The Union and Médecins Sans Frontières approach to operational research.

Operational research (OR) has become a hot topic at national meetings, international conferences and donor fora. The International Union Against Tuberculosis and Lung Disease (The Union) and Médecins Sans Frontières (MSF) Operational Centre Brussels strongly promote and implement OR with colleagues in low- and middle-income countries. Here we describe how the two organisations define OR, and explain the guiding principles and methodology that underpin the strategy for developing and expanding OR in those countries. We articulate The Union's and MSF's approach to supporting OR, highlighting the main synergies and differences. Then, using the Malawi National Tuberculosis Control Programme as an example, we show how OR can be embedded within tuberculosis control activities, leading to changes in policy and practice at the national level. We discuss the difficult, yet vitally important, issue of capacity building, and share our vision of a new paradigm of product-related training and performance-based OR fellowships as two ways of developing the necessary skills at country level to ensure research is actually performed. Finally, we highlight the need to consider and incorporate into practice the ethical components of OR. This is a key moment to be involved in OR. We are confident that in partnership with interested stakeholders, including the World Health Organization, we can stimulate the implementation of quality, relevant OR as an integral part of health service delivery that in turn will lead to better health for people, particularly for those living in the poorer parts of the world

Uloga testova otpuštanja interferona gama u nadzoru nad tuberkulozom

Tuberculosis is still one of the major global public health threats. Countries with low incidence must focus on exhausting the reservoir of future cases by preventing reactivation. Therefore, it is important to identify and effectively treat those individuals who have latent tuberculosis infection and who may develop active disease. The tuberculin skin test has been the standard for detection of immune response against M. tuberculosis since the beginning of the 20th century. The new millennium has brought advancement in the diagnosis of latent tuberculosis infection. The name of the new blood test is interferon-gamma release assay (IGRA). Croatia is a middle-incidence country with a long decreasing trend and developed tuberculosis control. To reach low incidence and finally eliminate tuberculosis, its tuberculosis programme needs a more aggressive approach that would include intensive contact investigation and treatment of persons with latent tuberculosis infection. This article discusses the current uses of IGRA and its role in tuberculosis control.Tuberkuloza je i danas jedan od vodećih javnozdravstvenih problema. Zemlje s niskom incidencijom fokusiraju se na iscrpljivanje rezervoara budućih slučajeva sprječavanjem reaktivacije bolesti. To se odnosi na traženje i učinkovito liječenje infi ciranih osoba, primarno onih koje su u riziku od obolijevanja nakon infekcije. Tuberkulinski test je od početka 20. stoljeća bio standard u otkrivanju imunosnog odgovora na kontakt s Mycobacterium tuberculosis. Novo tisućljeće donijelo je određeni napredak u obliku novih testova za dijagnozu latentne tuberkulozne infekcije, krvne testove otpuštanja interferona gama. Hrvatska je zemlja srednje incidencije tuberkuloze s dugogodišnjim silaznim trendom i razvijenim protutuberkuloznim aktivnostima. U težnji prema niskoj incidenciji i u konačnici eliminaciji tuberkuloze potrebne su opsežnije aktivnosti unutar državnog programa nadzora nad tuberkulozom, uključujući intenzivnu obradu kontakata i probir na postojanje latentne tuberkulozne infekcije. Ovaj rad razmatra trenutačnu uporabu IGRE (engl. interferon - gamma release assay) i njezinu ulogu u nadzoru nad tuberkulozom

Recommendations for the diagnosis of pediatric tuberculosis

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease

Impact of molecular genetic methods on the initiation of chemotherapy in multiple drug resistant tuberculosis patients in Arkhangelsk Region

In the Arkhangelsk Region, the prevalence of multiple drug-resistant tuberculosis is one of the highest in the world. In 2016, the portion of multiple drug resistant tuberculosis made 33.1% among new cases and 59.5% among relapses. Using new molecular genetic diagnostic techniques allows reducing the time for diagnostics of tuberculosis and drug resistance and should result in the earlier start of adequate treatment. The goal of the study is to assess the impact of new diagnostic molecular genetic methods on the time period from the first referral for medical care till the start of MDR-TB treatment. It was assumed that the introduction of molecular genetic tests would lead to early initiation of treatment in MDR TB patients (the research project of the International Union Against Tuberculosis and Lung Diseases and Tuberculosis Control Program of Arkhangelsk Region on The PROVE-IT LPA; Policy Relevant Outcomes from Validating Evidence on Impact of Line Probe Assays). Subjects and Methods. The results of the diagnostic procedure using cultures were compared with the results of the procedure based on molecular genetic tests aimed to detect MDR-TB. 295 MDR TB patients were enrolled into the study, of them, 163 had culture and 132 had molecular genetic tests. Results. The use of molecular genetic tests in smear-positive patients (AFB+) resulted in the reduction of the time period before initiation of MDRTB treatment by 50 and 66 days (median) versus culture by BacTAlert and absolute concentration on Lowenstein-Jensen medium respectively (p <0.001). Patients with a negative smear (AFB-), in whom MDR TB was detected by molecular genetic methods started treatment by 78 days earlier (median) versus patients who had culture (Lowenstein-Jensen, p < 0.001). Despite the significant reduction in the time period, even using molecular genetic methods, it took 24 days for cases with AFB+ and 62 days for cases with AFB- to be notified and start treatment of MDR TB

A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

BACKGROUND: Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-γ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells. METHODS AND RESULTS: IFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC(50)-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells. The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC(50 )concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle. CONCLUSION: Our data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors

Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil

Contexto: A implementação do teste rápido de sensibilidade a medicamentos (TSD) é uma prioridade global atual para o controle da TB. No entanto, há poucos dados sobre os resultados relevantes para o paciente para o diagnóstico presuntivo de tuberculose resistente a medicamentos (TB-DR) avaliados em condições de campo em países com alta carga. Métodos: Estudo observacional de pacientes com TB-DR encaminhados por unidades de saúde primárias e secundárias. Centros de referência para TB que abordam TB-DR em cinco cidades do Brasil. Pacientes com 18 anos ou mais eram elegíveis se TB-DR, resultados positivos de cultura para Mycobacterium tuberculosis e, se nenhum resultado de TSD anterior de outro laboratório fosse usado por um médico para iniciar o tratamento anti-TB. As medidas de resultados foram o tempo médio da triagem até o início do tratamento anti-TB apropriado, o tratamento empírico e os resultados do tratamento. Resultados: Entre 16 de fevereiro de 2011 e 15 de fevereiro de 2012, entre 175 casos de TB-DR, 110 (63,0%) casos confirmados de TB com resultados de TSD foram incluídos. Entre os participantes do estudo, 72 (65,5%) eram do sexo masculino e 62 (56,4%) tinham entre 26 e 45 anos. Na triagem, o tratamento empírico foi administrado a 106 (96,0%) indivíduos. Entre eles, 85 foram tratados com medicamentos de primeira linha e 21 com medicamentos de segunda linha. O tempo mediano para os resultados do DST foi de 69,5 [interquartil-IQR: 35,7–111,0] dias e, para iniciar o tratamento anti-TB apropriado, o tempo mediano foi de 1,0 (IQR: 0–41,2) dias. Entre 95 pacientes que foram acompanhados durante o primeiro período de 6 meses, 24 (25,3%; IC: 17,5%–34,9%) mudaram ou iniciaram o tratamento após os resultados do DST: 16/29 casos de MDRTB, 5/21 de DR-TB e 3/45 de DS-TB. Comparando o resultado do tratamento com os casos de DS-TB, a MDRTB teve maiores proporções de mudança ou início do tratamento após os resultados do DST (p = 0,01) e resultados favoráveis ​​(p = 0,07). Conclusões: Este estudo mostra uma alta taxa de tratamento empírico e longo atraso para os resultados do DST. Estratégias para acelerar a detecção e o tratamento precoce da TB resistente a medicamentos devem ser priorizadas.Background: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries. Methods: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes. Results: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile- IQR: 35.7–111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0–41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%–34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07). Conclusions: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized