Identifying patients with multidrug-resistant tuberculosis who may benefit from shorter durations of treatment.

OBJECTIVE: Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment. STUDY DESIGN AND SETTING: We conducted an individual patient data meta-analysis among MDR/RR-TB patients restricted to only those with successful treatment outcomes. Using multivariable linear regression, we estimated associations and their 95% confidence intervals (CI) between the outcome of individual deviation in treatment duration (in months) from the mean duration of their treatment site and patient characteristics, drug resistance, and treatments used. RESULTS: Overall, 6702 patients with successful treatment outcomes from 84 treatment sites were included. We found that factors commonly associated with poor treatment outcomes were also associated with longer treatment durations, relative to the site mean duration. Use of bedaquiline was associated with a 0.51 (95% CI: 0.15, 0.87) month decrease in duration of treatment, which was consistent across subgroups, while MDR/RR-TB with fluoroquinolone resistance was associated with 0.78 (95% CI: 0.36, 1.21) months increase. CONCLUSION: We describe a method to assess associations between clinical factors and treatment duration in observational studies of MDR/RR-TB patients, that may help identify patients who can benefit from shorter treatment.

In support of 2D:4D: More data exploring its conflicting results on handedness, sexual orientation and sex differences.

In the last few years, several studies have questioned the value of the second-to-fourth digit ratio (2D:4D) as a measure of exposure to sex hormones before birth. Controversy has also extended to the 2D:4D association with individual features previously related to this exposure such as handedness and sexual orientation. Given that it has been argued that sex differences in 2D:4D could be a consequence of body-size differences, we have tested in a large sample the allometric relationship between finger lengths and body size. Our results show that the association is either allometric or isometric, depending on the analyses performed. In any case, the deviation from isometry is not large enough to explain the typically observed sex difference in this trait. We have also tested the association between sexual orientation and 2D:4D, finding a relationship between 2D:4D and sexual orientation in men but not in women. We attribute this discordance with previously published meta-analysis to differences in genetic background, a variable that has gained relevance in recent years in studies involving 2D:4D. Finally, we did not find any relationship between 2D:4D and handedness, evaluated through self-reported preference and hand performance. Our main conclusion is that 2D:4D shows differences between sexes beyond their disparity in body size. In our opinion, 2D:4D can be used cautiously as an indicator of intrauterine exposure to sex hormones taking into account some considerations, such as analysing a very large sample and taking careful measurements of the ethnicity of the sample.

The paradigm shift to end tuberculosis. Are we ready to assume the changes?

INTRODUCTION: Tuberculosis (TB) is the number one infectious disease killer and exemplifies the most neglected of them. Drug-susceptible TB presents with high mortality especially in atypical forms, disproportionally affecting immunosuppressed and vulnerable populations. The drug-resistant TB (DR-TB) epidemic, a world crisis, is sustained and increased through person-to-person transmission in households and the community. TB diagnostics and treatment in recent years are highly evolving fields. New rapid molecular tests are changing the perspectives in diagnosis and resistance screening. Also, new drugs and shorter regimens for DR-TB are appearing. For the first time in recent history, a large number of randomized control trials are incoming. Areas covered: This article reviews most TB advances including new diagnostic tests, drugs, and regimens and outlines upcoming drug trials while disclosing the potential gaps the in development of patient-centered systems and current organizational challenges leading to a delay in the uptake of these innovations. Expert commentary: Innovations are occurring, but not many are implemented on a wide scale in developing countries. TB health systems and staff are not getting updated in parallel. More efforts and funds are needed not only to implement current novelties but also to research for future solutions to eliminate TB.

Two Algorithms for High-throughput and Multi-parametric Quantification of Drosophila Neuromuscular Junction Morphology.

Synaptic morphology is tightly related to synaptic efficacy, and in many cases morphological synapse defects ultimately lead to synaptic malfunction. The Drosophila larval neuromuscular junction (NMJ), a well-established model for glutamatergic synapses, has been extensively studied for decades. Identification of mutations causing NMJ morphological defects revealed a repertoire of genes that regulate synapse development and function. Many of these were identified in large-scale studies that focused on qualitative approaches to detect morphological abnormalities of the Drosophila NMJ. A drawback of qualitative analyses is that many subtle players contributing to NMJ morphology likely remain unnoticed. Whereas quantitative analyses are required to detect the subtler morphological differences, such analyses are not yet commonly performed because they are laborious. This protocol describes in detail two image analysis algorithms "Drosophila NMJ Morphometrics" and "Drosophila NMJ Bouton Morphometrics", available as Fiji-compatible macros, for quantitative, accurate and objective morphometric analysis of the Drosophila NMJ. This methodology is developed to analyze NMJ terminals immunolabeled with the commonly used markers Dlg-1 and Brp. Additionally, its wider application to other markers such as Hrp, Csp and Syt is presented in this protocol. The macros are able to assess nine morphological NMJ features: NMJ area, NMJ perimeter, number of boutons, NMJ length, NMJ longest branch length, number of islands, number of branches, number of branching points and number of active zones in the NMJ terminal.

Presynaptic Aß40 prevents synapse addition in the adult Drosophila neuromuscular junction.

Complexity in the processing of the Amyloid Precursor Protein, which generates a mixture of ßamyloid peptides, lies beneath the difficulty in understanding the etiology of Alzheimer's disease. Moreover, whether Aß peptides have any physiological role in neurons is an unresolved question. By expressing single, defined Aß peptides in Drosophila, specific effects can be discriminated in vivo. Here, we show that in the adult neuromuscular junction (NMJ), presynaptic expression of Aß40 hinders the synaptic addition that normally occurs in adults, yielding NMJs with an invariable number of active zones at all ages tested. A similar trend is observed for Aß42 at young ages, but net synaptic loss occurs at older ages in NMJs expressing this amyloid species. In contrast, Aß42arc produces net synaptic loss at all ages tested, although age-dependent synaptic variations are maintained. Inhibition of the PI3K synaptogenic pathway may mediate some of these effects, because western analyses show that Aß peptides block activation of this pathway, and Aß species-specific synaptotoxic effects persists in NMJs overgrown by over-expression of PI3K. Finally, individual Aß effects are also observed when toxicity is examined by quantifying neurodegeneration and survival. Our results suggest a physiological effect of Aß40 in synaptic plasticity, and imply different toxic mechanisms for each peptide species.

A New Fiji-Based Algorithm That Systematically Quantifies Nine Synaptic Parameters Provides Insights into Drosophila NMJ Morphometry.

The morphology of synapses is of central interest in neuroscience because of the intimate relation with synaptic efficacy. Two decades of gene manipulation studies in different animal models have revealed a repertoire of molecules that contribute to synapse development. However, since such studies often assessed only one, or at best a few, morphological features at a given synapse, it remained unaddressed how different structural aspects relate to one another. Furthermore, such focused and sometimes only qualitative approaches likely left many of the more subtle players unnoticed. Here, we present the image analysis algorithm 'Drosophila_NMJ_Morphometrics', available as a Fiji-compatible macro, for quantitative, accurate and objective synapse morphometry of the Drosophila larval neuromuscular junction (NMJ), a well-established glutamatergic model synapse. We developed this methodology for semi-automated multiparametric analyses of NMJ terminals immunolabeled for the commonly used markers Dlg1 and Brp and showed that it also works for Hrp, Csp and Syt. We demonstrate that gender, genetic background and identity of abdominal body segment consistently and significantly contribute to variability in our data, suggesting that controlling for these parameters is important to minimize variability in quantitative analyses. Correlation and principal component analyses (PCA) were performed to investigate which morphometric parameters are inter-dependent and which ones are regulated rather independently. Based on nine acquired parameters, we identified five morphometric groups: NMJ size, geometry, muscle size, number of NMJ islands and number of active zones. Based on our finding that the parameters of the first two principal components hardly correlated with each other, we suggest that different molecular processes underlie these two morphometric groups. Our study sets the stage for systems morphometry approaches at the well-studied Drosophila NMJ.

A new role of Klumpfuss in establishing cell fate during the GMC asymmetric cell division.

Studies in the Drosophila embryonic NB4-2 lineage have suggested that the transcription factor Klumpfuss (Klu) functions within embryonic neuroblast lineages to differentiate between the identities of two adjacent ganglion mother cells (GMCs). However, because of the limited lineage markers available, these observations have been made only for the NB4-2 lineage. Recent findings have placed this transcription factor in the vanguard of Drosophila neural stem cell biology by demonstrating that Klu is necessary for larval neuroblast growth and self-renewal. Here, we have studied the role of klu in an incipient model in order to address basic mechanisms of neural specification: the Va system. None of the previously reported roles of Klu satisfactorily explain our observations. Unexpectedly, in this lineage, klu is necessary for differentiating between the fates of the two neurons born from a unique GMC; klu mutants produce two B-type cells, rather than one B-type (Notch-OFF) and one A-type (Notch-ON) cell. Additionally, our results demonstrate that Klu operates in the GMC and/or in the newly born neuron, but not in the neuroblast. Unlike in larval neuroblasts in which Klu is an executor of Notch signaling, we have found that Klu does not lie downstream of the Notch pathway in this cell division context.

Changes in preference for male faces during the menstrual cycle in a Spanish population / Cambios en la preferencia por rostros masculinos durante el ciclo menstrual en población española

A recent and controversial hypothesis suggests the presence of an oestrus phase in women as in other mammals. This implies that women at their optimal fertility point of the menstrual cycle exhibit behaviors focused to maximize the genetic quality of their offspring. Several studies support this hypothesis, finding that women in the fertile phase tend to prefer men with traits associated to phenotypic quality, such as greater facial masculinization and symmetry. We experimentally tested some of the observations supporting this hypothesis in a population of 810 young Spanish women. We analyzed whether the preference for masculinized male faces is affected by I) the phase of the menstrual cycle, II) having a stable partner and III) the use of birth control pills. We could not repro-duce the effect of the first two factors, but we found that women using hormonal contraceptives tend to prefer men with less masculine faces. These results indicate that some of the evidences supporting the oestrus hypothesis in humans must be reviewed, incorporating data from different socio-cultural and ethnic populations

Recientemente se ha postulado una controvertida hipótesis que propone la presencia de un periodo de estro en las mujeres, como ocurre en otros mamíferos. Ello implica que las mujeres en el óptimo de fertilidad del ciclo menstrual presenten comportamientos encaminados a maximizar la calidad genética de su descendencia. Diversas investigaciones sostienen esta hipótesis, al encontrar que las mujeres en la fase fértil prefieren hombres con rasgos que denotan mayor calidad fenotípica, como un mayor grado de masculinización o una mayor simetría. Nuestro objetivo ha sido testar experimentalmente en una población de 810 jóvenes españolas alguna de estas observaciones. Analizamos si, tal como se recoge en la bibliografía, la preferencia por rostros de hombres masculinizados se ve afectada por I) la etapa del ciclo menstrual, II) el tener pareja estable y III) el empleo anticonceptivos hormonales. No hemos podido reproducir el efecto de los dos primeros factores, pero sí encontramos que las mujeres que emplean anticonceptivos hormonales prefirieron rostros de hombre menos masculinos. Estos resultados no refutan la hipótesis del estro en humanos, pero nos indican que algunas de las pruebas que la sustentan han de ser reconsideradas, incorporando datos de poblaciones étnica y socioculturalmente diferentes

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.

Common errors in multidrug-resistant tuberculosis management.

Multidrug-resistant tuberculosis (MDR-TB), defined as being resistant to at least rifampicin and isoniazid, has an increasing burden and threatens TB control. Diagnosis is limited and usually delayed while treatment is long lasting, toxic and poorly effective. MDR-TB management in scarce-resource settings is demanding however it is feasible and extremely necessary. In these settings, cure rates do not usually exceed 60-70% and MDR-TB management is novel for many TB programs. In this challenging scenario, both clinical and programmatic errors are likely to occur. The majority of these errors may be prevented or alleviated with appropriate and timely training in addition to uninterrupted procurement of high-quality drugs, updated national guidelines and laws and an overall improvement in management capacities. While new tools for diagnosis and shorter and less toxic treatment are not available in developing countries, MDR-TB management will remain complex in scarce resource settings. Focusing special attention on the common errors in diagnosis, regimen design and especially treatment delivery may benefit patients and programs with current outdated tools. The present article is a compilation of typical errors repeatedly observed by the authors in a wide range of countries during technical assistant missions and trainings.

Tuberculosis Multidrogorresistente: una enfermedad, dos realidades diferentes / No disponible

La tuberculosis multidrogorresistente (TB-MDR) es una de las enfermedades emergentes que más alerta está causando nivel mundial. Intrínsecamente ligada a pobreza, la TB-MDR está afectando de forma diferente a países desarrollados y en vías de desarrollo. La desigual distribución de la enfermedad, forma de diagnóstico, tratamiento y especialmente pronóstico, está condicionando dinámicas de epidemia distintas a pesar de una misma etiología y patogenia. En este artículo se muestran punto por punto las diferencias y similitudes entre la presentación de la enfermedad en países ricos y pobres (AU)

Multidrug resistant tuberculosis (MDR-TB) is one of the emerging infectious diseases that is worldwide creating most concern. Intrinsically linked to poverty, MDR-TB is differentially affecting developed and developing countries. Despite same a etiology and pathogenesis the differential distributions of the disease, ways of diagnose, treatment and especially prognosis is contributing to completely different epidemic dynamics. Along this article are shown in detailed similarities and differences between developed and developing countries disease presentation (AU)

Lineage-unrelated neurons generated in different temporal windows and expressing different combinatorial codes can converge in the activation of the same terminal differentiation gene.

It is becoming increasingly clear that the activation of specific terminal differentiation genes during neural development is critically dependent upon the establishment of unique combinatorial transcription factor codes within distinct neural cell subtypes. However, it is still unclear to which extent these codes are shared by lineage-unrelated neurons expressing the same terminal differentiation genes. Additionally, it is not known if the activation of a specific terminal differentiation gene is restricted to cells born at a particular developmental time point. Here, we utilize the terminal differentiation gene FMRFa which is expressed by the Ap4 and SE2 neurons in the Drosophila ventral nerve cord, to explore these issues in depth. We find that the Ap4 and SE2 neurons are generated by different neural progenitors and use different combinatorial codes to activate FMRFa expression. Additionally, we find that the Ap4 and SE2 neurons are generated in different temporal gene expression windows. Extending the investigation to include a second Drosophila terminal differentiation gene, Leucokinin, we find similar results, suggesting that neurons generated by different progenitors might commonly use different transcription factor codes to activate the same terminal differentiation gene. Furthermore, these results imply that the activation of a particular terminal differentiation gene in temporally unrestricted.

Management of multidrug-resistant tuberculosis: an update.

Multidrug-resistant tuberculosis (MDR-TB) is threatening control of TB in many parts of the world. As a result of limited treatment options, patients have a poor prognosis and low chances of cure. This situation can be exacerbated by HIV epidemics. In some cases, the risk exists of a real shift from susceptible to resistant strains. Despite its relevance, currently there are more contradictions and confusion surrounding MDR-TB than hard evidence. No randomized controlled trials have been performed and published evidence is limited. Rather than just the selection of expensive drugs, MDR-TB management requires well-structured programmes with a comprehensive approach, which involve the actions of a wide range of participants. Even with current investments in research and development, new drugs and vaccines will take many years to be applied in low and middle income countries. The most successful results will depend on the optimization of existing tools. The majority of the patients, even those with extensive patterns of bacilli resistance, have a possibility of cure if current clinical knowledge and effective logistics are applied. This paper is a critical review of current best practice regarding the diagnosis and treatment of MDR-TB.

MDR-/XDR-TB management: what it was, current standards and what is ahead.

Despite killing nearly 2 million people every year, TB is arguably the most neglected disease in terms of the funding and research it receives. In many ways, multidrug-resistant TB is a result of this disregard. In high-burden countries, not many improvements have been implemented in the diagnosis and treatment tools of TB since the 1960s. Following this period, fluoroquinolones, developed for other infections, are the only highly active new drugs against TB. Multidrug- and extensively drug-resistant TB is booming worldwide as a result of insufficient control measures. Furthermore, the prevalence of this disease is substantially facilitated by the HIV epidemic. After a deadly and well-reported extensively drug-resistant TB outbreak occurred in HIV-infected patients in South Africa, the threat of an untreatable TB epidemic is receiving increased attention internationally. Nevertheless, drug-resistant management has lacked research and funding over several decades and we are now faced with many controversial issues and little research-based evidence. There are no clinical trials comparing different treatments, and current management is based on personal experiences and agreement between experts. The major challenge for the next few years is to improve the evidence base in order to develop more rational recommendations that adequately address the current problem and avoid making a bad situation worse.