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Abstract Background Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. Methods endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. Discussion This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. Trial registration ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

IntroductionComparable indicators on complete cancer prevalence are increasingly needed in Europe to support survivorship care planning. Direct measures can be biased by limited registration time and estimates are needed to recover long term survivors. The completeness index method, based on incidence and survival modelling, is the standard most validated approach.MethodsWithin this framework, we consider two alternative approaches that do not require any direct modelling activity: i) empirical indices derived from long established European registries; ii) pre-calculated indices derived from US-SEER cancer registries. Relying on the EUROCARE-6 study dataset we compare standard vs alternative complete prevalence estimates using data from 62 registries in 27 countries by sex, cancer type and registration time.ResultsFor tumours mostly diagnosed in the elderly the empirical estimates differ little from standard estimates (on average less than 5% after 10-15 years of registration), especially for low prognosis cancers. For early-onset cancers (bone, brain, cervix uteri, testis, Hodgkin disease, soft tissues) the empirical method may produce substantial underestimations of complete prevalence (up to 20%) even when based on 35-year observations. SEER estimates are comparable to the standard ones for most cancers, including many early-onset tumours, even when derived from short time series (10-15 years). Longer observations are however needed when cancer-specific incidence and prognosis differ remarkably between US and European populations (endometrium, thyroid or stomach).DiscussionThese results may facilitate the dissemination of complete prevalence estimates across Europe and help bridge the current information gaps.

Abstract Background Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. Methods endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. Discussion The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. Trial registration ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15–64 years) diagnosed in 2000–2006 vs. 2007–2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.

Abstract Background There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. Results After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q val = 0.029 and q val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. Conclusions Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Objetivos. Realizar una revisión bibliográfica para responder a la pregunta: ¿Existe diferencia entre el método de evaluación vértebras cervicales de Baccetti y carpal de Fishman para determinar el pico máximo de crecimiento humano. Materiales y métodos. Se realizó una búsqueda en dos bases de datos (PubMed, y SciELO), en la que se seleccionaron estudios (2000-2020) que compararon uno o ambos métodos de evaluación para determinar pico de crecimiento. En la primera etapa de selección se obtuvieron 248 artículos. Finalmente, se incluyeron 8 artículos para la revisión. Resultados: Del total de estudios evaluados, 6 presentaron un alto nivel de correlación entre los métodos examinados y solo 2 definen una correlación moderadamente positiva. Conclusiones. Existe correlación entre los dos métodos de evaluación para la identificación del pico máximo de crecimiento. Se encontró que la valoración de la edad vertebral en las radiografías laterales de cráneo mediante el método de Baccetti, ha demostrado ser estadísticamente fiable, valido y clínicamente útil reduciendo la necesidad de una sobreexposición radiográfica para una evaluación carpal.

Fragmento Las enfermedades endocrinas han estado presentes en el arte desde tiempos inmemoriales, seguramente debido a la baja frecuencia de presentación de algunas de ellas, o por la dificultad de poder realizar un diagnóstico certero. En la antigüedad, por ejemplo, la glándula tiroides no se veía de la misma forma que en los tiempos contemporáneos. En el Renacimiento, los primero dibujos que nos hablan de ella son los realizados por Leonardo da Vinci en 1510, pero desafortunadamente sus cuadernos desaparecieron después de su fallecimiento en 1519. En la antigüedad se pensaba que la tiroides era una glándula laríngea que humectaba la tráquea y los pulmones; pero en 1543 Vesalio en De Humani Corporis Fabrica hizo que esta glándula fuera visible para los médicos. La primera vez que se utilizó el nombre de glandulee thyroideae fue en 1656 en la monografía publicada por Thomas Wharton sobre las glándulas del cuerpo; este nombre surgió por su cercanía al cartílago y su forma de escudo. Así pues, en general el conocimiento de las glándulas endocrinas y de las hormonas es muy reciente dentro de la historia de la medicina, motivo por el cual muchos investigadores médicos, como historiadores y artistas, han tratado de encontrar dentro del arte pictórico algunos trastornos endocrinológicos que en el momento en que fueron plasmados no se conocían.

La técnica moderna necesita cada vez más acero de calidad superior y aceros especiales, con propiedades adecuadas a unos propósitos muy amplios. Gracias a la interdependecia entre los factores que determinan el contenido de gases esta constituye un problema cada vez más importante para la elaboración, tratamiento y fundición de los aceros. Una gran importancia en el proceso de elaboración le corresponde a la escoria independientemente de la fase del proceso. Se analiza la influencia de la escoria sintética durante el tratamiento en la instalación LF sobre el grado de eliminación del hidrogeno. Después de procesar los datos experimentales se establecieron los campos óptimos de variación de la basicidad en base a la cual se puede determinar la composición química de la escoria (CaO, SiO2, Al2O3, MgO) para el tratamiento secundario del acero.

El enfriamiento primario del cristalizador tiene una gran importancia sobre el espesor de la costra de acero solidificado. Si al salir del cristalizador, esta costra es demasiado sutil, bajo la acción de la presión ferro estática ejercitada por el acero líquido del interior y gracias el peso propio del hilo, ésta, puede perforar resultando su rompimiento. Los parámetros que influenyen sobre la cantidad de calor cedida dependen del agua de enfriamiento del catalizador, de la presión y de la temperatura de agua de enfriamiento, pero también del sobrecalentamiento del acero fundido continuamente. A la salida del semiproducto del cristalizador, tiene lugar el enfriamiento secundario, a lo largo del que la solidificación tiene que realizarse en toda la sección transversal del hilo. Para eso, además de un enfriamiento primario manejado correctamente, tienen que correlacionarse a los factores que influyen en el enfriamiento secundario, también; el flujo del agua en las tres zonas de la instalación, la presión del agua en el circuito secundario, etc. Todo esto tiene que ver con una longitud correspondiente de solidificación; un enfriamiento intenso que puede llevar a la aparición de grietas debidas a las tensiones térmicas y un enfriamiento lento puede llevar a una solidificación parcial del hilo hasta la zona del agregado de flujo. El trabajo representa un modelo de simulación de la solidificación de los semiproductos de acero fundidos continuamente

En general, el azufre es considerado un elemento nocivo para la calidad del acero y, por eso, en la práctica, se toman todas las medidas de orden tecnológico para su eliminación del baño metálico. En este trabajo se analiza la influencia de la composición química, de la cantidad de escoria y del estado de agitación del baño sobre el proceso de desulfuración en la cuchara para fundir por tratamiento con escoria sintética. Los experimentos se han realizado en una acería evacuando el acero en dos ollas (en una cuchara se efectuó la desulfuración con escoria sintética y a la otra se consideró como patrón) y en un acería eléctrica y para la formación de la escoria sintética se utilizó una mezcla producida según muchas recetas, formada por: cal (50-75%), fluorina (0-17%), bauxita (0-32%) y escoria aluminosa (8-22%). Los datos han sido procesados en los programas de cálculo EXCEL y MATLAB, resultando una serie de correlaciones entre el grado de desulfuración y la composición química de la escoria, la cantidad de escoria respectivamente, tanto para las cargas burbujeadas con argón como no burbujeadas.

La calidad de productos semiacabados de la colada continua está influenciada, en gran parte, por el proceso de lubricación de la matriz que, a su vez, está influenciado por la viscosidad de escoria que resulta de la colada de polvos de fundición. Este trabajo analiza la influencia de composición química sobre la viscosidad de la escoria. La investigación ha tenido como meta establecer unas correlaciones entre la viscosidad dinámica y la composición química de la escoria. Para la composición química se han escogido como factores variables (componentes representativos) el contenido de CaO, MgO, Al2O3, SiO2 (los dos últimos expresados por la razón Al2O3/SiO2). Los ensayos sobre la viscosidad se han realizado sobre escoria a temperaturas de 1.350 °C. El análisis de los datos se ha efectuado en los laboratorios MATLAB y se han obtenido cuatro correlaciones múltiples. Los resultados se presentan tanto en forma analítica como gráfica. La utilización" de las relaciones obtenidas permite determinar la viscosidad de las escorias con un error matemático y la utilización de las correlaciones gráficas permite establecer el área de variación (los límites) de la viscosidad, para los componentes representativos.

The retrieval facilities of most Peer-to-Peer (P2P) systems are limited to queries based on unique identifiers or small sets of keywords. Unfortunately, this approach is very inadequate and inefficient when a huge amount of multimedia resources is shared. To address this major limitation, we propose an original image and video sharing system, in which a user is able to interactively search interesting resources by means of content-based image and video retrieval techniques. In order to limit the network traffic load, maximizing the usefulness of each peer contacted in the query process, we also propose the adoption of an adaptive overlay routing algorithm, exploiting compact representations of the multimedia resources shared by each peer. Experimental results confirm the validity of the proposed approach, that is capable of dynamically adapting the network topology to peer interests, on the basis of query interactions among users.