MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG

At its 100th birthday of its first administration to a newborn, BCG has been (and continues being) an inspiration for the construction and development of hundreds of new TB vaccine candidates in the last two and a half decades. Today, 14 candidates are in clinical development inside the global TB vaccine pipeline. MTBVAC is one of these candidates. Based on a live-attenuated Mycobacterium tuberculosis clinical isolate, MTBVAC''s 25 years of vaccine discovery, construction and characterisation have followed Pasteur principles, and in the process, BCG has served as a reference gold standard for establishing the safety and protective efficacy of new TB vaccine candidates. MTBVAC, which contains the antigen repertoire of M. tuberculosis, is now poised to initiate Phase 3 efficacy trials in newborns in TB-endemic countries. BCG''s efficacy extends beyond that against TB, shown to confer heterologous non-specific immunity to other diseases and reduce all-cause mortality in the first months of life. Today, WHO recognises the importance that any new TB vaccine designed for administration at birth, should show similar non-specific benefits as BCG vía mechanisms of trained immunity and/or cross-reactivity of adaptive immune responses to other pathogens. Key recent studies provide strong support for MTBVAC''s ability of inducing trained immunity and conferring non-specific heterologous protection similar to BCG. Research on alternative delivery routes of MTBVAC, such as a clinically feasible aerosol route, could facilitate vaccine administration for long-term TB eradication programmes in the future. © 2021 The Author(s

The Maximal Denumerant of a Numerical Semigroup

Given a numerical semigroup S = and n in S, we consider the factorization n = c_0 a_0 + c_1 a_1 + ... + c_t a_t where c_i >= 0. Such a factorization is maximal if c_0 + c_1 + ... + c_t is a maximum over all such factorizations of n. We provide an algorithm for computing the maximum number of maximal factorizations possible for an element in S, which is called the maximal denumerant of S. We also consider various cases that have connections to the Cohen-Macualay and Gorenstein properties of associated graded rings for which this algorithm simplifies.Comment: 13 Page

Update on the approach to smoking. Interactions of tobacco with pharmacological treatments

El tabaquismo es una enfermedad adictiva crónica de carácter multifactorial y, por tanto, de abordaje complejo. El terapeuta en tabaquismo debe conocer todos los aspectos que pueden afectar el proceso de cesación tabáquica. Las interacciones del tabaco con los tratamientos farmacológicos han sido estudiadas durante los últimos años. Pueden ser de tipo farmacocinético, propiciadas por el potente efecto inductor de diferentes componentes del humo del tabaco sobre isoenzimas del citocromo P450, y farmacodinámicas, esencialmente debidas a efectos de la nicotina. Aunque las más significativas corresponden a fármacos utilizados en patologías psiquiátricas, con las que el tabaquismo presenta elevada comorbilidad, se pueden producir con otros fármacos de diversos grupos terapéuticos, con mayor o menor significación clínica dependiendo del propio fármaco y la posología planteada, o del individuo y sus circunstancias personales. El médico prescriptor debe conocer estos aspectos para valorar posibles ajustes posológicos cuando el paciente inicia la cesación o comienza a fumar. Se propone bibliografía de consulta y la necesidad de una permanente actualización al respecto.Smoking is a chronic multifactorial addictive disease of complex approach. The smoking therapist must know all aspects that may affect the process of smoking cessation. The drug interactions with tobacco smoke have been studied in recent years. They can be of the pharmacokinetic type, favored by the powerful inducer effect of different components of tobacco smoke on cytochrome P450 isoenzimes, and pharmacodynamic interactions, essentially due to the nicotine effects. Although the most significant interactions occur with drugs used in psychiatric pathologies, which present high comorbidity with smoking, they may also occur with drugs for another diseases, with greater or lesser clinical significance depending on the drug itself and dosage, or the individual and their personal circumstances. The physician should be aware of these aspects to assess possible dose adjustment when patients start smoking cessation or begin to smoke. Bibliography and the need for a permanent update in this matter are recommended

Sensor placement for combined sewer system monitoring in the Besòs river basin

In this paper, a sensor placement methodology for sewer systems monitoring in order to measure direct discharge to the river during intense rainfall events is presented. During these events, Combined Sewer Overflows (CSOs) may occur, causing serious problems of contamination of the corresponding receiving waters. The current national regulation compels sewer systems’ managers to monitor and quantify direct discharge to these receiving waters, in order to track these events. Hence, the selection of the appropriate sensor set in order to monitor the critical outlets of the network is of paramount importance to adequately monitor CSOs and minimize their effect by using the information gathered from these measurements. Here, a methodology considering relevant characteristics of each potential monitoring point —e.g. number of discharges, volume discharged or percentage of polluted mass— is defined to select the final sensor set. The presented methodology is applied to three different combined sewer systems in the Besòs river basin nearby Barcelona city area in Catalonia (Spain), i.e. Granollers, La Llagosta and Montornès systems.Peer ReviewedPostprint (published version

Pulmonary but not subcutaneous vaccination confers protection to TB susceptible mice by an IL17-dependent mechanism.

Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis–specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis–specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis

Therapeutic efficacy of pulmonary live tuberculosis vaccines against established asthma by subverting local immune environment

Background: Substantial recent advances in the comprehension of the molecular and cellular mechanisms behind asthma have evidenced the importance of the lung immune environment for disease outcome, making modulation of local immune responses an attractive therapeutic target against this pathology. Live attenuated mycobacteria, such as the tuberculosis vaccine BCG, have been classically linked with a type 1 response, and proposed as possible modulators of the type 2 response usually associated with asthma. Methods: In this study we used different acute and chronic murine models of asthma to investigate the therapeutic efficacy of intranasal delivery of the live tuberculosis vaccines BCG and MTBVAC by regulating the lung immune environment associated with airway hyperresponsiveness (AHR). Findings: Intranasal administration of BCG, or the novel tuberculosis vaccine candidate MTBVAC, abrogated AHR-associated hallmarks, including eosinophilia and lung remodeling. This correlated with the re-polarization of allergen-induced M2 macrophages towards an M1 phenotype, as well as with the induction of a strong allergen-specific Th1 response. Importantly, vaccine treatment was effective in a scenario of established chronic asthma where a strong eosinophil infiltration was already present prior to immunization. We finally compared the nebulization efficiency of clinical formulations of MTBVAC and BCG using a standard commercial nebulizer for potential aerosol application. Interpretation: Our results demonstrate that pulmonary live tuberculosis vaccines efficiently revert established asthma in mice. These data support the further exploration of this approach as potential therapy against asthma

The LISA PathFinder DMU and Radiation Monitor

The LISA PathFinder DMU (Data Management Unit) flight model was formally accepted by ESA and ASD on 11 February 2010, after all hardware and software tests had been successfully completed. The diagnostics items are scheduled to be delivered by the end of 2010. In this paper we review the requirements and performance of this instrumentation, specially focusing on the Radiation Monitor and the DMU, as well as the status of their programmed use during mission operations, on which work is ongoing at the time of writing.Comment: 11 pages, 7 figures, prepared for the Proceedings of the 8th International LISA Symposium, Classical and Quantum Gravit

Search for supersymmetry in pp collisions at 7 TeV in events with jets and missing transverse energy

A search for supersymmetry with R-parity conservation in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented. The data correspond to an integrated luminosity of 35 inverse picobarns collected by the CMS experiment at the LHC. The search is performed in events with jets and significant missing transverse energy, characteristic of the decays of heavy, pair-produced squarks and gluinos. The primary background, from standard model multijet production, is reduced by several orders of magnitude to a negligible level by the application of a set of robust kinematic requirements. With this selection, the data are consistent with the standard model backgrounds, namely t t-bar, W + jet and Z + jet production, which are estimated from data control samples. Limits are set on the parameters of the constrained minimal supersymmetric extension of the standard model. These limits extend those set previously by experiments at the Tevatron and LEP colliders

Measurement of the t¯t production cross section in pp collisions at √s = 7 TeV using the kinematic properties of events with leptons and jets

A measurement of the tt production cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV has been performed at the LHC with the CMS detector. The analysis uses a data sample corresponding to an integrated luminosity of 36 pb−1 and is based on the reconstruction of the final state with one isolated, high transverse-momentum electron or muon and three or more hadronic jets. The kinematic properties of the events are used to separate the tt signal from W+jets and QCD multijet background events. The measured cross section is 173+39−32 (stat+syst) pb, consistent with standard model expectations