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IntroductionDevelopment of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood.MethodsIn this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination.ResultsAnalyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response.DiscussionThe results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.

Abstract Background Delamanid and bedaquiline are two of the most recently developed antituberculosis (TB) drugs that have been extensively studied in patients with multidrug-resistant TB. There is currently a need for more potent, less-toxic drugs with novel mechanisms of action that can be used in combination with these newer agents to shorten the duration of treatment as well as prevent the development of drug resistance. Quabodepistat (QBS) is a newly discovered inhibitor of decaprenylphosphoryl-β-D-ribose-2′-oxidase, an essential enzyme for Mycobacterium tuberculosis to synthesize key components of its cell wall. The objective of this study is to evaluate the safety, efficacy, and appropriate dosing of a 4-month regimen of QBS in combination with delamanid and bedaquiline in participants with drug-susceptible pulmonary TB in comparison with the 6-month standard treatment (i.e., rifampicin, isoniazid, ethambutol, and pyrazinamide). Methods This phase 2b/c, open-label, randomized, parallel group, dose-finding trial will enroll approximately 120 participants (including no more than 15% with human immunodeficiency virus [HIV] coinfection) aged ≥ 18 to ≤ 65 years at screening with newly diagnosed pulmonary drug-sensitive TB from ~8 sites in South Africa. Following a screening period of up to 14 days, eligible participants will be randomized in a ratio of 1:2:2:1 to one of four arms. Randomization will be stratified by HIV status and the presence of bilateral cavitation on a screening chest x-ray. After the end of the treatment period, participants will be followed until 12 months post randomization. The primary efficacy endpoint is the proportion of participants achieving sputum culture conversion in Mycobacteria Growth Indicator Tube by the end of the treatment period. The safety endpoints consist of adverse events, clinical laboratory tests, vital signs, physical examination findings, and electrocardiographic changes. Discussion QBS’s potent bactericidal activity and distinct mechanism of action (compared with other TB drugs currently available for human use) may make it an ideal candidate for inclusion in a novel treatment regimen to improve efficacy and potentially prevent resistance to concomitant TB drugs. This trial will assess the effectiveness, safety, and dosing of a new, shorter, QBS-based, combination anti-TB treatment regimen. Trial status ClinicalTrials.gov NCT05221502. Registered on February 3, 2022

Shear thickening fluids (STFs) have garnered attention as potential enhancers of protective capabilities and for the optimization of Kevlar® armor design. To assess the possible shear thickening properties and potential application in ballistic protection, ten formulations were developed by employing polyethylene glycol (PEG) or polypropylene glycol (PPG), along with fumed silica or Aerosil HDK®. Rheological characterization facilitated the identification of formulations displaying shear thickening behavior. The potential integration of the selected shear thickening fluids (STFs) into Kevlar®-based composites was investigated by studying the impact resistance of Kevlar® soft armor structures. Also, high-velocity impact testing revealed that the distance between aramid layers plays a crucial role in the impact resistance effectiveness of Kevlar®–STF composite structures and that there is a very narrow domain between optimal and undesired scenarios in which STF could facilitate the penetration of Kevlar. The introduction of STF between the Kevlar sheets disrupted this packing and the energy absorption capacity of the material was not improved. Only one formulation (PEG400, Aerosil 27 wt.%) led to a less profound traumatic imprint and stopped the bullet when it was placed between layers no.1 and no.2 from a total of 11 layers of Kevlar XP. These experimental findings align with the modeling and simulation of Kevlar®–STF composites using Ansys simulation software (Ansys® AutoDyn 2022 R2).

The present work combats the problem of violence and aggressive behaviour through mentoring. The theoretical point of view certified studies that highlight various aspects of the problem of violent and aggressive behaviour remediation of preadolescents and adolescents. At present there are no publications that completely synthesize the institutional and normative field of mentoring. The existing publications reference to the regulation regarding the establishment of the mentoring system for teaching staff in education. Thus, the problem of mentoring valorization in combating violent behaviour among preadolescents and adolescents remains unresolved. The viable solution to solving these actual problems of the postmodern world is to focus on the personality value system.

Abstract The first aim of this study is to develop a photo‐ATRP process using methyl methacrylate (MMA) by employing a novel perylenediimide derivative (PDI) as photoinitiator. The analysis of the MMA photopolymerization process kinetics is performed in solution and in bulk, demonstrating control over the reaction progress even if the polymerizations display a slow initiation step. The photo‐ATRP process for MMA in suspension is also developed and the obtained PMMA particles are further used to reinitiate the ATRP polymerization of thermoresponsive polymers (different molecular weights poly(ethylene glycol) methyl ether methacrylate and poly(N‐isopropylacrylamide)) (PNIPAM) in solution and surface‐initiated processes. The synthesized polymers by surface‐initiated process display a bimodal molecular weight distribution with a clear modification of the signal areas ratio depending on the grafted monomer and on the reaction conditions. The grafting process can take place on the surface of the polymer particles (Mn2), or it can also involve polymer chains located further at the interior of the polymer particles (Mn1). The lower critical solution temperature (LCST) transition is demonstrated for the PNIPAM functionalized polymer particles.

This study describes the development of hydrogel formulations with ionic crosslinking capacity and photocatalytic characteristics. The objective of this research is to provide an effective, accessible, “green”, and facile route for the decontamination of chemical warfare agents (CWAs, namely the blistering agent—mustard gas/sulfur mustard (HD)) from contaminated surfaces, by decomposition and entrapment of CWAs and their degradation products inside the hydrogel films generated “on-site”. The decontamination of the notorious warfare agent HD was successfully achieved through a dual hydrolytic–photocatalytic degradation process. Subsequently, the post-decontamination residues were encapsulated within a hydrogel membrane film produced via an ionic crosslinking mechanism. Polyvinyl alcohol (PVA) and sodium alginate (ALG) are the primary constituents of the decontaminating formulations. These polymeric components were chosen for this application due to their cost-effectiveness, versatility, and their ability to form hydrogen bonds, facilitating hydrogel formation. In the presence of divalent metallic ions, ALG undergoes ionic crosslinking, resulting in rapid gelation. This facilitated prompt PVA-ALG film curing and allowed for immediate decontamination of targeted surfaces. Additionally, bentonite nanoclay, titanium nanoparticles, and a tetrasulfonated nickel phthalocyanine (NiPc) derivative were incorporated into the formulations to enhance absorption capacity, improve mechanical properties, and confer photocatalytic activity to the hydrogels obtained via Zn2+—mediated ionic crosslinking. The resulting hydrogels underwent characterization using a variety of analytical techniques, including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), viscometry, and mechanical analysis (shear, tensile, and compression tests), as well as swelling investigations, to establish the optimal formulations for CWA decontamination applications. The introduction of the fillers led to an increase in the maximum strain up to 0.14 MPa (maximum tensile resistance) and 0.39 MPa (maximum compressive stress). The UV-Vis characterization of the hydrogels allowed the determination of the band-gap value and absorption domain. A gas chromatography–mass spectrometry assay was employed to evaluate the decontamination efficacy for a chemical warfare agent (sulfur mustard—HD) and confirmed that the ionic crosslinked hydrogel films achieved decontamination efficiencies of up to 92.3%. Furthermore, the presence of the photocatalytic species can facilitate the degradation of up to 90% of the HD removed from the surface and entrapped inside the hydrogel matrix, which renders the post-decontamination residue significantly less dangerous.

ABSTRACT We assessed the performance of a novel real-time PCR-based transrenal DNA (trDNA) assay for the specific detection of Mycobacterium tuberculosis as a candidate marker of the early anti-tuberculosis therapy response. The study was performed on 288 urine samples from 72 tuberculosis patients collected at baseline and days 3, 7, and 14 of treatment with amoxicillin-clavulanic acid alone or in combination with meropenem, ertapenem, optimized-dose rifampicin, or standard treatment control in South Africa. trDNA was detected in one-third of the samples. The highest proportion of positive PCR results (cycle threshold < 36) was observed on days 3 and 7, reflecting the point in time when maximum bacterial killing and disintegration are expected. When analyzed by study arms, the trend was observed in groups treated with active antibiotics affecting cell wall integrity (meropenem, control) but not in inactive drugs (ertapenem, amoxicillin/clavulanic acid alone) or active drugs not affecting the cell wall (rifampicin). Overall, however, the trDNA assay did not correlate well with sputum culture-based decline of viable bacteria. This is possibly due to trDNA reflecting the killing of both culturable and non-culturable bacteria and should be explored further. IMPORTANCE This study presents the results of the evaluation of a novel method for the detection of Mycobacterium tuberculosis, the causative agent of tuberculosis, in urine. Detecting parts of the mycobacteria in urine is of particular interest as it allows us to use a sample that is easy to obtain and that does not require uncomfortable procedures or safety precautions like obtaining sputum for culture, which is the most commonly used sample in the diagnosis of tuberculosis. In certain groups of individuals who cannot produce sputum, for example, children, non-sputum-based methods have particular importance. We found that the method tested was able to detect bacterial killing by active antibiotics that disrupt the cell wall and lead to fragmentation of bacteria. However, the assay can't detect inactive bacteria or bacteria that are active with an intact cell wall.

(1) Background: Some individuals are more susceptible to developing respiratory tract infections (RTIs) or coronavirus disease (COVID-19) than others. The aim of this work was to identify risk factors for symptomatic RTIs including COVID-19 and symptomatic COVID-19 during the coronavirus pandemic by using infection incidence, participant baseline, and regional COVID-19 burden data. (2) Methods: Data from a prospective study of 1000 frontline healthcare workers randomized to Bacillus Calmette–Guérin vaccination or placebo, and followed for one year, was analyzed. Parametric time-to-event analysis was performed to identify the risk factors associated with (a) non-specific symptomatic respiratory tract infections including COVID-19 (RTIs+COVID-19) and (b) symptomatic RTIs confirmed as COVID-19 using a polymerase chain reaction or antigen test (COVID-19). (3) Results: Job description of doctor or nurse (median hazard ratio [HR] 1.541 and 95% confidence interval [CI] 1.299–1.822), the reported COVID-19 burden (median HR 1.361 and 95% CI 1.260–1.469 for 1.4 COVID-19 cases per 10,000 capita), or a BMI > 30 kg/m2 (median HR 1.238 and 95% CI 1.132–1.336 for BMI of 35.4 kg/m2) increased the probability of RTIs+COVID-19, while positive SARS-CoV-2 serology at enrollment (median HR 0.583 and 95% CI 0.449–0.764) had the opposite effect. The reported COVID-19 burden (median HR 2.372 and 95% CI 2.116–2.662 for 1.4 COVID-19 cases per 10,000 capita) and a job description of doctor or nurse (median HR 1.679 and 95% CI 1.253–2.256) increased the probability of developing COVID-19, while smoking (median HR 0.428 and 95% CI 0.284–0.648) and positive SARS-CoV-2 serology at enrollment (median HR 0.076 and 95% CI 0.026–0.212) decreased it. (4) Conclusions: Nurses and doctors with obesity had the highest probability of developing RTIs including COVID-19. Non-smoking nurses and doctors had the highest probability of developing COVID-19 specifically. The reported COVID-19 burden increased the event probability, while positive SARS-CoV-2 IgG serology at enrollment decreased the probability of RTIs including COVID-19, and COVID-19 specifically.

This review presents polyurea (PU) synthesis, the structure–properties relationship, and characterization aspects for ballistic protection applications. The synthesis of polyurea entails step-growth polymerization through the reaction of an isocyanate monomer/prepolymer and a polyamine, each component possessing a functionality of at least two. A wide range of excellent properties such as durability and high resistance against atmospheric, chemical, and biological factors has made this polymer an outstanding option for ballistic applications. Polyureas are an extraordinary case because they contain both rigid segments, which are due to the diisocyanates used and the hydrogen points formed, and a flexible zone, which is due to the chemical structure of the polyamines. These characteristics motivate their application in ballistic protection systems. Polyurea-based coatings have also demonstrated their abilities as candidates for impulsive loading applications, affording a better response of the nanocomposite-coated metal sheet at the action of a shock wave or at the impact of a projectile, by suffering lower deformations than neat metallic plates.

This study describes the development of a fast and cost-effective method for the detection and removal of Hg2+ ions from aqueous media, consisting of hydrogels incorporating chelating agents and a rhodamine derivative (to afford a qualitative evaluation of the heavy metal entrapment inside the 3D polymeric matrix). These hydrogels, designed for the simultaneous detection and entrapment of mercury, were obtained through the photopolymerization of 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPSA) and N-vinyl-2-pyrrolidone (NVP), utilizing N,N′-methylenebisacrylamide (MBA) as crosslinker, in the presence of polyvinyl alcohol (PVA), a rhodamine B derivative, and one of the following chelating agents: phytic acid, 1,3-diamino-2-hydroxypropane-tetraacetic acid, triethylenetetramine-hexaacetic acid, or ethylenediaminetetraacetic acid disodium salt. The rhodamine derivative had a dual purpose in this study: firstly, it was incorporated into the hydrogel to allow the qualitative evaluation of mercury entrapment through its fluorogenic switch-off abilities when sensing Hg2+ ions; secondly, it was used to quantitatively evaluate the level of residual mercury from the decontaminated aqueous solutions, via the UV-Vis technique. The ICP-MS analysis of the hydrogels also confirmed the successful entrapment of mercury inside the hydrogels and a good correlation with the UV-Vis method.

Abstract Background Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a “real-time” measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681)

This study presents the synthesis and characterization of nanocomposites based on polymer colloids (PC) and MXenes for applications in EMI shielding. The PCs were synthesized in the presence of MXenes by soap-free emulsion polymerization. The presence of the MXenes during the polymerization process induces changes in the nucleation process, which also occurs between the MXenes layers, leading to intercalated and finally fully exfoliated structures arising from the polymerization progress. Two co-monomer systems were synthesized in the presence of MXenes, both based on styrene (ST) and a second monomer, with different hydrophilic characteristics acrylic acid (AA) and hydroxypropyl methacrylate (HPMA), respectively. The nanocomposites were characterized by SEM, DLS, XRD, TGA, and EMI shielding capacity analyses. The analyses confirmed better compatibility between HPMA and the MXenes, which facilitated the formation of an exfoliated structure. The polymer colloids were incorporated into an epoxy resin to evaluate their EMI shielding abilities. The EMI tests showed that the electromagnetic properties of the epoxy film varied depending on the concentration of ST-HPMA-MXenes, resulting in increased electromagnetic transparency or absorption capacity. [ABSTRACT FROM AUTHOR]

Shear thickening fluids (STFs) have garnered attention as potential enhancers of protective capabilities and for the optimization of Kevlar® armor design. To assess the possible shear thickening properties and potential application in ballistic protection, ten formulations were developed by employing polyethylene glycol (PEG) or polypropylene glycol (PPG), along with fumed silica or Aerosil HDK®. Rheological characterization facilitated the identification of formulations displaying shear thickening behavior. The potential integration of the selected shear thickening fluids (STFs) into Kevlar®-based composites was investigated by studying the impact resistance of Kevlar® soft armor structures. Also, high-velocity impact testing revealed that the distance between aramid layers plays a crucial role in the impact resistance effectiveness of Kevlar®–STF composite structures and that there is a very narrow domain between optimal and undesired scenarios in which STF could facilitate the penetration of Kevlar. The introduction of STF between the Kevlar sheets disrupted this packing and the energy absorption capacity of the material was not improved. Only one formulation (PEG400, Aerosil 27 wt.%) led to a less profound traumatic imprint and stopped the bullet when it was placed between layers no.1 and no.2 from a total of 11 layers of Kevlar XP. These experimental findings align with the modeling and simulation of Kevlar®–STF composites using Ansys simulation software (Ansys® AutoDyn 2022 R2). [ABSTRACT FROM AUTHOR]

Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration–time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15–20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with (NCT01936831). [ABSTRACT FROM AUTHOR]

This study describes the development of hydrogel formulations with ionic crosslinking capacity and photocatalytic characteristics. The objective of this research is to provide an effective, accessible, "green", and facile route for the decontamination of chemical warfare agents (CWAs, namely the blistering agent—mustard gas/sulfur mustard (HD)) from contaminated surfaces, by decomposition and entrapment of CWAs and their degradation products inside the hydrogel films generated "on-site". The decontamination of the notorious warfare agent HD was successfully achieved through a dual hydrolytic–photocatalytic degradation process. Subsequently, the post-decontamination residues were encapsulated within a hydrogel membrane film produced via an ionic crosslinking mechanism. Polyvinyl alcohol (PVA) and sodium alginate (ALG) are the primary constituents of the decontaminating formulations. These polymeric components were chosen for this application due to their cost-effectiveness, versatility, and their ability to form hydrogen bonds, facilitating hydrogel formation. In the presence of divalent metallic ions, ALG undergoes ionic crosslinking, resulting in rapid gelation. This facilitated prompt PVA-ALG film curing and allowed for immediate decontamination of targeted surfaces. Additionally, bentonite nanoclay, titanium nanoparticles, and a tetrasulfonated nickel phthalocyanine (NiPc) derivative were incorporated into the formulations to enhance absorption capacity, improve mechanical properties, and confer photocatalytic activity to the hydrogels obtained via Zn2+—mediated ionic crosslinking. The resulting hydrogels underwent characterization using a variety of analytical techniques, including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), viscometry, and mechanical analysis (shear, tensile, and compression tests), as well as swelling investigations, to establish the optimal formulations for CWA decontamination applications. The introduction of the fillers led to an increase in the maximum strain up to 0.14 MPa (maximum tensile resistance) and 0.39 MPa (maximum compressive stress). The UV-Vis characterization of the hydrogels allowed the determination of the band-gap value and absorption domain. A gas chromatography–mass spectrometry assay was employed to evaluate the decontamination efficacy for a chemical warfare agent (sulfur mustard—HD) and confirmed that the ionic crosslinked hydrogel films achieved decontamination efficiencies of up to 92.3%. Furthermore, the presence of the photocatalytic species can facilitate the degradation of up to 90% of the HD removed from the surface and entrapped inside the hydrogel matrix, which renders the post-decontamination residue significantly less dangerous. [ABSTRACT FROM AUTHOR]

The smartphone apps have revolutionized the markets of goods and services more than other recent technologies. Although they modified the market paradigm in sectors like accommodation, transport, or “gigs”, the changes in the way the economics systems function are still widely neglected by the literature. We intend to analyze some of these changes and their impact, which in economic history could only be compared with trade liberalization. The smartphone apps increase market transparency, reduce or eliminate the entrance barriers and expand the markets to unprecedented levels. Although we limit our observations to a few cases, the apps have the potential to revolutionize any given market. For the first time since the economy has become a recognized science, market transparency is more than a utopian goal. The apps are facilitating instant information transfer between suppliers and customers. What is clear is that the increase of market transparency is not limited to the sharing economy, but it can be found in all the segments.