Treatment outcomes and risk factors for an unsuccessful outcome among patients with highly drug-resistant tuberculosis in Ukraine.

OBJECTIVES: To describe demographics, clinical features, and treatment outcomes of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome. METHODS: Data from patients with multi-, pre-extensively, or extensively drug-resistant TB were collected prospectively from TB dispensaries in 15 out of 24 Ukrainian oblasts (regions) from 2020 to 2021. Treatment outcomes were evaluated using WHO definitions. Risk factors for an unsuccessful outcome were identified using a multivariable logistic regression model. RESULTS: Among 1748 patients, the overall proportion of successful outcomes was 58% (95% confidence interval [95% CI] 56-60) (n = 1015/1748), ranging from 65% (95% CI: 62-69) (n = 531/814) for multidrug-resistant TB to 54% (95% CI: 49-58) (n = 301/563) for pre-extensively drug-resistant TB and 49% (95% CI: 44-55) (n = 183/371) for extensively drug-resistant TB. Results were similar across oblasts, with few exceptions. The strongest risk factors for an unsuccessful outcome were extensively drug-resistant TB (adjusted OR [aOR] 3.23; 95% CI: 1.88-5.53), total serum protein below 62 g/L in adults and below 57 g/L for children and adolescents (aOR 2.79; 95% CI: 1.93-4.04), psychiatric illness (aOR 2.79; 95% CI: 1.46-5.33), age at TB diagnosis >65 years (aOR 2.50; 95% CI: 1.42-4.42), and alcohol misuse (aOR 2.48; 95% CI: 1.89-3.26). DISCUSSION: The overall proportion of successful outcomes among Ukrainians treated for highly drug-resistant TB was 58%, notably better compared with previous years, but still low for extensively drug-resistant TB. Risk factors for unsuccessful outcomes highlight that addressing socioeconomic factors in TB management is crucial. Efforts in maintaining TB dispensaries during and following the ongoing war are highly warranted.

RISK FACTORS FOR GC-RESISTANT PULMONARY SARCOIDOSIS.

OBJECTIVE: The aim: The study aimed to conduct a retrospective analysis of unfavorable outcome rate and to search for clinical and anamnestic criteria for predicting glucocorticoid-resistant pulmonary sarcoidosis. PATIENTS AND METHODS: Materials and methods: There were examined 37 women and 31 men with stage II to III pulmonary sarcoidosis from 2018-2022. The mean patients' age was (35.7±6.6) years. All patients underwent a chest computed tomography scan on the Toshiba Aquilion Prime CT scanner before the start of treatment and after the three-month glucocorticoid therapy. Anamnestic, age- and gender related factors of unfavorable treatment outcomes were studied. RESULTS: Results: Dyspnea (86%), coughing (67%), general weakness and fatigue (29%) on the background of maintaining the indicators of lung tissue density at the level of -893.5 Hounsfield units and above according to the chest computed tomography imaging represented the three-month treatment failure. Glucocorticoid-resistant sarcoidosis was most diagnosed in patients with stage III disease; the mean patients' age was (44.3±3.2) years; B positive men prevailed; 85% of patients developed extrapulmonary manifestations; in 43% of cases, concomitant cardiovascular pathology was diagnosed. CONCLUSION: Conclusions: Age, gender, comorbid conditions, extrapulmonary lesions, and blood type can be used as predictive criteria for GC-resistant sarcoidosis.

Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of molnupiravir for intra-household post-exposure prophylaxis (PEP) of COVID-19. METHODS: MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800 mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. RESULTS: The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. CONCLUSIONS: Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.

PREVALENCE OF SENSORY DYSFUNCTIONS IN ADULT UKRAINIAN POPULATION WITH LABORATORY CONFIRMED COVID-19.

OBJECTIVE: The aim: To analyse the structure of sensory impairments, associated with COVID-19. To identify terms of recovery periods depending on severity of disease, age and gender of the patients. PATIENTS AND METHODS: Materials and methods: Within two weeks, 2225 patients with confirmed COVID-19 completed a questionnaire, created by Google Forms. General complaints, peculiarities of sensory impairments and recovery time were specified. After exclusion criteria application, data of 2108 patients were analyzed by R Statistics Package, Student's t-test, Wilcoxon rank-sum test, Fisher's exact test, Spearman's rank test. RESULTS: Results: Among patients enrolled (973 males and 1135 females, mean age 28.6±0.18) the most frequent were olfactory (91.32%) and gustatory (66.03%) dysfunctions. Olfactory manifestations were usually accompanied by gustatory disorders (73.72%). Average duration of olfactory dysfunction was 15.46±0.45 days, gustatory - 11.3±0.33, hearing - 4.3±0.16, and visual - 6.53±0.23 days. It was found a correlation between duration of olfactory and gustatory impairments (r=0.65; p < 0.001), hearing and visual disorders (r=0.49; p < 0.05). CONCLUSION: Conclusions: Olfactory and gustatory disorders are prevalent symptoms in Ukrainian population. 7.87% of respondents who had impairment of all four sensory functions had the longest recovery time. Duration of sensory impairments did not depend on age, type of treatment and severity of disease, which rises the question about the neurogenic pathway of virus.

NEW POSSIBILITIES FOR MODIFYING THE COURSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE: THE EFFECT OF TIOTROPIUM BROMIDE ON CERTAIN PATHOGENETIC LINKS OF NEOCOLLAGENOGENESIS AND LOCAL IMMUNE DEFENCE OF THE BRONCHIAL TREE.

OBJECTIVE: The aim: To evaluate the dynamics of the interferon and collagen-IV systems in bronchoalveolar lavage in the treatment of chronic obstructive pulmonary disease using the tiotropium bromide medication. PATIENTS AND METHODS: Materials and methods: The study involved 60 COPD patients with bronchial obstruction of the II degree before and on days 30 and 60 of therapy using conventional treatment regimens and inhalations of tiotropium bromide a the dose of 18 mcg once a day. The collagen-IV levels in bronchoalveolar fluid were determined by means of enzyme-linked immunoassay using "StatFax 303 Plus" analyzer and "Biotrin Collagen IV EIA" reagents. The level of IFN-γ was identified with the help of enzyme-linked immunoassay using "StatFax 303 Plus" analyzer and "ProKon" reagents (LLC "Protein Contour", Russia) in bronchoalveolar fluid obtained during fiber-optic bronchoscopy. RESULTS: Results: When examining Group I patients on the 30th day we found out that the content of collagen-IV in the bronchoalveolar fluid had decreased by only 10.29% (p <0.05). Detection of collagen-IV indices in Group II patients on the 30th day of tiotropium bromide use showed the 29.43% (p <0.05) decrease in its content as compared to the initial indices. In Group III patients, the concentration of collagen-IV had a maximum tendency to normalize and made up (24.72 ± 1.15) ng/ml, and decreased by 2.44 times (p <0.05) as compared to the initial indices. Our examination of 12 patients from the comparison group I on the 60th day of treatment revealed even a slight increase in the content of collagen-IV in the bronchoalveolar fluid, as compared with the data obtained on the 30th day. The identified IFN-γ deficiency is indicative for the COPD of the II degree of bronchial obstruction, and its indices were 2.29 times lower than those observed in people from the control group. On day 30, we found out that the content of IFN-γ in Group I patients increased by only 10.29% (p>0.05). Detection of IFN-γ in Group II patients showed 42.27% (p<0,05) increase in its content as compared to the initial indices. The most favorable dynamics of IFN-γ levels in bronchoalveolar contents was observed in Group III patients, and at the time of observation it made up (1.16 ± 0.08) pg/ml, having 2 times (p<0.05) increased as compared to the initial indices. However, in contrast to those taking tiotropium bromide, we examined 12 patients from Group I on the 60th day of treatment and found no significant positive dynamics of IFN-γ content in bronchoalveolar fluid as compared to the indices obtained on day 30. CONCLUSION: Conclusions: The obtained findings indicate the effect of tiotropium bromide on the reduction of interferon-γ and reduce of collagen-IV levels, which depend on the duration of its use.

EVALUATION OF THE QUALITY OF LIFE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN OVERWEIGHT PATIENTS.

OBJECTIVE: The aim: To evaluate the effect of overweight on the quality of life of chronic obstructive pulmonary disease (COPD) patients GOLD III. PATIENTS AND METHODS: Materials and methods: 65 patients with chronic obstructive pulmonary disease (COPD GOLD III) were examined in different phases of pathological process. The pulmonary function (PF) test was performed by means of "SPIROKOM" device (Ukraine). The degree of overweight was determined by calculating the body mass index (BMI) using the formula І = m/h² (m - body mass in kilograms, h - height, square of the height in meters (kg/m²). Patients' quality of life was evaluated with the help of standardized St.George's Respiratory Questionnaire (SGRQ). RESULTS: Results: The study revealed changes in the PF indices and the decrease in quality of life in overweight patients, especially in case of destabilization of the pathological process. CONCLUSION: Conclusions: The obtained results show that overweight is the underlying condition for more severe course of the pathology and requires further study of its impact on the health and quality of life of patients in order to improve the effectiveness of treatment.

NITRIC OXIDE METABOLISM IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA ASSOCIATED WITH CORONARY HEART DISEASE AND THE POSSIBILITY OF ITS MEDICAMENTOUS MANAGEMENT.

OBJECTIVE: The aim: To assess the metabolic by-products of nitric oxide in peripheral blood before and after the medicamentous management in patients suffering from community-acquired pneumonia associated with coronary heart disease. PATIENTS AND METHODS: Materials and methods: We have examined 102 patients with community-acquired pneumonia aged from 50 to 65 years, of which 58 patients were diagnosed with coronary heart disease (CHD). The complex treatment of patients with coronary heart disease was supplemented by the additional use of tivortin aspartate, which was taken orally with food at the dose of 5 ml (1g) 3 times a day for 15 days. The NO content in blood plasma was assessed by the concentration of the amount of final NO metabolites (NO3 + NO2), identified by means of the photocalorimetric method. RESULTS: Results: The content of (NO3 + NO2) in peripheral blood of patients with CAP was slightly higher (6.83 ± 0.29) µmol/l as compared to the group of apparently healthy individuals (5.19 ± 0.14) µmol/l, while in patients with CAP associated with CHD it has markedly increased to (12.74 ± 1.09) µmol/l. Against the background of administered treatment, the index of (NO3 + NO2) in patients with coronary heart disease has decreased to (5.76 ± 0.33) µmol/l, while in the group of patients who were not given tivortin aspartate additionally, this index has even slightly increased (7.01 ± 0.40) µmol/l. CONCLUSION: Conclusions: Marked increase of (NO3 + NO2) levels in blood pointed to destabilization of the course of coronary heart disease with CAP, which was eliminated by the involvement of tivortin aspartate (15 days) to the main course of treatment.

3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats.

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.

Activation of Nigrostriatal Dopamine Neurons during Fear Extinction Prevents the Renewal of Fear.

Manipulations that increase dopamine (DA) signaling can enhance fear extinction, but the circuits involved remain unknown. DA neurons originating in the substantia nigra (SN) projecting to the dorsal striatum (DS) are traditionally viewed in the context of motor behavior, but growing data implicate this nigrostriatal circuit in emotion. Here we investigated the role of nigrostriatal DA in fear extinction. Activation of SN DA neurons with designer Gq-coupled receptors exclusively activated by designer drugs (Gq-DREADD) during fear extinction had no effect on fear extinction acquisition, but enhanced fear extinction memory and blocked the renewal of fear in a novel context; a pattern of data paralleled by cFos expression in the central amygdala. D1 receptors in the DS are a likely target mediating the effects of SN DA activation. D1-expressing neurons in the medial DS (DMS) were recruited during fear extinction, and Gq-DREADD-induced DA potentiated activity of D1-expressing neurons in both the DMS and the lateral DS (DLS). Pharmacological activation of D1 receptors in the DS did not impact fear extinction acquisition or memory, but blocked fear renewal in a novel context. These data suggest that activation of SN DA neurons and DS D1 receptors during fear extinction render fear extinction memory resistant to the disrupting effects of changes in contextual contingencies, perhaps by recruiting habitual learning strategies involving the DLS. Nigrostriatal DA thus represents a novel target to enhance long-term efficacy of extinction-based therapies for anxiety and trauma-related disorders.

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.