Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Multiple neoplasms in patients with uveal melanoma: a systematic review.

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.

Novel foods, food enzymes, and food additives derived from food by-products of plant or animal origin: principles and overview of the EFSA safety assessment.

The European Union (EU) is committed to transitioning toward a circular economy model, with food waste being one of the areas to be targeted. To close the loop of food waste generated during food processing and discarded at the retail or consumption phases, research and innovation parties proposed to valorize agro-food by-products to produce novel foods and food improvement agents (food additives, food enzymes, and food flavorings). In the EU, the authorization of such novel foods and food improvement agents is governed by different regulatory frameworks. A centralized safety assessment by the European Food Safety Authority (EFSA) is the prerequisite for their authorization through the so-called Union Lists. Up to December 2023, EFSA published 45 scientific opinions on the safety of novel foods, food enzymes, and food additives derived from by-products of plant and animal origin. The current study illustrates examples of these by-products for the production of novel foods or food improvement agents and the data requirements behind their respective safety assessments conducted by EFSA. In this review, applications on novel foods, food enzymes, and food additives received by EFSA were screened and analyzed to find the common scientific requirements and differences in terms of the safety evaluation of such products. Various by-products (i.e., corncobs, coffee husks, spent grains of barley and rice, grape pomace, pumpkin peels, bovine whey, eggshells, shrimp heads, and animal organs or tissues) were described in the applications as being processed (extraction, physical treatments, and chemical and enzymatic reactions) to obtain novel foods and food improvement agents. The heterogeneity and complexity of these products emphasize the challenge of their safety assessment, depending on the characteristics of each product. However, as this study shows, the scientific requirements underpinning their safety do not differ substantially in the different regulated product areas considered, with similar information needed to assess their safety in terms of identity, production process, compositional characterization, proposed/intended uses and exposure assessment, toxicological information, and allergenicity data. Additional nutritional information and data on the history of use are required in the case of novel foods.

Strain-Phonon Cooperation as a Necessary Ingredient to Understand the Jahn-Teller Effect in Solids.

Spatial degeneracy is the cause of the complex electronic, geometrical, and magnetic structures found in a number of materials whose more representative example is KCuF3. In the literature the properties of this lattice are usually explained through the Kugel--Khomskii model, based on superexchange interactions. Here we provide rigorous theoretical and computational arguments against this view proving that structural and magnetic properties essentially arise from electron-vibration (vibronic) interactions. Moreover, based on the work of Öpik and Pryce, we show that the coupling between lattice (homogeneous strain) and motif (phonons) distortions is essential to understand the main stable configurations of the lattice. Using this information, we predict a new low-energy phase in KCuF3 that could strongly alter its properties and provide guidance on how to stabilize it through strain engineering.

Tooth autotransplantation outcomes using platelet-rich fibrin: A promising approach; case study.

BACKGROUND: Autogenous tooth transplantation refers to a surgical procedure involving the relocation of a tooth within the same individual. Incorporating platelet-rich fibrin (PRF) in this procedure holds the potential to improve healing, accelerate recovery, and optimize treatment outcomes. METHODS: In this article, the authors illustrate a PRF-based approach for autogenous tooth transplantation through two case scenarios. These cases outline the surgical steps of tooth transplantation and demonstrate the potential role of PRF in enhancing soft tissue healing. Furthermore, the article provides insights from a long-term follow-up spanning over 7 years. RESULTS: Tooth transplantation in young adults is promising but depends on factors such as root development stage and donor tooth size matching. Including PRF may improve healing, at least in the short term, due to its rich concentration of growth factors and cytokines, promoting effective tissue regeneration. CONCLUSIONS: Autogenous tooth transplantation has shown to be a viable treatment option for replacing the missing dentition. Adding PRF to the autogenous tooth transplantation procedure may speed up and enhance the treatment outcome. While the favorable results of these cases might be partially attributed to the use of PRF, the contribution of PRF to the healing process of tooth transplant remains conjectural and requires validation through additional research. KEY POINTS/HIGHLIGHTS: Tooth autotransplantation can be performed in younger patients without requiring root canal treatment, while also potentially benefiting from the incorporation of platelet-rich fibrin (PRF).

Differences and Similarities in the Feet of Metatarsalgia Patients with and without Rheumatoid Arthritis in Remission.

Objectives: Metatarsalgia continues to be a problem in patients with rheumatoid arthritis (RA) in remission (remRA), as well as in the non-rheumatic population, with a mechanical origin. Identify and compare clinical, morphological, disability, synovitis (ultrasound), and radiological osteoarticular damage characteristics in two groups of patients with lesser-ray metar-tarsalgia, with remRA, and without RA. Methods: Cross-sectional study with 84 patients with remRA (mRA) and 60 patients without RA (nmRA). The study evaluated five clinical variables (pain, Foot Function Index (FFI), joint mobility, digital deformities, and foot type), a radiological variable (osteoarticular damage), and an ultrasound variable (metatarsal synovitis). The data were analysed using descriptive and correlational techniques. Results: There were no significant differences in sex, age, body mass index (BMI), or degree of pain. Both groups showed a high prevalence of limited joint mobility for the ankle and first metatarsal phalanx (DF1st MTPJ) and digital deformities, with no statistically significant differences. Similarly, there were no differences in lesser-ray synovitis. On the other hand, there were differences in mRA with greater disability and activity limitation (FFI), LDD (lesser-ray digital deformities) stiffness, first-ray deformities, radiological damage, synovitis in 1st MTPJ, and positive Doppler (five patients). Conclusions: Metatarsalgia presents similarities in both populations. Biomechanical factors may influence the symptoms and presence of synovitis in patients with RA in remission. Other characteristics are more frequent in mRA, which could be related to the disease; thus, future research should include both biomechanical and ultrasound exploration of the foot in the valuation of patients in remission.

Different Diagnostic Criteria for Determining the Prevalence of Sarcopenia in Older Adults: A Systematic Review.

Background: Sarcopenia is defined as a loss of muscle mass, strength, and physical function associated with aging. It is due to a combination of genetic, environmental, and physiological factors. It is also associated with an increased risk of health problems. Since there are many different researchers in the field, with their own algorithms and cut-off points, there is no single criterion for diagnosis. This review aims to compare the prevalence of sarcopenia according to these different diagnostic criteria in older adult populations by age group and sex. Methods: Different databases were searched: Web of Science, Pubmed, Dialnet, Scopus, and Cochrane. The keywords used were "sarcopenia", "diagnosis", "prevalence", "assessment", "aged", "aging" and "older". Studies conducted in a population aged ≥65 assessing the prevalence of sarcopenia were selected. Results: Nineteen articles met the inclusion criteria, with a total of 33,515 subjects, 38.08% female and 61.42% male, at a mean age of 74.52. The diagnostic algorithms used were 52.63% AWGS2, 21.05% EWGSOP2, 10.53% AWGS1 and EWGS1, and 5.26% FNIH. Prevalence ranged from 1.7% to 37.47%, but was higher in males and increased with age. Conclusions: The prevalence of sarcopenia varies depending on the diagnostic algorithm used, but it increases with age and is higher in men. The EWGSOP2 and AWGS2 are the most used diagnostic criteria and measure the same variables but have different cut-off points. Of these two diagnostic algorithms, the one with the highest prevalence of sarcopenia and severe sarcopenia is the AWGS2. These differences may be due to the use of different tools and cut-off points. Therefore, a universal diagnostic criterion should be developed to allow early diagnosis of sarcopenia.

Glycerol Electrolyzer with Graphite Anode and Cathode Produces Carbonyl Compounds and Hydrogen: Background Electrocatalysis of a "Nonparticipating" Current Collector.

This study unveils a novel role of bare graphite as a catalyst in glycerol electrooxidation and hydrogen evolution reactions, challenging the prevailing notion that current collectors employed in electrolyzers are inert. Half-cell experiments elucidate the feasibility of glycerol oxidation and hydrogen production on bulk graphite electrodes at potentials exceeding 1.7 V. The investigation of varying glycerol concentrations (0.05 to 1.5 mol L-1) highlights a concentration-dependent competition between glycerol electrooxidation and oxygen evolution reactions. Employing an H-type glycerol electrolyzer, polarization curves reveal significant activation polarization attributed to the low electroactivity of the anode. Glycerol electrolysis at different concentrations yields diverse product mixtures, including formate, glycolate, glycerate, and lactate at the anode, with concurrent hydrogen generation at the cathode. The anolyte composition changes with glycerol concentration, resulting in less-oxidized compounds at higher concentrations and more oxidized compounds at lower concentrations. The cell voltage also influences the product formation selectivity, with an increased voltage favoring more oxidized compounds. The glycerol concentration also affects hydrogen production, with lower concentrations yielding higher hydrogen amounts, peaking at 3.5 V for 0.05 mol L-1. This model quantitatively illustrates graphite's contribution to current and product generation in glycerol electrolyzers, emphasizing the significance of background current and products originating from current collectors if in contact with the reactants. These results have an impact on the efficiency of the electrolyzer and raise questions regarding possible extra non-noble "nonparticipating" current collectors that could affect overall performance. This research expands our understanding of electrocatalysis on graphite surfaces with potential applications in optimizing electrolyzer configurations for enhanced efficiency and product selectivity.

[Necrosis and intestinal perforation associated with feeding by jejunostomy]. / Necrosis y perforación intestinal asociada a alimentación por yeyunostomía.

Enteral nutrition through jejunostomy is a common practice in any general surgery service; it carries a low risk of complications and morbidity and mortality. We present the case of a patient with an immediate history of subtotal gastrectomy that began nutrition through jejunostomy and complicated with intestinal necrosis due to non-occlusive ischemia in the short period. The purpose of this work is to report on this complication, its pathophysiology and risk factors to take it into account and be able to take appropriate therapeutic action early.

La nutrición enteral por yeyunostomía es una práctica frecuente en cualquier servicio de cirugía general, esta conlleva bajo riesgo de complicaciones y morbimortalidad. Presentamos el caso de una paciente con antecedente inmediato de gastrectomía subtotal que inició nutrición por yeyunostomía y complicó con necrosis intestinal por isquemia no oclusiva en el corto lapso. La finalidad de este trabajo es informar sobre esta complicación, su fisiopatología y factores de riesgo para tenerla en cuenta y poder tomar precozmente una conducta terapéutica adecuada.

Supportive therapy following peri-implantitis treatment: A retrospective study on compliance.

BACKGROUND: The compliance rate with supportive therapy following peri-implantitis treatment (SPIT) remains unknown. The present retrospective study was carried out to assess the compliance rate and the factors influencing compliance in a private practice setting. MATERIALS AND METHODS: Patients were divided into three groups according to compliance rate: regular compliance (RC ≥2 SPIT/year), erratic compliance (EC <2 SPIT/year), and non-compliance (NC <1 SPIT/year). Overall, 17 patient- (n = 8) and site-related variables (n = 9) were explored as potential confounders of compliance. The Chi2 test was applied to assess the association between categorical variables and determine the odds ratio (OR). RESULTS: The study comprised 159 patients restored with 1075 implants, of which 469 were treated for peri-implantitis and met the inclusion criteria. A total of 57.2% were RC, 25.8% EC, and 17% NC. The multivariate analysis showed that smoking and grade C periodontitis reduced the likelihood of RC (OR = 0.28, p < .001) when compared to complete edentulism or non-smoking. Moreover, age demonstrated being associated with follow-up when SPIT was interrupted in EC and NC (OR = 0.94, p = .007). CONCLUSION: Comprehensive information, provided prior to peri-implantitis treatment, regarding the importance of adhering to SPIT after peri-implantitis treatment to achieve/maintain peri-implant health, resulted in ~60% regular compliance rate (NCT05772078).

Association of aortic stiffness with abdominal vascular and coronary calcifications in patients with stage 3 and 4 chronic kidney disease.

RATIONALE AND OBJECTIVES: Increased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC). The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries(CAC). MATERIALS AND METHODS: We included 87 pacientes with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respecti-vely. For the study of the association between Pvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). RESULTS: Pvc-f and Pvc-f index were 11.3 ± 2.6 and 10.6 m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively. Albuminuria (ß = 0.13, p = 0.005) and Kauppila score (ß = 0.36, p = 0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (ß = 0.39, p = 0.001), DM (ß = 0.46, p = 0.01), and smoking (ß = 0.53; p = 0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6-6.9; p = 0.001)]. The Kauppila score was independently associated with the Agatston score (ß = 1.53, p = 0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%. The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04-10.2, p = 0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95%CI: 0.71-0.93, p = 0.001) and 0.81 (95% CI: 0.67-0.96, p = 0.02), respectively. CONCLUSIONS: When stage 3-4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3-4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

Unraveling the transcriptomic landscape of eye migration and visual adaptations during flatfish metamorphosis.

Flatfish undergo a remarkable metamorphosis from symmetrical pelagic larvae to fully asymmetrical benthic juveniles. The most distinctive features of this transformation is the migration of one eye. The molecular role of thyroid hormone in the metamorphosis process in flatfishes is well established. However, the regulatory network that facilitates eye movement remains enigmatic. This paper presents a morphological investigation of the metamorphic process in turbot eyes, using advanced imaging techniques and a global view of gene expression. The study covers migrant and non-migrant eyes and aims to identify the genes that are active during ocular migration. Our transcriptomic analysis shows a significant up-regulation of immune-related genes. The analysis of eye-specific genes reveals distinct patterns during the metamorphic process. Myosin is highlighted in the non-migrant eye, while ependymin is highlighted in the migrant eye, possibly involved in optic nerve regeneration. Furthermore, a potential association between the alx3 gene and cranial restructuring has been identified. Additionally, it confirmed simultaneous adaptation to low light in both eyes, as described by changes in opsins expression during the metamorphic process. The study also revealed that ocular migration activates systems asynchronously in both eyes, providing insight into multifaceted reorganization processes during metamorphosis of flatfish.

Clinical, glycometric features and treatment in a family with monogenic diabetes due to a new mutation in the insulin gene.

Monogenic diabetes caused by changes in the gene that encodes insulin (INS) is a very rare form of monogenic diabetes (<1%). The aim of this work is to describe the clinical and glycaemic control characteristics over time from four members of a family diagnosed with monogenic diabetes with the novel mutation: c.206del,p.(Gly69Aalfs*62) located in exon 3 of the gene INS. 75% are females, with debut in adolescence and negative autoimmunity. In all cases, C-peptide is detectable decades after diagnosis (>0.6ng/ml). Currently, patients are being treated either with insulin in a bolus-basal regimen, oral antidiabetics or hybrid closed loop system. Monogenic diabetes due to mutation in the INS is an entity with heterogeneous presentation, whose diagnosis requires high suspicion and presents an important clinical impact. Given the lack of standards in this regard, therapy must be individualized, although insulin therapy could help preserve beta cell functionality in these subjects.

Khinchin Families, Set Constructions, Partitions and Exponentials.

In this paper, we give a simple criterion to verify that functions of the form eg are in the Hayman class when g is a power series with nonnegative coefficients. Thus, using the Hayman and Báez-Duarte formulas, we obtain asymptotics for the coefficients of generating functions that arise in many examples of set construction in analytic combinatorics. This new criterion greatly simplifies the one obtained previously by the authors.

Interlayer Coupling Controlled Ordering and Phases in Polar Vortex Superlattices.

The recent discovery of polar topological structures has opened the door for exciting physics and emergent properties. There is, however, little methodology to engineer stability and ordering in these systems, properties of interest for engineering emergent functionalities. Notably, when the surface area is extended to arbitrary thicknesses, the topological polar texture becomes unstable. Here we show that this instability of the phase is due to electrical coupling between successive layers. We demonstrate that this electrical coupling is indicative of an effective screening length in the dielectric, similar to the conductor-ferroelectric interface. Controlling the electrostatics of the superlattice interfaces, the system can be tuned between a pure topological vortex state and a mixed classical-topological phase. This coupling also enables engineering coherency among the vortices, not only tuning the bulk phase diagram but also enabling the emergence of a 3D lattice of polar textures.

Alkali metal bilayer intercalation in graphene.

Alkali metal (AM) intercalation between graphene layers holds promise for electronic manipulation and energy storage, yet the underlying mechanism remains challenging to fully comprehend despite extensive research. In this study, we employ low-voltage scanning transmission electron microscopy (LV-STEM) to visualize the atomic structure of intercalated AMs (potassium, rubidium, and cesium) in bilayer graphene (BLG). Our findings reveal that the intercalated AMs adopt bilayer structures with hcp stacking, and specifically a C6M2C6 composition. These structures closely resemble the bilayer form of fcc (111) structure observed in AMs under high-pressure conditions. A negative charge transferred from bilayer AMs to graphene layers of approximately 1~1.5×1014 e-/cm-2 was determined by electron energy loss spectroscopy (EELS), Raman, and electrical transport. The bilayer AM is stable in BLG and graphite superficial layers but absent in the graphite interior, primarily dominated by single-layer AM intercalation. This hints at enhancing AM intercalation capacity by thinning the graphite material.

MptpB Inhibitor Improves the Action of Antibiotics against Mycobacterium tuberculosis and Nontuberculous Mycobacterium avium Infections.

Treatment of Mycobacterium tuberculosis and Mycobacterium avium infections requires multiple drugs for long time periods. Mycobacterium protein-tyrosine-phosphatase B (MptpB) is a key M. tuberculosis virulence factor that subverts host antimicrobial activity to promote intracellular survival. Inhibition of MptpB reduces the infection burden in vivo and offers new opportunities to improve current treatments. Here, we demonstrate that M. avium produces an MptpB orthologue and that the MptpB inhibitor C13 reduces the M. avium infection burden in macrophages. Combining C13 with the antibiotics rifampicin or bedaquiline showed an additive effect, reducing intracellular infection of both M. tuberculosis and M. avium by 50%, compared to monotreatment with antibiotics alone. This additive effect was not observed with pretomanid. Combining C13 with the minor groove-binding compounds S-MGB-362 and S-MGB-363 also reduced the M. tuberculosis intracellular burden. Similar additive effects of C13 and antibiotics were confirmed in vivo using Galleria mellonella infections. We demonstrate that the reduced mycobacterial burden in macrophages observed with C13 treatments is due to the increased trafficking to lysosomes.

Impact of diesel exhaust particles on infections with Mycobacterium bovis BCG in in vitro human macrophages and an in vivo Galleria mellonella model.

There are strong suggestions for a link between pulmonary tuberculosis (TB) and air quality. Diesel exhaust is one of the main contributors to pollution and it is reported to be able to modify susceptibility to lung infections. In this study we exposed THP-1 human macrophages and Mycobacterium bovis BCG to diesel exhaust particles (DEPs). High cytotoxicity and activation of apoptosis was found in THP-1 cells at 3 and 6 days, but no effect was found on the growth of M. bovis BCG. Infection of THP-1 cells exposed to a non-cytotoxic DEP concentration showed a limited capacity to engulf latex beads. However, M. bovis BCG infection of macrophages did not result in an increase in the bacterial burden, but it did result in an increase in the bacteria recovered from the extracellular media, suggesting a poor contention of M. bovis BCG. We also observed that DEP exposure limited the production of cytokines. Using the Galleria mellonella model of infection, we observed that larvae exposed to low levels of DEPs were less able to survive after infection with M. bovis BCG and had a higher internal bacterial load after 4 days of infection. Unraveling the links between air pollution and impairment of human antimycobacterial immunity is vital, because pollution is rapidly increasing in areas where TB incidence is extremely high.