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BackgroundMolecular typing and whole genome sequencing (WGS) information is used for (inter-) national outbreak investigations. To assist the implementation of these techniques for tuberculosis (TB) surveillance and outbreak investigations at European level there is a need for inter-country collaboration and standardization. This demands more information on molecular typing practices and capabilities of individual countries. We aimed to review the use of molecular/genomic typing for TB surveillance in European Union and European Economic Area countries in 2016; assess its public health value; and collect experiences on typing data use for cross-border cluster investigations.MethodA web-based questionnaire was provided to all TB National Focal Points. The questionnaire consisted of three parts: i) Use and integration of molecular and genomic typing data into TB surveillance; ii) Cross-border cluster investigation and international collaboration, and iii) Perception and evaluation of public health benefits of molecular and genomic typing for TB surveillance.ResultsOf 26 responding countries, 20 used molecular typing for TB surveillance, including nine applying WGS. The level of integration into the national surveillance was heterogeneous. Among six countries not using typing for TB surveillance, more than half planned its implementation soon. Overall, most countries perceived an added public health value of molecular typing for TB control. Concerning international cluster investigations, countries had little experience and did not have standard protocols to exchange typing data.ConclusionOur study shows a wide use of molecular and genomic typing data for TB surveillance in EU/EEA countries and reveals that transition to WGS-based typing is ongoing or is considered in most countries. However, our results also show a high heterogeneity in the use and integration of typing data for TB surveillance. Standardization of typing data use for TB surveillance is needed and formal procedures should be developed to facilitate international collaboration.

BackgroundAn estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children.Methods and findingsTo inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged ConclusionsThis study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

BACKGROUND:Vulnerable individuals with tuberculosis (TB) struggle to access and stay on treatment. While patient-related and social barriers to TB treatment adherence are well documented, less is known about how the organisation and delivery of TB care influences adherence behaviour. AIM:To examine the influence of TB service organisation and culture on patients' experience of starting and staying on treatment in Riga, Latvia. METHODS:An intervention package to support adherence to TB treatment amongst vulnerable patients in Riga, Latvia was piloted between August 2016 and March 2017. Qualitative observations (5), interviews with staff (20) and with TB patients (10) were conducted mid-way and at the end of the intervention to understand perceptions, processes, and experiences of TB care. RESULTS:The organisation of TB services is strongly influenced by a divide between medical and social aspects of TB care. Communication and care practices are geared towards addressing individual risk factors for non-adherence rather than the structural vulnerabilities that patients experience in accessing care. Support for vulnerable patients is limited because of standardised programmatic approaches, resource constraints and restricted job descriptions for non-medical staff. CONCLUSION:Providing support for vulnerable patients is challenged in this setting by the strict division between medical and social aspects of TB care, and the organisational focus on patient-related rather than systems-related barriers to access and adherence. Potential systems interventions include the introduction of multi-disciplinary approaches and teams in TB care, strengthening patient literacy at the point of treatment initiation, as well as stronger linkages with social care organisations.

BACKGROUND:External quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants. METHODS:The ERLTB-Net developed seven EQA modules to test laboratories' proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme. RESULTS:A total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010-2014. The participation rate ranged from 52.9% - 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4). CONCLUSIONS:The European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA.

OBJECTIVE: To obtain an estimate of the prevalence of new cases of smear-positive tuberculosis in Eritrea using a new low-cost approach. METHODS: The study was designed to include a sample of 35 000 people divided between 40 clusters. The clusters were selected by sampling proportional to population size. In each cluster, census data were obtained from eligible individuals. Individuals aged 15 years or more were questioned about cough and its duration and smoking and were asked to provide two samples of sputum (spot and morning) for examination by fluorescence microscopy. FINDINGS: A total of 38 032 individuals were included in the study. Of the 19 197 individuals aged 15 years or more, 18 152 (94.6%) provided at least one sample of sputum. Fifteen individuals fulfilled the case definition, providing a prevalence of new cases of smear-positive tuberculosis of 90 per 100 000 (95% confidence interval, CI, 35-145 per 100 000) individuals aged 15 years or more and 50 per 100 000 (95% CI, 19-80 per 100 000) in the total population. CONCLUSION: The estimated prevalence of new cases of smear-positive tuberculosis obtained from our study is considerably lower than the estimate published by the World Health Organization. The new methodology for surveys to determine the prevalence of tuberculosis that we used is feasible in the field. This methodology should be validated in other countries and compared with other methods for measuring prevalence.

This study assessed progress towards tuberculosis (TB) elimination in the Netherlands by using DNA fingerprinting. Mycobacterium tuberculosis strains were defined as new if the IS6110 restriction fragment length polymorphism pattern had not been observed in any other patient during the previous 2 years. Other cases were defined as clustered and attributed to recent transmission. In the period 1995–2002, the incidence of TB with new strains was stable among non-Dutch residents and declined among the Dutch. However, the decline among the Dutch was restricted to those >65 years of age. Moreover, the average number of secondary cases per new strain did not change significantly over time. We conclude that the decline of TB in the Netherlands over the past decade was mainly the result of a cohort effect: older birth cohorts with high infection prevalence were replaced by those with lower infection prevalence. Under current epidemiologic conditions and control efforts, TB may not be eliminated.

A recent systematic review concluded that there is insufficient evidence on the effectiveness to support or reject preventive therapy for treatment of contacts of patients with multidrug resistant tuberculosis (MDR-TB). Whether preventive therapy is favorable depends both on the effectiveness and the adverse events of the drugs used. We performed a systematic review to assess adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB. We searched MEDLINE, EMBASE, and other databases (August 2011). Record selection, data extraction, and study quality assessment were done in duplicate. The quality of evidence was assessed using the GRADE approach. Of 6,901 identified references, 20 studies were eligible. Among the 16 studies in healthy volunteers (a total of 87 persons on either levofloxacin, moxifloxacin, ofloxacin, or rifabutin, mostly for 1 week), serious adverse events and treatment discontinuation due to adverse events were rare (

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning.In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition.As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.

BackgroundRecently, the tuberculosis (TB) Task Force Impact Measurement acknowledged the need to review the assumptions underlying the TB mortality estimates published annually by the World Health Organization (WHO). TB mortality is indirectly measured by multiplying estimated TB incidence with estimated case fatality ratio (CFR). We conducted a meta-analysis to estimate the TB case fatality ratio in TB patients having initiated TB treatment.MethodsWe searched for eligible studies in the PubMed and Embase databases through March 4(th) 2011 and by reference listing of relevant review articles. Main analyses included the estimation of the pooled percentages of: a) TB patients dying due to TB after having initiated TB treatment and b) TB patients dying during TB treatment. Pooled percentages were estimated using random effects regression models on the combined patient population from all studies.Main resultsWe identified 69 relevant studies of which 22 provided data on mortality due to TB and 59 provided data on mortality during TB treatment. Among HIV infected persons the pooled percentage of TB patients dying due to TB was 9.2% (95% Confidence Interval (CI): 3.7%-14.7%) and among HIV uninfected persons 3.0% (95% CI: -1.2%-7.4%) based on the results of eight and three studies respectively providing data for this analyses. The pooled percentage of TB patients dying during TB treatment was 18.8% (95% CI: 14.8%-22.8%) among HIV infected patients and 3.5% (95% CI: 2.0%-4.92%) among HIV uninfected patients based on the results of 27 and 19 studies respectively.ConclusionThe results of the literature review are useful in generating prior distributions of CFR in countries with vital registration systems and have contributed towards revised estimates of TB mortality This literature review did not provide us with all data needed for a valid estimation of TB CFR in TB patients initiating TB treatment.

BACKGROUND: The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data. METHODOLOGY AND PRINCIPAL FINDINGS: To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis. CONCLUSIONS: Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

BackgroundTuberculosis is a leading cause of death in people living with HIV (PLWH). We conducted a meta analysis to assess the effect of tuberculosis on mortality in people living with HIV.MethodsMeta-analysis of cohort studies assessing the effect of tuberculosis on mortality in PLWH. To identify eligible studies we systematically searched electronic databases (until December 2008), performed manual searches of citations from relevant articles, and reviewed conference proceedings. Multivariate hazard ratios (HR) of mortality in PLWH with and without tuberculosis, estimated in individual cohort studies, were pooled using random effect weighting according to "Der Simonian Laird method" if the p-value of the heterogeneity test was ResultsFifteen cohort studies were systematically retrieved. Pooled overall analysis of these 15 studies estimating the effect of tuberculosis on mortality in PLWH showed a Hazard Ratio (HR) of 1.8 (95% confidence interval (CI): 1.4-2.3). Subanalysis of 8 studies in which the cohort was not exposed to highly active antiretroviral therapy (HAART) showed an HR of 2.6 (95% CI: 1.8-3.6). Subanalysis of 6 studies showed that tuberculosis did not show an effect on mortality in PLWH exposed to HAART: HR 1.1 (95% CI: 0.9-1.3).ConclusionThese results provide an indication of the magnitude of benefit to an individual that could have been expected if tuberculosis had been prevented. It emphasizes the need for additional studies assessing the effect of preventing tuberculosis or early diagnosis and treatment of tuberculosis in PLWH on reducing mortality. Furthermore, the results of the subgroup analyses in cohorts largely exposed to HAART provide additional support to WHO's revised guidelines, which include promoting the initiation of HAART for PLWH co-infected with tuberculosis. The causal effect of tuberculosis on mortality in PLWH exposed to HAART needs to be further evaluated once the results of more cohort studies become available.

BACKGROUND: In 2004, an anti-tuberculosis (TB) drug resistance survey in Heilongjiang province, China, enrolled 1574 (79%) new and 421 (21%) retreatment patients. Multi-drug resistant (MDR) TB was detected in 7.2% of new and 30.4% of retreatment patients. All received treatment with standardized first-line drug (FLD) regimens. METHODOLOGY/PRINCIPAL FINDINGS: We report treatment outcomes of the 2004 cohort, and long-term outcomes as assessed in the second half of 2008. The reported cure rate for MDR-TB patients was 83% (94/113) among new and 66% (85/128) among retreatment patients (P

BACKGROUND: Cognitive dysfunction is clearly recognized in bipolar patients, but the degree of impairment varies due to methodological factors as well as heterogeneity in patient populations. The goal of this study was to evaluate cognitive functioning in bipolar patients and to assess its association with depressive symptoms. Post hoc the relationship with lifetime alcohol use disorder was explored. METHODOLOGY/PRINCIPAL FINDINGS: The study included 110 bipolar patients and 75 healthy controls. Patients with severe depressive symptoms, (hypo)manic symptoms and current severe alcohol use disorder were excluded. Diagnoses were evaluated via the Mini-International Neuropsychiatric Interview. Cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating. Patients were euthymic (n = 46) or with current mild (n = 38) or moderate (n = 26) depressive symptoms. Cognitive impairment was found in 26% (z-score 2 or more above reference control group for at least one domain) of patients, most prominent in executive functioning (effect size; ES 0.49) and speed of information processing (ES 0.47). Depressive symptoms were associated with dysfunction in psychomotor speed (adjusted beta 0.43; R(2) 7%), speed of information processing (adjusted beta 0.36; R(2) 20%), attentional switching (adjusted beta 0.24; R(2) 16%) and the mean score (adjusted beta 0.23; R(2) 24%), but not with verbal and visual memory and executive functioning. Depressive symptoms explained 24% of the variance in the mean z-score of all 6 cognitive domains. Comorbid lifetime alcohol use (n = 21) was not associated with cognitive dysfunction. CONCLUSIONS/SIGNIFICANCE: Cognitive dysfunction in bipolar disorder is more severe in patients with depressive symptoms, especially regarding speed and attention. Therefore, interpretation of cognitive functioning in patients with depressive symptoms should be cautious. No association was found between cognitive functioning and lifetime comorbid alcohol use disorder.

The targets of tuberculosis (TB) control programmes are to detect 70% of new sputum smear-positive cases of TB and to cure 85% of these. The Stop TB Partnership has set additional targets related to the Millennium Development Goals: to halve TB prevalence and mortality between 1990 and 2015. This paper assesses how confident we can be about the data on TB case detection, cure rates, prevalence and mortality. Countries were grouped into those with good, limited or poor information on the burden of TB (based on notification data, population surveys and vital registration systems). Of 211 countries with a total population of 6.4 billion and an estimated 8.9 million cases of TB, 27 countries with a total population of 2.2 billion and an estimated 1.8 million cases of TB had estimates based on good information (i.e. a good-quality surveillance system detecting > 70% of all cases, or a good-quality TB prevalence survey). Of the 22 countries with a high burden of TB and bearing 80% of the global burden, none had a good surveillance system in 1997. Vital registration systems were good in 81 countries with a total population of 2.7 billion. This paper suggests that globally and in the 22 countries with a high burden of TB there is considerable uncertainty about indicators to measure progress towards the Millennium Development Goals. Routine surveillance and vital registration systems need to be strengthened. We recommend that national TB prevalence surveys be performed in selected high-burden countries, in Africa in particular.

Background: Pulmonary tuberculosis (TB) is a major health problem worldwide. Detection of the most infectious cases of tuberculosis - sputum smear-positive pulmonary cases - by passive case finding is an essential component of TB control. The district of Sidoarjo in East Java reported a low case detection rate (CDR) of 14% in 2003. We evaluated the diagnostic process for TB in primary health care centers (PHC) in Sidoarjo district to assess whether problems in identification of TB suspects or in diagnosing TB patients can explain the low CDR. Methods: We performed interviews with the staff (general nurse, TB worker, laboratory technician, and head of health center) of the 25 PHCs of Sidoarjo district to obtain information about the knowledge of TB, health education practices, and availability of support services for TB diagnosis. The quality of the laboratory diagnosis was examined by providing 10 slides with a known result to the laboratory technicians for re-examination. Results: Eighty percent of the nurses and 84% of the TB workers knew that cough >3 weeks can be a symptom of TB. Only 40% of the nurses knew the cause of TB, few could mention complications of TB and none could mention the duration of infectiousness after start of treatment. Knowledge of TB workers was much better. Information about how to produce a good sputum sample was provided to TB suspects by 76% of the nurses and 84% of the TB workers. Only few provided all information. Fifty-five percent of the 11 laboratory technicians correctly identified all positive slides as positive and 45% correctly identified 100% of the negative slides as negative. All TB workers, one general nurses and 32% of the laboratory technicians had received specific training in TB control. There has been no shortage of TB forms and laboratory materials in 96% of the PHCs. Conclusion: The quality of the diagnostic process for TB at PHC in Sidoarjo district should be improved on all levels. Training in TB control of all general nurses and the laboratory technicians that have not received training would be a good first step to enhance diagnosis of TB and to improve the case detection rate. [ABSTRACT FROM AUTHOR]

Abstract Background The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro-GASP results from 2019 (26 countries), linked to patient epidemiological data, and compared with data from previous years. Methods Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-test and the Pearson's χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance. Results European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly-susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut-off (ECOFF); and ciprofloxacin which is displaying a similar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men-who-have-sex-with-men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and heterosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age. Conclusions Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithromycin “resistance” (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriaxone + azithromycin), i.e., for ceftriaxone-resistant cases, currently recommended in many countries internationally and requires close monitoring.

Abstract Background Tuberculosis (TB) control programmes rely heavily on laboratories to support both clinical care and public health. Qualified personnel with adequate technical and managerial skills comprise an integral component of any quality assured laboratory. Training a new generation of TB laboratory specialists was identified as a critical priority in the European Union /European Economic Area (EU/EEA). A tailored training programme for TB reference laboratory professionals was developed and implemented within the European Reference Laboratory Network for Tuberculosis to increase the pool of technical experts available to step into leadership roles in the TB laboratory community. Three cohorts of selected laboratory specialists participated in a series of trainings from 2009 to 2016. Methods We conducted an evaluation of the training programme using a structured questionnaire administered via the EUSurvey website, with the aim of documenting the benefits and contribution as well as suggesting improvements and future direction of the programme. All graduated participants and all current ERLTB-Net members were invited to participate in the online survey and descriptive quantitative analysis was performed. Results The evaluation found significant benefits for both the participants and the participants’ institutions, with improvements being reported in laboratory practices and management including implementation of new diagnostic techniques and career progression for participants. The training programme differed from other international and European initiatives in a number of important ways; the curriculum is unique in the scope and range of topics covered; the programme targets senior level professionals and future directors; cohorts were limited to 8–10 participants; and the programme involved a number of workshops (5–7) taking place over a two-year period. Relationships and collaborations established between individuals and institutions were valued as an important success of the initiative. Suggestions on how the impact of the programme could be enhanced included equipping participants to perform laboratory assessments in low-resource settings outside the EU, thus bolstering global TB control. Conclusion Based on the findings presented the training programme has proved to be successful in developing leadership, expertise, partnerships and networks to support TB laboratories and has contributed significant benefits to strengthening European National Reference laboratories in the fight against TB.

We surveyed availability of phenotypic drug susceptibility testing for drug-resistant Mycobacterium tuberculosis in Europe. Of 27 laboratories, 17 tested for linezolid, 11 for clofazimine, 9 for bedaquiline, and 6 for delamanid during 2019. Our findings indicate that testing capacity for newer and repurposed tuberculosis drugs exists, but its availability is limited.

Introduction An estimated 12% of tuberculosis (TB) patients are co-infected with HIV in the World Health Organization European Region (the Region). Reducing morbidity and mortality from HIV-associated TB requires strong collaboration between TB and HIV services at all levels with integrated people-centred models of care. Methods We collected information on the current models of integration of TB and HIV services in the Region via a comprehensive survey among the TB and HIV National Focal Points, and identified challenges and opportunities. Results 47 out of 55 (85%) countries responded. HIV testing in all TB patients and screening for active TB in all people living with HIV (PLHIV) was recommended in 40 (85%) and 34 (72%) countries, respectively. 30 (64%) countries recommended latent TB infection (LTBI) screening in all PLHIV, while 13 (28%) had a selective approach and four (9%) did not recommend LTBI screening. In most countries, testing for HIV and screening for active TB and LTBI was done by the specialist treating the patient, i.e. TB patients were tested for HIV by a TB specialist in 42 (89%) countries and PLHIV were screened for active TB by an HIV specialist in 34 (72%) countries. Conclusions TB and HIV care are well integrated in policies of especially high TB and high HIV burden countries; however, implementation needs to be improved. Continuous monitoring of TB and HIV services integration enables assessing the quality of TB/HIV care and to identify where further improvements are needed.

Abstract Background The Millennium Development Goals (MDG) provide targets for 2015. MDG 6 includes a target to reduce the tuberculosis (TB) death rate by 50% compared with 1990. We aimed to assess whether this target was reached by the European Union (EU) and European Economic Area countries. Methods We used Eurostat causes of death data to assess whether the target was reached in the EU. We calculated the reduction in reported and adjusted death rates and the annual average percentage decline based on the available data. Results Between 1999 and 2014, the TB death rate decreased by 50%, the adjusted death rate by 56% and the annual average percentage decline was 5.43% (95% confidence interval 4.94–6.74) for the EU. Twenty of 26 countries reporting >5 TB deaths in the first reporting year reached the target of 50% reduction in adjusted death rate. Conclusions The EU reached the MDG target of a 50% reduction of the TB death rate and also the annual average percentage decline was larger than the 2.73% needed to reach the target. The World Health Organization ‘End TB Strategy’ requires a further reduction of the number of TB deaths of 35% by 2020 compared to 2015, which will challenge TB prevention and care services in the EU.

Abstract Background In the European Union and European Economic Area only 38% of multidrug-resistant tuberculosis patients notified in 2011 completed treatment successfully at 24 months’ evaluation. Socio-economic factors and patient factors such as demographic characteristics, behaviour and attitudes are associated with treatment outcomes. Characteristics of healthcare systems also affect health outcomes. This study was conducted to identify and better understand the contribution of health system components to successful treatment of multidrug-resistant tuberculosis. Methods We selected four European Union countries to provide for a broad range of geographical locations and levels of treatment success rates of the multidrug-resistant tuberculosis cohort in 2009. We conducted semi-structured interviews following a conceptual framework with representatives from policy and planning authorities, healthcare providers and civil society organisations. Responses were organised according to the six building blocks of the World Health Organization health systems framework. Results In the four included countries, Austria, Bulgaria, Spain, and the United Kingdom, the following healthcare system factors were perceived as key to achieving good treatment results for patients with multidrug-resistant tuberculosis: timely diagnosis of drug-resistant tuberculosis; financial systems that ensure access to a full course of treatment and support for multidrug-resistant tuberculosis patients; patient-centred approaches with strong intersectoral collaboration that address patients’ emotional and social needs; motivated and dedicated healthcare workers with sufficient mandate and means to support patients; and cross-border management of multidrug-resistant tuberculosis to secure continuum of care between countries. Conclusion We suggest that the following actions may improve the success of treatment for multidrug-resistant tuberculosis patients: deployment of rapid molecular diagnostic tests; development of context-specific treatment guidance and criteria for hospital admission and discharge in the European context; strengthening patient-centred approaches; development of collaborative mechanisms to ensure cross-border care, and development of long-term sustainable financing strategies.

Background: Whole-genome sequencing (WGS) can support the investigation of tuberculosis (TB) outbreaks. The technique has been applied to estimate the timing and directionality of transmission and to exclude cases from an investigation. This review assesses how WGS was applied in international outbreak investigations and discusses the advantages and challenges of the application of WGS.Methods: Databases were searched for reports on international TB outbreak investigations. Information was extracted on: Why was WGS applied?; How was WGS applied?; Organizational issues; WGS methodology; What was learned/what were the implications of the WGS investigation?; and challenges and lessons learned.Results: Three studies reporting on international outbreak investigations were identified. Retrospective WGS sequencing was performed in all studies and prospective typing in two to study TB transmission. In one study, WGS data were produced centrally (i.e., in one laboratory) and analysis was done centrally. In two studies, WGS data production was done in a decentralized manner, and analysis was centralized in one laboratory. Three groups of professionals were involved in the international outbreak investigation: public health authorities, laboratory experts, and clinicians. The reported WGS methodology applied differed between the studies in some aspects, e.g., sequencing platform; quality measures, percentage of the reference genome covered, and the mean genomic coverage; analysis, use of a reference genome or de novo assembly; and software used for alignment and analysis. In all three studies, in-house scripts were used for variance calling, and the single nucleotide polymorphism (SNP) approach was used for analysis. All outbreak investigation reports stated that WGS refuted suspected transmission events and provided supporting evidence for epidemiological data. Several challenges were reported of which most were not related to WGS. The only challenge related to WGS was the timeframe of getting WGS data if WGS is not routinely performed.Conclusions: WGS was considered a useful addition in international TB outbreak investigations. Further standardization of the WGS methodology and good structures for international collaboration and coordination are needed to take full advantage of this new technology. Whether the use of WGS results in earlier detection of cases and thus limits transmission still needs to be determined.

Background: Despite the implementation of Directly Observed Treatment Short-course (DOTS) strategy in all public health centers in Papua Province, Indonesia, since 1998, the rate of loss to follow-up (LTFU) during tuberculosis (TB) treatment remains high (above 16%). Objectives: We aimed to identify factors associated with non-adherence during TB treatment among patients treated at public health centers (PHCs) in Jayapura, Papua. Method: We conducted a case-control study including new TB patients registered at eight PHCs from 2007 to 2009. Non-adherent cases were TB patients with a history of not taking anti-TB drugs for >2 consecutive weeks or >30 days cumulatively. Controls were randomly selected from patients who completed all doses of TB drugs in time. Data were collected by face-to-face interview using a pre-structured questionnaire and analyzed with logistic regression models. Results: Data were available for 81 of 103 eligible cases and 183 of 206 eligible controls. Difficult access to healthcare (i.e. reported to have a problem with distance/travel cost and history of moving residence in the past year), lack of TB knowledge (i.e. lack of knowledge about TB transmission and the cause of TB and unawareness of the consequences of stopping TB treatment), and treatment experience (i.e. lack of TB education provided by TB nurse and the use of loose vs. fixed-dose combinations) were associated with non-adherence during TB treatment in the adjusted model, as were being aged under 35 years and having a history of TB in the family. Conclusion: Our results suggest the need to improve TB treatment delivery especially to those who have difficult access to healthcare, and to routinely provide education to increase patients’ knowledge about TB and TB treatment. In addition, more attention to younger patients and those with a history of TB in their family is also needed.

We conducted a case–control study to investigate risk factors for multidrug-resistant tuberculosis (MDR TB) in the People’s Republic of China. Genotyping analysis was used to estimate the percentage of cases from recent transmission among 100 MDR TB case-patients hospitalized during April 2007–July 2009. Molecular subtyping of isolates showed that 41% of MDR TB strains clustered. Beijing genotype was found in 94% of the MDR TB isolates and 79% of the pan-susceptible isolates. In multivariate analysis, MDR TB was independently associated with Beijing genotype, retreatment for TB, symptoms lasting >3 months before first evaluation at the hospital, lack of health insurance, and being a farmer (vs. being a student). MDR TB was associated with Beijing genotype and lower socioeconomic status. A large percentage of MDR TB cases seemed to result from recent transmission. Early detection, effective treatment, and infection control measures for MDR TB are needed to reduce transmission.

The frequency of typical and atypical Beijing strains of Mycobacterium tuberculosis was determined in the Netherlands; Vietnam; and Hong Kong Special Administrative Region, People’s Republic of China. The strains’ associations with drug resistance, M. bovis BCG vaccination, and patient characteristics were assessed. BCG vaccination may have positively selected the prevalent typical Beijing strains.

This study describes the epidemiology of extrapulmonary tuberculosis (TB) in the Netherlands from 1993 through 2001. We assessed whether the increasing numbers of inhabitants with a non-Western ethnic background had an effect on the number of extrapulmonary patients. We used data from the Netherlands Tuberculosis Register and included all cases of TB diagnosed in the Netherlands between January 1, 1993, and December 31, 2001. Information on age, sex, nationality, year of diagnosis, culture result, anatomic location of the site of disease, and HIV status was retrieved from the register. Of 13,258 patients with TB, 8,216 (62%) had pulmonary TB, and 5,042 (38%) had extrapulmonary TB. Non-Dutch nationals were more likely to have most types of extrapulmonary TB. The growth of the number of inhabitants with a non-Western ethnic background in the Netherlands explains the proportional growth of extrapulmonary TB. Physicians need to be aware of the changing clinical picture of TB.

We used results from a national tuberculosis prevalence survey in Eritrea to calculate case detection rate (CDR) and compared it with the published CDR. The CDR obtained from the survey was ≈40%, whereas the CDR published by the World Health Organization was 3× lower (14%).

In 2004, we tested all patients with newly diagnosed tuberculosis (TB) for HIV in Kiev City. The results were compared to information from medical records of 2002, when co-infection prevalence was 6.3%. Of 968 TB patients, 98 (10.1%) were HIV infected. TB-HIV co-infection is increasing, especially in injecting drug users.