COVID-19 and Tuberculosis: Mathematical Modeling of Infection Spread Taking into Account Reduced Screening.

The COVID-19 pandemic resulted in the cessation of many tuberculosis (TB) support programs and reduced screening coverage for TB worldwide. We propose a model that demonstrates, among other things, how undetected cases of TB affect the number of future M. tuberculosis (M. tb) infections. The analysis of official statistics on the incidence of TB, preventive examination coverage of the population, and the number of patients with bacterial excretion of M. tb in the Russian Federation from 2008 to 2021 is carried out. The desired model can be obtained due to the fluctuation of these indicators in 2020, when the COVID-19 pandemic caused a dramatic reduction in TB interventions. Statistical analysis is carried out using R v.4.2.1. The resulting model describes the dependence of the detected incidence and prevalence of TB with bacterial excretion in the current year on the prevalence of TB with bacterial excretion in the previous year and on the coverage of preventive examinations in the current and previous years. The adjusted coefficient of model determination (adjusted R-squared) is 0.9969, indicating that the model contains almost no random component. It clearly shows that TB cases missed due to low screening coverage and left uncontrolled will lead to a significant increase in the number of new infections in the future. We may conclude that the obtained results clearly demonstrate the need for mass screening of the population in the context of the spread of TB infection, which makes it possible to timely identify patients with TB with bacterial excretion.

Assessment of Comorbidity in Patients with Drug-Resistant Tuberculosis.

A wide range of comorbidities, especially in multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) patients, markedly complicates selecting effective treatment of tuberculosis (TB) and preventing the development of adverse events. At present, it is impossible to assess the severity of comorbid pathologies and develop indications for the administration of accompanying therapy in TB patients. The aim of this study was to identify the difference in the range of comorbidities between patients with MDR-TB and XDR-TB and assess the impact of comorbidities on TB treatment. Materials and Methods: A retrospective, prospective study was conducted where 307 patients with MDR-TB and XDR-TB pulmonary tuberculosis aged 18 to 75 years who received eTB treatment from 2016 to 2021 in St. Petersburg hospitals were analyzed. The analysis showed that the comorbidity level in MDR-TB and XDR-TB patients with TB treatment success and treatment failure was comparable with the use of the Charlson Comorbidity Index (CCI). The CCI demonstrated declining data in terms of TB treatment outcome period in both groups. A slight predominance of CCI score (3 to 4 points) in XDR-TB (22.7%) vs. MDR-TB (15.4%) patients was found. In the case of an TB treatment failure, the CCI level in MDR-TB vs. XDR-TB patients was characterized by a significantly higher rate of low magnitude (ranging from 1 to 2 points) in 21.1% vs. 4.5% (p < 0.05), which was higher in XDR-TB patients (ranging from 4 to 5 points, in 10.0% vs. 0, χ2 = 33.7 (p < 0.01)). Chronic viral hepatitis B and C infection, cardiovascular pathology, chronic obstructive pulmonary disease, and chronic alcoholism were found to be significant comorbidity factors that influenced the TB treatment success. Conclusions: It is evident that XDR-TB patients comprise a cohort with the most severe disease course due to comorbidities impacting TB treatment efficacy. The obtained data pointed to the need to determine comorbidity severity in patients with drug-resistant Mbt prior to administering TB treatment schemes.

Tuberculosis in the Russian Federation: Prognosis and Epidemiological Models in a Situation After the COVID-19 Pandemic.

AIM: Because of the COVID-19 pandemic, many support programs for tuberculosis (TB) patients have been discontinued and TB mass screening activities decreased worldwide, resulting in a decrease in new case detection and an increase in TB deaths (WHO, WHO global lists of high burden countries for TB, multidrug/rifampicin-resistant TB (MDR/RR-TB) and TB/HIV, 2021-2025, 2021). The study aimed to assess changes in epidemiological indicators of tuberculosis in the Russian Federation and to simulate these indicators in the post-COVID-19 period. MATERIALS AND METHODS: The main epidemiological indicators of tuberculosis were analyzed with the use of government statistical data for the period from 2009 to 2021. Further mathematical modeling of epidemiological indicators for the coming years was carried out, taking into account the TB screening by chest X-ray. Statistical analysis was carried out using the software environment R (v.3.5.1) for statistical computing and the commercial software Statistical Package for the Social Sciences (SPSS Statistics for Windows, version 24.0, IBM Corp., 2016). Time series forecasting was performed using the programming language for statistical calculations R, version 4.1.2 and the bsts package, version 0.9.8. STUDY RESULTS: The study has found that the mean regression coefficient of a single predictor differs in the model for TB incidence and mortality (0.0098 and 0.0002, respectively). Forecast of overall incidence, the incidence of children and the forecast for mortality using the basic scenario (screening 75-78%) for the period from 2022 to 2026 was characterized by a mean decrease rate of 23.1%, 15.6% and 6.0% per year, respectively. A conservative scenario (screening 47-63%) of overall incidence indicates that the incidence of children and the forecast for mortality will continue to decrease with a mean decrease rate of 23.2%, 15.6% and 6.0% per year, respectively. Comparable data were obtained from the forecast of overall incidence, the incidence of children and the forecast for mortality using the optimistic scenario (screening 82-89%) with a mean decrease rate of 22.9%, 15.4% and 6.0% per year, respectively. CONCLUSIONS: It has been proven that the significance of screening with chest X-ray as a predictor of mortality is minimal. However, TB screening at least 60% of the population (chest X-ray in adults and immunological tests in children) have provided relationship between the TB screening rate and TB mortality rate (TB mortality rate increases with an increase in the population coverage and, conversely, decreases with a decrease in the population coverage).

Efficacy of Tuberculosis Treatment in Patients with Drug-Resistant Tuberculosis with the Use of Bedaquiline: The Experience of the Russian Federation.

In the conditions of the continued growth of multiple- and extensive drug-resistant tuberculosis, use of the new highly effective anti-tuberculosis drugs in this patient category is of great relevance. The aim of the study was determination the efficacy of treatment in patients with multidrug- and extensive drug-resistant tuberculosis using bedaquiline based on studies published in the Russian Federation. MATERIALS AND METHODS: The authors analyzed data published in studies from 2014 to 2022; 41 publications were included in total and 17 articles corresponded to the study design. The results of treatment of 1404 tuberculosis patients with MDR/XDR TB were described. Bedaquiline was used according to the standard scheme with a description of the treatment results after 24-26 weeks. Treatment efficacy was estimated according to accepted criteria. RESULTS OF THE STUDY: The analysis showed that the treatment efficacy on conversion was achieved in 79.5% of cases (95% Cl 76.5-82.3), and recovery was observed in 82.0% of cases (95% Cl 78.6-85.1). Departure from the therapy was observed in rare cases (9.8%; 95% Cl 7.9-12.2). Deaths were recorded in 6.5% of cases (95% Cl 4.9-8.3), which were associated with the severe disease and concomitant pathology in 74.3%. The development of adverse events was noted in half of the patients (55.7%); however, bedaquiline cancellation occurred in a few cases (7.0%; 95% Cl 3.0-13.0). From analyzing data in patients with MDR and XDR TB, the efficacy of treatment was 89.9% (95% Cl 85.9-93.2) and 71.9% (95% Cl 66.2-77.1), respectively. CONCLUSION: Use of bedaquiline in treatment makes it possible to achieve recovery of patients with MDR/XDR TB in 82.0% of cases with patients dropping out of treatment in 9.8%. At the same time, in patients with MDR TB, recovery was achieved in 89.9% of cases, while in patients with XDR TB, 71.9% of cases recovered.

Specificity of oligonucleotide gene therapy (OGT) agents.

Oligonucleotide gene therapy (OGT) agents (e. g. antisense, deoxyribozymes, siRNA and CRISPR/Cas) are promising therapeutic tools. Despite extensive efforts, only few OGT drugs have been approved for clinical use. Besides the problem of efficient delivery to targeted cells, hybridization specificity is a potential limitation of OGT agents. To ensure tight binding, a typical OGT agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma. Here, we assess the scale of this problem by analyzing OGT hybridization-dependent off-target effects (HD OTE) in vitro, in animal models and clinical studies. All OGT agents except deoxyribozymes exhibit HD OTE in vitro, with most thorough evidence of poor specificity reported for siRNA and CRISPR/Cas9. Notably, siRNA suppress non-targeted genes due to (1) the partial complementarity to mRNA 3'-untranslated regions (3'-UTR), and (2) the antisense activity of the sense strand. CRISPR/Cas9 system can cause hundreds of non-intended dsDNA breaks due to low specificity of the guide RNA, which can limit therapeutic applications of CRISPR/Cas9 by ex-vivo formats. Contribution of this effects to the observed in vivo toxicity of OGT agents is unclear and requires further investigation. Locked or peptide nucleic acids improve OGT nuclease resistance but not specificity. Approaches that use RNA marker dependent (conditional) activation of OGT agents may improve specificity but require additional validation in cell culture and in vivo.

Small Fiber Neuropathy in Sarcoidosis.

Sarcoidosis (SC) is a granulomatous disease of an unknown origin. The most common SC-related neurological complication is a small fiber neuropathy (SFN) that is often considered to be the result of chronic inflammation and remains significantly understudied. This study aimed to identify the clinical and histological correlates of small fiber neuropathy in sarcoidosis patients. The study was performed in 2018-2019 yy and included 50 patients with pulmonary sarcoidosis (n = 25) and healthy subjects (n = 25). For the clinical verification of the SFN, the "Small Fiber Neuropathy Screening List" (SFN-SL) was used. A punch biopsy of the skin was performed followed by enzyme immunoassay analysis with PGP 9.5 antibodies. Up to 60% of the sarcoidosis patients reported the presence of at least one complaint, and it was possible that these complaints were associated with SFN. The most frequent complaints included dysfunctions of the cardiovascular and musculoskeletal systems and the gastrointestinal tract. A negative, statistically significant correlation between the intraepidermal nerve fiber density (IEND) and SFN-SL score was revealed. In patients with pulmonary sarcoidosis, small fiber neuropathy might develop as a result of systemic immune-mediated inflammation. The most common symptoms of this complication were dysautonomia and mild sensory dysfunction.

Recombinant tuberculosis allergen (Diaskintest®) in tuberculosis diagnostic in Russia (meta-analysis).

Immunological testing for tuberculosis has been one of the most rapidly developing areas in the last decade. A new-generation immunological skin test, Diaskintest (DST), has been developed in the Russian Federation and successfully implemented into clinical practice since 2009. This article presents the results of a meta-analysis of publications reporting data on the use of the recombinant tuberculosis allergen DST (n = 121) from 2009 to 2019 included in Russian and international databases. The analysis included a total of 61 papers consistent with the study design, which cumulatively presented the results of 3,777,083 patients tested with DST (83.0%). The obtained data showed that the overall diagnostic sensitivity of the test in this population, regardless of age, was 86.0%, with 98.0% negative results. It was found that the intensity of the immune response of tuberculosis patients to specific ESAT-6 and CFP-10 antigens of DST may depend on the biological properties of the pathogen characteristic to various Mycobacterium tuberculosis genotypes, tuberculosis severity, and the presence of concomitant diseases. These factors are more prevalent in the adult population. In children, however, the test sensitivity reaches 100%. The proportion of positive DST results in HIV-positive patients tested for tuberculosis was 60.0%. The analysis showed that the accuracy (overall validity) of DST was 95.1% in the total studied population (95% confidence interval [CI]: 95.06-95.1) and 92.4% in HIV-positive patients (95% CI: 91.9-92.7).

Adaptation and Probiotic Potential of Lactobacilli, Isolated from the Oral Cavity and Intestines of Healthy People.

The present study shows that, from 300 Lactobacillus strains isolated from the oral cavity and large intestine of 600 healthy people, only 9 had high antagonistic activity against pathogens and opportunistic pathogens. All antagonistic strains of lactobacilli have been identified by 16S rRNA sequencing and assigned to four species: Lactobacillus fermentum, Lactobacillus rhamnosus, Lactobacillus plantarum, and Lactobacillus casei. In addition, these lactobacilli appeared to be nonpathogenic and had some probiotic potential: the strains produced lactic acid and bacteriocins, showed high sensitivity to broad-spectrum antibiotics, and were capable of forming biofilms in vitro. With the help of PCR and specific primers, the presence of genes for prebacteriocins in L. plantarum (plnEF, plnJ, plnN) and L. rhamnosus (LGG_02380 and LGG_02400) has been revealed. It was found that intestinal strains of lactobacilli were resistant to hydrochloric acid and bile. Lactobacilli isolated from the oral cavity were characterized by a high degree of adhesion, whereas intestinal strains were characterized by average adhesion. Both types of lactobacilli had medium to high rates of auto-aggregation and hydrophobicity and could coaggregate with pathogens and opportunistic pathogens. Additionally, the ability of the lactobacilli strains to produce gasotransmitters, CH4, CO2, C2H6, CO, and NH3, has been revealed.