Objective To conduct two systematic reviews with the aim of identifying chemoprophylactic approaches that are effective in contacts of MDR-TB patients to assist in policy making. Design We systematically searched the Medline, Embase, Central, LILACS, TRIP and BIOSIS Preview databases for studies on the effectiveness of anti-tuberculosis drugs in preventing active TB in persons at risk of developing MDR-TB. This was done as an update of a systematic review from 2006 using the same methodology. In addition, we searched for studies including persons at risk of developing TB after exposure to non-MDR-TB patients who were treated with anti-tuberculosis drugs other than isoniazid or rifampicin. Results Of 1195 references assessed in the update, one additional study could be included. As the initial review included two studies, the total number of included studies equals three. One study reported no contacts who developed TB, whether or not they received prophylaxis. The other two studies showed non-significant risk differences of 4% (95%CI -3 to 12), and 5% (95%CI -2 to 11), both in favour of chemoprophylaxis. For the additional review, 2480 references were assessed, but none could be included. Conclusion The attention given to MDR-TB in recent years has not resulted in publications on preventive treatment for contacts of MDR-TB patients. The available evidence is not sufficient to support or reject preventive treatment. Furthermore, the combined available evidence is of very low quality.

SUMMARYThe aim of this study was to determine the nationwide prevalence of smear-positive tuberculosis (TB) in Bangladesh. A multi-stage cluster survey of a random sample of persons aged ⩾15 years was included in 40 clusters (20 urban, 20 rural). Two sputum samples were collected from study participants and tested initially by fluorescence microscopy and confirmed by the Ziehl–Neelsen method. The crude and adjusted prevalence rates and 95% confidence intervals (CIs) were calculated using standard methods. A total of 33 new smear-positive TB cases were detected among 52 098 individuals who participated in the study. The average participation rate was over 80%. The overall crude prevalence of new smear-positive TB in persons aged ⩾15 years was estimated as 63·3/100 000 (95% CI 43·6–88·9) and the adjusted prevalence was 79·4/100 000 (95% CI 47·1–133·8). TB prevalence was higher in males (n=24) and in rural areas (n=20). The prevalence was highest in the 55–64 years age group (201/100 000) and lowest in 15–24 years age group (43·0/100 000). The prevalence was higher in persons with no education (138·6/100 000, 95% CI 78·4–245·0). The overall prevalence of smear-positive TB was significantly lower than the prevalence estimate of the previous nationwide survey in Bangladesh in 1987–1988 (870/100 000).

Addressing social determinants in the field of tuberculosis (TB) has received great attention in the past years, mainly due to the fact that worldwide TB incidence has not declined as much as expected, despite highly curative control strategies. One of the objectives of the World Health Organization Global Task Force on TB Impact Measurement is to assess the prevalence of TB disease in 22 high-burden countries by active screening of a random sample of the general population. These surveys provide a unique opportunity to assess socio-economic determinants in relation to prevalent TB and its risk factors. This article describes methods of measuring the socio-economic position in the context of a TB prevalence survey. An indirect measurement using an assets score is the most feasible way of doing this. Several examples are given from recently conducted prevalence surveys of the use of an assets score, its construction, and the analyses of the obtained data.

Tuberculosis (TB) control in Tashkent City, Uzbekistan, is organised in accordance with the DOTS strategy. Intensive phase treatment is provided in hospital, while the continuation phase is given on an ambulatory basis. In 2005, the defaulter rate was 21%. An earlier quantitative study explored when patients default and identified some of the risk factors associated with default, but did not answer the question: 'Why do patients default?'To investigate reasons for defaulting and to identify possible solutions.We conducted a qualitative follow-up study consisting of 32 in-depth interviews with defaulters, patients who had completed treatment and health care providers.Communication between patients and health care staff is poor. Patients lack proper information on TB and its treatment. There is a widespread belief that TB is not curable. Hospitalisation is problematic due to poor general conditions in TB hospitals, costs incurred by patients during hospitalisation and because TB patients need to earn a living or take care of their families.Poor communication between health care staff and TB patients is a key issue underlying several of the causes of default identified, and needs to be addressed. Reducing the period of hospitalisation may also improve adherence to TB treatment.

To assess the availability of second-line drugs (SLDs) and the use of drug susceptibility testing (DST) results for the treatment of tuberculosis (TB) in China.Cross-sectional survey in 4675 health care facilities, 1960 of which have a dedicated TB clinic, in 12 provinces in China.More than 70% of TB clinics at the provincial and prefecture levels had at least one SLD available compared to 41.8% of facilities at the county/district level. The proportion of facilities at provincial, prefecture and county levels with any fluoroquinolone was respectively 74.1%, 64.9% and 34.5%. Sputum culture was performed at 6.0% of TB clinics at the county level, 37.5% at the prefecture and 59.3% at the provincial levels, while DST was performed only at the prefecture (28.6%) and provincial (44.4%) levels. Only 18% of the facilities that used SLDs for the treatment of multidrug-resistant TB (MDR-TB) based treatment regimens on DST results.SLDs are widely available in China for the treatment of both TB and other infectious diseases. To prevent the development of Mycobacterium tuberculosis resistance to SLDs, the availability of SLDs should be limited and they should be used with caution in the treatment of MDR-TB.

Kenya, a country with a high burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection.To assess the prevalence of TB infection, bacille Calmette-Guérin (BCG) coverage and the annual risk of tuberculosis infection (ARTI), and to compare estimates with previous findings.A sample of primary school children aged 6-14 years from the same study districts sampled in previous surveys were tuberculin skin tested using the Mantoux method from September 2004 to July 2007. The prevalence of TB infection was estimated by the mirror method, with the mode at 17 mm.Of the 94 771 registered children, 76 676 (80.9%) completed the survey investigations, 12 107 (15.8%) of whom had no BCG scar. The prevalence of TB infection was estimated at 10.2%, with a corresponding ARTI of 1.1%. The ARTI obtained from the current survey is comparable to that of the 1994-1996 survey and higher than that of the 1986-1990 survey. The BCG coverage was comparable with the 1994-1996 survey and higher than in the 1986-1990 survey.TB transmission in Kenya has remained the same over the last decade, which suggests that activities undertaken by the TB control programme have been sufficient to hold TB transmission steady, but insufficient to reduce it.

Uzbekistan has had 100% DOTS coverage since 2005; however, the treatment success rate has remained at around 80% for the last 4 years. Surveys from the capital city of Tashkent and from western Uzbekistan have shown high levels of primary multidrug resistance.To assess treatment regimens prescribed for new cases of tuberculosis (TB), including the prescription of additional non-TB drugs, and the cost implications for the patient.We randomly sampled 30 clusters of seven new TB patients. Enrolled patients were interviewed and their medical records were reviewed.In general, the treatment regimens prescribed were correct; doses were high rather than low. Second-line anti-tuberculosis drugs were rarely prescribed. In addition to anti-tuberculosis drugs, patients were prescribed on average seven to eight non-TB drugs. The rationale for prescribing the non-TB drugs was, however, questionable. Patients incurred substantial costs for these drugs, some of which were not without risk.Prescriptions of anti-tuberculosis drugs for new TB patients are adequate; however, the practice of prescribing additional non-TB drugs needs to be reconsidered.

Background Many tuberculosis (TB) patients in Indonesia are diagnosed late. We seek to document patient journeys toward TB diagnosis and treatment and factors that influence health care seeking behavior. Methods TB patients in Jogjakarta municipality (urban) and Kulon Progo district (rural) were recruited from health care facilities participating in the DOTS strategy and health care facilities not participating in the DOTS strategy, using purposive sampling methods. Data were collected through in-depth interviews with TB patients and members of their family and through Focus Group Discussions (FGD) with community members. Results In total, 67 TB patients and 22 family members were interviewed and 6 FGDs were performed. According to their care seeking behavior patients were categorized into National TB program's (NTP) dream cases (18%), 'slow-but-sure patients' (34%), 'shopaholics' (45%), and the NTP's nightmare case (3%). Care seeking behavior patterns did not seem to be influenced by gender, place of residence and educational level. Factors that influenced care seeking behavior include income and advice from household members or friends. Family members based their recommendation on previous experience and affordability. FGD results suggest that the majority of people in the urban area preferred the hospital or chest clinic for diagnosis and treatment of TB whereas in the rural area private practitioners were preferred. Knowledge about TB treatment being free of charge was better in the urban area. Many community members from the rural area doubted whether TB treatment would be available free of charge. Conclusion Most TB patients took over a month to reach a DOTS facility after symptoms appeared and had consulted a number of providers. Their income and advice from household members and friends were factors that influenced their care seeking behavior most.

The identification of pulmonary tuberculosis (TB) cases in a prevalence survey is a challenge, as diagnostic methods are labour-intensive and large numbers of individuals need to be screened because the prevalence rate is low (almost never greater than 1,200 per 100,000 population). Three testing methods are used: questionnaires, chest radiography (CXR) and bacteriological tests, including sputum smear microscopy and culture. These methods can be applied in four strategies to identify cases. The most sensitive strategy is to apply all methods to each eligible individual. The next most sensitive option is to apply the questionnaire, CXR and sputum smear microscopy to each eligible individual and obtain sputum for culture from those individuals with symptoms, abnormalities on the CXR or a positive smear. If laboratory capacity is limited, screening using symptom enquiry and CXR can be used to select those individuals at highest risk of TB. These individuals are then requested to submit sputum for smear microscopy and culture. If neither CXR nor culture is available, sputum samples may be collected from all eligible individuals and examined by an enhanced microscopy method such as fluorescence microscopy. Case definitions are ideally based on the combined results of symptom enquiry, CXR and bacteriology.

The size of the tuberculosis (TB) problem in Nepal is unknown, as no national tuberculin or TB prevalence survey has yet been performed.To assess the prevalence of TB infection and the annual risk of TB infection (ARTI) in primary schoolchildren in the three ecological zones (mountains, hills and terai) and Kathmandu valley.A representative sample of primary schoolchildren were tuberculin skin tested using the Mantoux method. The data were analysed using cut-off levels to define infection and by the mirror method.Of 19577 children registered, 17260 (88.2%) were available for analysis. Seventy-eight per cent had a visible bacille Calmette-Guérin scar. The best estimate of the prevalence of TB infection was 7.0% (95%CI 4.2-9.7), with an ARTI of 0.86% (95%CI 0.49-1.23) using the mirror method, with a mode at 16 mm. Although the ARTI was higher in Kathmandu and the mountains compared to the hills and terai, the difference between the areas was not significant.The ARTI in Nepal is lower than previous estimates, indicating a decrease in transmission or overestimation of previous estimates. To obtain information about the trend of the ARTI in Nepal, the survey needs to be repeated in 5 to 7 years.

To describe the epidemiology of extrapulmonary and pulmonary tuberculosis (TB) in The Netherlands between 1993 and 2001, with special attention given to the relationship between disease site and patient nationality.Retrospective descriptive and comparative study.Data were collected from all patients diagnosed with TB and entered in The Netherlands Tuberculosis Register between 1 January 1993 and 31 December 2001. Information on age, sex, nationality, year of diagnosis, culture result, disease site and HIV status was retrieved and compared.Of the total 13,258 TB patients, 8,216 (62%) had pulmonary TB and 5,042 (38%) had extrapulmonary TB. The proportion of extrapulmonary TB cases increased during the study period. The most common types of extrapulmonary TB were lymphatic TB, pleural TB and TB of the bones and/or joints. Patients with a non-Dutch nationality were diagnosed with extrapulmonary TB more often than Dutch patients.The proportional increase in extrapulmonary TB was explained by an increase in the number of inhabitants with non-Western ethnic backgrounds in The Netherlands. Physicians must be aware of the changing clinical picture of TB.

South Sulawesi Province, Republic of Indonesia.To compare relapse rates among tuberculosis (TB) patients treated with fixed-dose combination drugs (FDCs) and patients treated with the same regimen using loose drugs.Between 1999 and 2001, new smear-positive TB patients were randomly allocated to treatment with four-drug FDCs or loose drugs to study differences in treatment outcomes. Although it was not in the original study design, in 2004-2005 we performed a follow-up study by home visit of cured patients. We conducted an interview and tried to collect a sputum sample from each patient. If the patient was absent or had died, a proxy interview was conducted. The sputum samples were examined by microscopy and culture.The overall relapse rate was 7.0% in patients who were able to produce a sputum sample. Relapse appeared to be more frequent in the FDC group compared to the loose drug group (10.1% vs. 2.7%, P = 0.074).This is the first documented long-term follow-up study of patients treated with four-drug FDCs. There is an indication that treatment of new sputum smear-positive TB patients with FDCs provides an increased risk of relapse compared to treatment with loose drugs. The long-term results of treatment with FDCs should be carefully evaluated in other settings.

OBJECTIVE: To evaluate the validity of the fixed mathematical relationship between the annual risk of tuberculous infection (ARTI), the prevalence of smear-positive tuberculosis (TB) and the incidence of smear-positive TB specified as the Styblo rule, which TB control programmes use to estimate the incidence of TB disease at a population level and the case detection rate. METHODS: Population-based tuberculin surveys and surveys on prevalence of smear-positive TB since 1975 were identified through a literature search. For these surveys, the ratio between the number of tuberculous infections (based on ARTI estimates) and the number of smear-positive TB cases was calculated and compared to the ratio of 8 to 12 tuberculous infections per prevalent smear- positive TB case as part of the Styblo rule. FINDINGS: Three countries had national population-based data on both ARTI and prevalence of smear-positive TB for more than one point in time. In China the ratio ranged from 3.4 to 5.8, in the Philippines from 2.6 to 4.4, and in the Republic of Korea, from 3.2 to 4.7. All ratios were markedly lower than the ratio that is part of the Styblo rule. CONCLUSION: According to recent country data, there are typically fewer than 8 to 12 tuberculous infections per prevalent smear-positive TB case, and it remains unclear whether this ratio varies significantly among countries. The decrease in the ratio compared to the Styblo rule probably relates to improvements in the prompt treatment of TB disease (by national TB programmes). A change in the number of tuberculous infections per prevalent smear-positive TB case in population-based surveys makes the assumed fixed mathematical relationship between ARTI and incidence of smear-positive TB no longer valid.

We assessed the prevalence of tuberculosis (TB) human immunodeficiency virus (HIV) co-infection and identified risk factors for HIV infection in smear-positive TB patients diagnosed by the TB programme in Eritrea. Of 365 notified TB patients, 220 (60.3%) could be traced and provided a blood sample that was tested. Of these, 26 (11.8%, 95%CI 7.6-16.1) were HIV-infected. Risk factors were age, urban residence and schooling level. The data indicate that, starting with the urban areas, it is time for Eritrea to introduce HIV testing of all TB patients.

The Kiev City Health Administration published a new policy for human immunodeficiency virus (HIV) testing of tuberculosis (TB) patients. According to this policy, all TB patients should be offered voluntary HIV testing after counselling.To evaluate the implementation of the new HIV testing policy and to determine the HIV prevalence in TB patients in Kiev City.TB patient medical records were retrieved from eight TB facilities in Kiev City. They were reviewed for information about offering an HIV test, accepting to be HIV tested and outcome of the HIV test. Information was collected about patient characteristics and TB risk groups.Of 914 patients, 75% were offered HIV testing. Females were less frequently and alcohol abusers more frequently offered HIV testing. Of the patients who were offered HIV testing, 84% accepted. Of the 574 who were HIV tested, 36 (6.3%) had a positive test result.Not all TB facilities adhere strictly to the new policy. HIV testing seemed to be targeted to individuals with a high risk for HIV infection. To improve adherence to the new policy we recommend training of TB physicians in voluntary counselling and testing. The HIV prevalence among TB patients in Kiev City was 6.3%.

A novel nicotinoprotein, catalyzing the dichlorophenolindophenol-dependent oxidation of carveol to carvone, was purified to homogeneity from Rhodococcus erythropolis DCL14. The enzyme is specifically induced after growth on limonene and carveol. Dichlorophenolindophenol-dependent carveol dehydrogenase (CDH) is a homotetramer of 120 kDa with each subunit containing a tightly bound NAD(H) molecule. The enzyme is optimally active at pH 5.5 and 50 degrees C and displays a broad substrate specificity with a preference for substituted cyclohexanols. When incubated with a diastereomeric mixture of (4R)- or (4S)-carveol, CDH stereoselectively catalyzes the conversion of the (6S)-carveol stereoisomers only. Kinetic studies with pure stereoisomers showed that this is due to large differences in V(max)/K(m) values and simultaneous product inhibition by (R)- or (S)-carvone. The R. erythropolis CDH gene (limC) was identified in an operon encoding the enzymes involved in limonene degradation. The CDH nucleotide sequence revealed an open reading frame of 831 base pairs encoding a 277-amino acid protein with a deduced mass of 29,531 Da. The CDH primary structure shares 10-30% sequence identity with members of the short chain dehydrogenase/reductase superfamily. Structure homology modeling with trihydroxynaphthalene reductase from Magnaporthe grisea suggests that CDH from R. erythropolis DCL14 is an alpha/beta one-domain protein with an extra loop insertion involved in NAD binding and a flexible C-terminal part involved in monoterpene binding.

The Rhodobacter sphaeroides hemA gene codes for 5-aminolevulinate (ALA) synthase. This enzyme catalyzes the pyridoxal phosphate-dependent condensation of succinyl coenzyme A and glycine-forming ALA. The R. sphaeroides hemA gene in the pUC18/19 vector system was transformed into Escherichia coli. The effects of both genetic and physiological factors on the expression of ALA synthase and the production of ALA were studied. ALA synthase activity levels were maximal when hemA had the same transcription direction as the lac promoter. The distance between the lac promoter and hemA affected the expression of ALA synthase on different growth substrates. The E. coli host strain used had an enormous effect on the ALA synthase activity level and on the production of ALA, with E. coli DH1 being best suited. The ALA synthase activity level was also dependent on the carbon source. Succinate, L-malate, fumarate, and L-aspartate gave the highest levels of ALA synthase activity, while the use of lactose as a carbon source resulted in a repression of ALA synthase. After growth on succinate, ALA synthase represented approximately 5% of total cellular protein. The ALA synthase activity level was also dependent on the pH of the medium, with maximal activity occurring at pH 6.5. ALA production by whole cells was limited by the availability of glycine, and the addition of 2 g of glycine per liter to the growth medium increased the production of ALA fivefold, to 2.25 mM. In recombinant E. coli extracts, up to 22 mM ALA was produced from succinate, glycine, and ATP.