Distinctive antibody responses to Mycobacterium tuberculosis in pulmonary and brain infection.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a global health burden. While Mtb is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that leads to differential disease across organs. Attention has focused on differences in T cell responses in the control of Mtb in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood brain barrier, here we characterized the antibody profiles across the blood and brain compartments during TBM, and determined whether Mtb-specific humoral immune responses differed between Mtb infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different Mtb antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n=10) vs TBM (n=60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4), the capacity of Mtb-specific antibodies to bind to Fc receptors or C1q, and to activate innate immune effectors functions (complement and NK cells activation, monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against Mtb, characterized by an enrichment of Mtb-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited Mtb-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared to individuals with pulmonary TB, despite having lower IgG titers and Fcγ receptors (FcγR)-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs vs brain), and demonstrate a highly compartmentalized Mtb-specific antibody response within the CSF during TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.

The effect of M. tuberculosis lineage on clinical phenotype.

Six lineages of Mycobacterium tuberculosis sensu stricto (which excludes M. africanum) are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR = 1.40(1.09-1.79), p = 0.007; aOR = 2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR = 0.69(0.57-0.83), p<0.001) and L4 strains (aOR = 0.73(0.59-0.90), p = 0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p = 0.033, p = 0.008 and p = 0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

Regenerative Endodontic Procedures of Immature Permanent Premolars with Periapical Lesions: A Report of Two Cases Using Two Different Materials, 18-Month Follow-Up.

Regenerative endodontic procedure is an emerging alternative to traditional therapies for immature teeth with necrotic pulp with or without periapical lesions. This innovative approach, also known as revitalization procedures, is aimed at enhancing canal wall thickness, stimulating root lengthening, and promoting apical closure. The regenerative endodontic procedures involve minimally invasive cleaning to preserve stem cells, stimulation of bleeding and clot formation within the canal, and the use of biomaterials to stimulate differentiation. This method is the first choice in biologically based treatments for immature permanent teeth. We present two successful clinical cases in which regenerative endodontic procedures were performed on permanent premolars with necrotic pulp with symptomatic apical periodontitis and chronic apical abscess due to dens evaginatus. The same procedure was employed for both cases, utilizing two differential materials: ProRoot MTA (Dentsply Tulsa Dental Specialities, USA) and Biodentine™ (Septodont, Saint-Maur-des-Fossés, France). Both cases exhibited positive clinical and radiographic outcomes after an 18-month follow-up period including periapical healing, increased dentin thickness, root lengthening, and apical closure.

Rolling out new anti-tuberculosis drugs without diagnostic capacity.

Deaths from tuberculosis (TB) reached over 1.6 million in 2021 with 10.6 million people becoming ill. Multidrug-resistant TB, defined as the Mycobacterium tuberculosis organism having resistance to at least isoniazid and rifampicin, represented 3.9% of new TB cases and 18% of previously treated cases. While new drug regimens continue to be developed and introduced to improve treatment of drug-resistant forms of TB, diagnostic capability to identify drug resistance lags woefully behind. While significant mortality benefits exist for these newer drug regimens, implementing them without proper drug resistance diagnostic capacity could lead to development of more drug resistances and exhaust these new therapeutic tools. Moving forward, the roll-out of new TB drugs and regimens must be paired with implementation of diagnostics to ensure judicious use of resources and the best chance for improving TB worldwide.

The effect of M. tuberculosis lineage on clinical phenotype.

Eight lineages of Mycobacterium tuberculosis sensu stricto are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p<0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.

Risk factors for poor treatment outcomes of 2266 multidrug-resistant tuberculosis cases in Ho Chi Minh City: a retrospective study.

BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) remains a serious public health problem with poor treatment outcomes. Predictors of poor outcomes vary in different regions. Vietnam is among the top 30 high burden of MDR-TB countries. We describe demographic characteristics and identify risk factors for poor outcome among patients with MDR-TB in Ho Chi Minh City (HCMC), the most populous city in Vietnam. METHODS: This retrospective study included 2266 patients who initiated MDR-TB treatment between 2011 and 2015 in HCMC. Treatment outcomes were available for 2240 patients. Data was collected from standardized paper-based treatment cards and electronic records. A Kruskal Wallis test was used to assess changes in median age and body mass index (BMI) over time, and a Wilcoxon test was used to compare the median BMI of patients with and without diabetes mellitus. Chi squared test was used to compare categorical variables. Multivariate logistic regression with multiple imputation for missing data was used to identify risk factors for poor outcomes. Statistical analysis was performed using R program. RESULTS: Among 2266 eligible cases, 60.2% had failed on a category I or II treatment regimen, 57.7% were underweight, 30.2% had diabetes mellitus and 9.6% were HIV positive. The notification rate increased 24.7% from 2011 to 2015. The treatment success rate was 73.3%. Risk factors for poor treatment outcome included HIV co-infection (adjusted odds ratio (aOR): 2.94), advanced age (aOR: 1.45 for every increase of 5 years for patients 60 years or older), having history of MDR-TB treatment (aOR: 5.53), sputum smear grade scanty or 1+ (aOR: 1.47), smear grade 2+ or 3+ (aOR: 2.06), low BMI (aOR: 0.83 for every increase of 1 kg/m2 of BMI for patients with BMI < 21). CONCLUSION: The number of patients diagnosed with MDR-TB in HCMC increased by almost a quarter between 2011 and 2015. Patients with HIV, high smear grade, malnutrition or a history of previous MDR-TB treatment are at greatest risk of poor treatment outcome.

Endodontic system obturation by technique of the three dimensional obturation/ warm/vertical condensation of gutta-parcha

50 patients with the odontopathy and odontic advantages of technique of the three dimensional obturation/warm vertical condensation of gutta- percha included easy implementation, close obturation of the accessory root canals and high rate of healing the lesion of endodontic origin and limitations included no application for the odontic pedicle that have not been closed.