Ectopic Expression of Neurogenin 2 Alone is Sufficient to Induce Differentiation of Embryonic Stem Cells into Mature Neurons

Recent studies show that combinations of defined key developmental transcription factors (TFs) can reprogram somatic cells to pluripotency or induce cell conversion of one somatic cell type to another. However, it is not clear if single genes can define a cell̀s identity and if the cell fate defining potential of TFs is also operative in pluripotent stem cells in vitro. Here, we show that ectopic expression of the neural TF Neurogenin2 (Ngn2) is sufficient to induce rapid and efficient differentiation of embryonic stem cells (ESCs) into mature glutamatergic neurons. Ngn2-induced neuronal differentiation did not require any additional external or internal factors and occurred even under pluripotency-promoting conditions. Differentiated cells displayed neuron-specific morphology, protein expression, and functional features, most importantly the generation of action potentials and contacts with hippocampal neurons. Gene expression analyses revealed that Ngn2-induced in vitro differentiation partially resembled neurogenesis in vivo, as it included specific activation of Ngn2 target genes and interaction partners. These findings demonstrate that a single gene is sufficient to determine cell fate decisions of uncommitted stem cells thus giving insights into the role of key developmental genes during lineage commitment. Furthermore, we present a promising tool to improve directed differentiation strategies for applications in both stem cell research and regenerative medicine

ShORRT (Short, all-Oral Regimens for Rifampicin-resistant Tuberculosis) Research Package

TDR in close collaboration with the Global TB Programme at WHO and technical partners the WHO Global TB Programme is leading the development of ShORRT (Short, all-Oral Regimens For Rifampicin-resistant Tuberculosis), an operational research package to assess the effectiveness, safety, feasibility, acceptability, cost and impact (including on health-related quality of life) of the use of all-oral shorter drug regimens for adults and children with MDR/RR-TB

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking

Efficacy and tolerability of ethionamide<i>versus</i>prothionamide: a systematic review

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Treatment of drug-susceptible and drug-resistant tuberculosis

The treatment of TB, both drug-susceptible and drug-resistant forms, should be based on two principles: 1) the combination of drugs (at least four) to avoid selection pressure resulting in the emergence of DR-TB strains and 2) the need for prolonged treatment in order to sterilise all infectious sites and thus cure the patient and prevent relapses. The selection of drugs should be based on their bactericidal and sterilising properties, their ability to prevent drug resistance and their safety profile. Based on these principles, and on the mode of action of the different drugs, this chapter describes in detail anti-TB treatment, the most appropriate choice of drugs based on in vitro susceptibility testing, starting withdrug-susceptible TB (DS-TB), and a proposal to standardise as much as possible the difficult-to-manage patients with DR-TB. The chapter delineates the recommended treatment for DS-TB, mono- and polyresistant TB, MDR-TB, XDR-TB and forms of TB beyond XDR-TB. Special attention is given to the 2018 WHO guidelines regarding the revised grouping of second-line TB drugs recommended for use in longer MDR-TB regimens, the shorter MDR-TB regimens, the possibility of designing a standardised pre-XDR and XDR-TB regimen adapted to the country, and some relevant management issues

Treatment of drug-susceptible and drug-resistant tuberculosis

The treatment of TB, both drug-susceptible and drug-resistant forms, should be based on two principles: 1) the combination of drugs (at least four) to avoid selection pressure resulting in the emergence of DR-TB strains and 2) the need for prolonged treatment in order to sterilise all infectious sites and thus cure the patient and prevent relapses. The selection of drugs should be based on their bactericidal and sterilising properties, their ability to prevent drug resistance and their safety profile. Based on these principles, and on the mode of action of the different drugs, this chapter describes in detail anti-TB treatment, the most appropriate choice of drugs based on in vitro susceptibility testing, starting with drug-susceptible TB (DS-TB), and a proposal to standardise as much as possible the difficult-to-manage patients with DR-TB. The chapter delineates the recommended treatment for DS-TB, mono- and polyresistant TB, MDR-TB, XDR-TB and forms of TB beyond XDR-TB. Special attention is given to the 2018 WHO guidelines regarding the revised grouping of second-line TB drugs recommended for use in longer MDR-TB regimens, the shorter MDR-TB regimens, the possibility of designing a standardised pre-XDR and XDR-TB regimen adapted to the country, and some relevant management issues

Pediatric Tuberculosis Research and Development: Progress, Priorities and Funding Opportunities

In this article, we highlight technological pediatric TB research advances across the TB care cascade; discuss recently completed or ongoing work in adults and corresponding significant research gaps for children; and offer recommendations and opportunities to increase investments and accelerate pediatric TB R&amp;D

Classifying new anti-tuberculosis drugs: rationale and future perspectives

The classification of anti-tuberculosis (TB) drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO) has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2–5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification) and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed