The impact of the COVID-19 pandemic on TB notifications in Ukraine in 2020.

BACKGROUND: We assessed the impact of the COVID-19 pandemic on TB notifications in Ukraine, stratified by multiple subgroups. DESIGN/METHODS: We analyzed data from Ukraine's National TB Program from January 2015 to December 2020 using interrupted time series models. We compared observed cases to counterfactual estimated cases had the pandemic not occurred and estimated trends through December 2020 nationally and by various demographics. We compared the proportions of individuals who underwent drug susceptibility testing (DST) in February 2020 and April 2020 to assess the pandemic impact on drug resistance testing. RESULTS: In April 2020, there were 39% (95% CI 36-42) fewer TB notifications than the estimated counterfactual (3,060 estimated; 95% CI 2,918-3,202; 1,872 observed). We observed a greater decrease in notifications among refugees/migrants compared with non-refugees/migrants (64%, 95% CI 60-67 vs. 39%, 95% CI 36-42), and individuals aged <15 years compared with those aged ≥15 years (60%, 95% CI 57-64 vs. 38%, 95% CI 36-41). We also observed a decrease in the proportion of individuals receiving DST for several drugs. CONCLUSIONS: These findings underscore the challenges to TB prevention and care during disruption and may be generalizable to the current wartime situation, especially considering the substantial increase in refugees within and leaving Ukraine.

CONTEXTE: Nous avons évalué l'impact de la pandémie de COVID-19 sur les notifications de TB en Ukraine, stratifiées en plusieurs sous-groupes. CONCEPTION/MÉTHODES: Nous avons analysé les données du Programme national de lutte contre la TB de l'Ukraine de janvier 2015 à décembre 2020 à l'aide de modèles de séries chronologiques interrompues. Nous avons comparé les cas observés aux cas contrefactuels estimés si la pandémie n'avait pas eu lieu et les tendances estimées jusqu'en décembre 2020 à l'échelle nationale et selon divers groupes démographiques. Nous avons comparé les proportions de personnes ayant subi un test de sensibilité aux médicaments (DST) en février 2020 et avril 2020 pour évaluer l'impact de la pandémie sur les tests de résistance aux médicaments. RÉSULTATS: En avril 2020, il y avait 39% (IC à 95% 36­42) de notifications de TB de moins que le contrefactuel estimé (3 060 estimés ; IC à 95% 2 918­3 202 ; 1 872 observés). Nous avons observé une plus grande diminution des notifications chez les réfugiés/migrants par rapport aux non-réfugiés/migrants (64%, IC à 95% 60­67 contre 39%, IC à 95% 36­42), et les personnes âgées de <15 ans par rapport à celles âgées de ≥15 ans (60% ; IC à 95% 57­64 contre 38% ; IC à 95% 36­41). Nous avons également observé une diminution de la proportion de personnes recevant le DST pour plusieurs médicaments. CONCLUSIONS: Ces résultats soulignent les défis de la prévention et des soins de la TB pendant les perturbations et peuvent être généralisés à la situation actuelle en temps de guerre, en particulier compte tenu de l'augmentation substantielle du nombre de réfugiés à l'intérieur et à l'extérieur de l'Ukraine.

Application of Artificial Intelligence to Assess the Risks of Simultaneous Operations for Patients with Concomitant Atherosclerotic Damage of Coronary and Carotid Arteries.

The aim of the study is to assess the possibility of using artificial intelligence to determine the most significant predictors of the operative correction outcomes for patients with damaged coronary and carotid arteries. Materials and Methods: The retrospective study of the simultaneous (or single-stage) surgical intervention results has been carried out in patients with combined atherosclerotic damage of the coronary bed and cerebral arteries (n=42), which was severe and extensive. The parameters which may be predictors of the cardiovascular risk were analyzed using the TADA program. Ten models were built for program learning. The model with 92% predictive accuracy appeared to be the most successful. Results: Simultaneous correction resulted in the absence of 30-day coronary complications in all patients. With respect to the cerebral vascular territory, acute ischemic stroke developed in 2 patients. The lethality rate was 2.4%, the fatal outcome was caused by postoperative gastrointestinal bleeding.The TADA program model considered the following parameters to be the most significant predictors: internal carotid artery cross-clamping time in minutes (51.24%); damage to the left coronary artery stem (30.42%); diastolic AP (18.28%). If cross-clamping of the internal carotid artery lasts for less than 18 min, complications are not likely to occur, while they are practically inevitable if the time exceeds 46 min. The probability of complications grows nonlinearly with the increase of the extent of the left coronary artery stem injury. A high diastolic AP never virtually coincides with the presence of complications, nor does the low one. The highest probability of complications is at the values from 70 to 80 mm Hg.In patients with a triple vessel injury of the coronary arteries, a representative picture of a nonsignificant feature is observed. Conclusion: Application of artificial intelligence for determining risk predictors for patients with concurrent atherosclerotic damage of the coronary and carotid arteries is an effective method for prognosticating the risks of simultaneous interventions.

Molecular origin of structural defects in the zinc phthalocyanine film.

Controlling the growth of thin phthalocyanine films is a long-term challenge for the science of applied nanomaterials. So, this contribution deals with films of unsubstituted zinc phthalocyanine (ZnPc) and seeks to acquire structural information that is unavailable via physical experiments, thus, finding out how the film morphology can be seriously improved. A model of the vapor-deposited film has been created using the molecular dynamics method. Specifically, the ZnPc molecules are dosed into the simulation box under normal conditions, reproducing key features of the real film, such as the trimolecular wetting layer and the island-like three-dimensional (3D) phase that is structured like the α-polymorph; then all film fragments are characterized via their radial distribution functions and mean-squared displacements. The simulation model indicates that the 3D phase starts to develop smoothly through multimolecular cofacial stacking but finally becomes fragmental because the wetting layer is too meager to be a good platform for regular film growth. Accordingly, the film morphology may be improved if the wetting layer is thickened via restraining the vertical development of the 3D phase. Following this idea, uniform ZnPc films impaired by neither grain boundaries nor coarser defects were deposited from solutions and visualized at the nanometer scale.

Preindustrial 14CH4 indicates greater anthropogenic fossil CH4 emissions.

Atmospheric methane (CH4) is a potent greenhouse gas, and its mole fraction has more than doubled since the preindustrial era1. Fossil fuel extraction and use are among the largest anthropogenic sources of CH4 emissions, but the precise magnitude of these contributions is a subject of debate2,3. Carbon-14 in CH4 (14CH4) can be used to distinguish between fossil (14C-free) CH4 emissions and contemporaneous biogenic sources; however, poorly constrained direct 14CH4 emissions from nuclear reactors have complicated this approach since the middle of the 20th century4,5. Moreover, the partitioning of total fossil CH4 emissions (presently 172 to 195 teragrams CH4 per year)2,3 between anthropogenic and natural geological sources (such as seeps and mud volcanoes) is under debate; emission inventories suggest that the latter account for about 40 to 60 teragrams CH4 per year6,7. Geological emissions were less than 15.4 teragrams CH4 per year at the end of the Pleistocene, about 11,600 years ago8, but that period is an imperfect analogue for present-day emissions owing to the large terrestrial ice sheet cover, lower sea level and extensive permafrost. Here we use preindustrial-era ice core 14CH4 measurements to show that natural geological CH4 emissions to the atmosphere were about 1.6 teragrams CH4 per year, with a maximum of 5.4 teragrams CH4 per year (95 per cent confidence limit)-an order of magnitude lower than the currently used estimates. This result indicates that anthropogenic fossil CH4 emissions are underestimated by about 38 to 58 teragrams CH4 per year, or about 25 to 40 per cent of recent estimates. Our record highlights the human impact on the atmosphere and climate, provides a firm target for inventories of the global CH4 budget, and will help to inform strategies for targeted emission reductions9,10.

Old carbon reservoirs were not important in the deglacial methane budget.

Permafrost and methane hydrates are large, climate-sensitive old carbon reservoirs that have the potential to emit large quantities of methane, a potent greenhouse gas, as the Earth continues to warm. We present ice core isotopic measurements of methane (Δ14C, δ13C, and δD) from the last deglaciation, which is a partial analog for modern warming. Our results show that methane emissions from old carbon reservoirs in response to deglacial warming were small (<19 teragrams of methane per year, 95% confidence interval) and argue against similar methane emissions in response to future warming. Our results also indicate that methane emissions from biomass burning in the pre-Industrial Holocene were 22 to 56 teragrams of methane per year (95% confidence interval), which is comparable to today.

[Surgical treatment of rupture of the anterior wall of the left ventricle in the apical region with the formation of a false aneurysm in the acute stage of myocardial infarction].

One of the most dangerous complications of acute myocardial infarction (MI) is external or internal left ventricular rupture. Despite multiple studies on early diagnostics and algorithms for routing of patients with complicated MI, mortality in this patient group remains extremely high. Presently available publications on the tactics of managing patients with cardiac rupture are very scarce, and expectancies of surgical treatment are questionable. The provided clinical example demonstrates effectiveness of early open-heart surgical intervention, which supports the requirement for aggressive tactics for patients with cardiac rupture.

Amine-assisted solubilization of unsubstituted zinc phthalocyanine for film deposition purposes.

Typical zinc phthalocyanines (ZnPc) exhibit poor solubility in common solvents and, hence, are processed into thin films mostly from the vapor phase. The present work discloses how these limitations can be effectively overcome. Specifically, highly concentrated molecular solutions of unsubstituted ZnPc are prepared by combining a weakly structured ZnPc polymorph with binary liquid systems composed of a π-accepting solvent and a simple nitrogenous base, such as ammonia or tertiary aliphatic amine. The amine-assisted solubilization of ZnPc is rationalized by quantitative analysis of optical spectra and electrostatic potential maps of the dye molecule. A volatile aminoalcohol is proposed in order to rationally modify the habit of ZnPc crystallites and concurrently to produce uniform deposition of the crystallites by drop-casting the dye solutions onto a glass substrate. Finally, a versatile algorithm for wet-processed ZnPc films is declared.

Cell-specific resetting of mouse islet cellular clocks by glucagon, glucagon-like peptide 1 and somatostatin.

AIM: Molecular clocks, operative in pancreatic islet cells, represent an intrinsic mechanism regulating intracellular metabolism and hormone secretion. Glucagon, somatostatin and glucagon-like peptide 1 (GLP-1) are essential coordinators of islet physiology. Here, we assess the synchronizing capacity of glucagon, somatostatin and GLP-1 on pancreatic α- and ß-cell circadian clocks. METHODS: Triple transgenic mice, expressing a circadian PER2::luciferase (luc) reporter combined with α- and ß-cell-specific fluorescent reporters, were employed. Isolated pancreatic islets and fluorescence-activated cell sorting-separated α- and ß-cells were synchronized with glucagon, somatostatin analogue or GLP-1 mimetics, with subsequent real-time PER2::luc bioluminescence recording. Gene expression of Gcgr, Sstr2, Sstr3 and Glp1r in islet cells was assessed by RNA sequencing and RT-qPCR. RESULTS: Glucagon and GLP-1 mimetics (liraglutide and exenatide) induced high-amplitude rhythmic expression of the PER2::luc reporter in ß-cells, but not in α-cells, while the somatostatin analogue octreotide generated a significant phase shift between α- and ß-cells. Enrichment of Gcgr and Glp1r transcripts was detected in ß-cells compared to their α-cell counterparts. The synchronizing effect of glucagon was dose-dependent and mediated by the adenylate cyclase signalling cascade, as it was diminished by adenylate cyclase inhibitor. CONCLUSION: We conclude that proglucagon-derived peptides and somatostatin exhibit receptor-mediated cell-specific synchronizing effects for mouse α- and ß-cell oscillators. Differential islet cell clock modulation by glucagon and somatostatin may represent a physiological mechanism underlying paracrine regulation of rhythmic glucagon and insulin secretion. The reported here strong synchronizing properties of GLP-1 mimetics, widely used for treatment of type 2 diabetes, are of high clinical relevance.

The effect of solution pH on the structural stability of magnetoferritin.

The structural stability of magnetoferritin, a synthetic analogue of ferritin, at various pH levels is assessed here. The structural and electrical properties of the complexes were determined by small-angle X-ray scattering (SAXS), dynamic light scattering (DLS) and zeta potential measurements. At pH 3-6 a reduction of electrostatic repulsion on the suspended colloids resulted in aggregation and sedimentation of magnetoferritin. At neutral to slightly alkaline conditions (pH 7-9) the magnetoferritin structure was stable for lower iron loadings. Higher solution pH 10-12 induced destabilization of the protein structure and dissociation of subunits. Increasing the loading factor in the MFer complex leads to decrease of the stability versus pH changes.

Secretion of Thioredoxin Peroxidase Protein of Cat Liver Fluke Opisthorchis felineus during Modeling of Experimental Opisthorchiasis.

Mechanisms of thioredoxin peroxidase secretion by Opisthorchis felineus were studied in vivo and in vitro. Specific antibodies were obtained and used for western blotting and immunohistochemical detection in Syrian hamster model of opisthorchiasis. Secreted thioredoxin peroxidase protein was accumulated in the worm incubation medium under conditions of oxidative stress and in bile duct cells of hamsters with chronic opisthorchiasis.

Double-targeted polymersomes and liposomes for multiple barrier crossing.

In order to treat metastasis in the brain, drug delivery systems must overcome multiple physical barriers between the point of administration and the target, such as the Blood-brain barrier, that hinder their free access across them. Multiple targeting approaches arise as a promising alternative to this barrier and target certain tissues inside the brain at a time. Herein, two surface modification methods are presented to obtain dual-targeted vesicle-like carriers functionalized with an MCF-7-specific phage protein and a BBB-specific peptide, providing the system the ability to cross a BBB model, target breast cancer cells and deliver its payload. The aim of this study was to compare new designed polymersomes with liposomes, a well-established delivery vehicle, in terms of drug loading, targeting, release and tumor cell killing. The bilayer structure of both systems allowed the conjugation with different ligands both by insertion and covalent binding. Different behaviour was observed in release, uptake and tumor cell killing corresponding to differences in membrane permeability of both vehicles and type of targeting and ligands' combination. Preliminary results showed that both formulations were able to cross the BBB monolayer without harming it, showing cytotoxic activity in the abluminal compartment.

A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells.

AIM: To determine the impact of a functional human islet clock on insulin secretion and gene transcription. METHODS: Efficient circadian clock disruption was achieved in human pancreatic islet cells by small interfering RNA-mediated knockdown of CLOCK. Human islet secretory function was assessed in the presence or absence of a functional circadian clock by stimulated insulin secretion assays, and by continuous around-the-clock monitoring of basal insulin secretion. Large-scale transcription analysis was accomplished by RNA sequencing, followed by quantitative RT-PCR analysis of selected targets. RESULTS: Circadian clock disruption resulted in a significant decrease in both acute and chronic glucose-stimulated insulin secretion. Moreover, basal insulin secretion by human islet cells synchronized in vitro exhibited a circadian pattern, which was perturbed upon clock disruption. RNA sequencing analysis suggested alterations in 352 transcript levels upon circadian clock disruption. Among them, key regulators of the insulin secretion pathway (GNAQ, ATP1A1, ATP5G2, KCNJ11) and transcripts required for granule maturation and release (VAMP3, STX6, SLC30A8) were affected. CONCLUSIONS: Using our newly developed experimental approach for efficient clock disruption in human pancreatic islet cells, we show for the first time that a functional ß-cell clock is required for proper basal and stimulated insulin secretion. Moreover, clock disruption has a profound impact on the human islet transcriptome, in particular, on the genes involved in insulin secretion.

Structural self-organization of C60 and cisplatin in physiological solution.

The specific features of structural self-organization of C60 fullerene and antitumor drug cisplatin (Cis) in physiological solution (0.9% NaCl) have been investigated by means of small-angle neutron scattering, scanning electron and atomic force microscopies, as well as isothermal titration calorimetry, dynamic light scattering and UV-Vis spectroscopy. The formation of C60 + Cis complexes, has been reported, unveiling the mechanism of medico-biological synergy observed during administration of the mixture of these drugs.

Effect of iron oxide loading on magnetoferritin structure in solution as revealed by SAXS and SANS.

Synthetic biological macromolecule of magnetoferritin containing an iron oxide core inside a protein shell (apoferritin) is prepared with different content of iron. Its structure in aqueous solution is analysed by small-angle synchrotron X-ray (SAXS) and neutron (SANS) scattering. The loading factor (LF) defined as the average number of iron atoms per protein is varied up to LF=800. With an increase of the LF, the scattering curves exhibit a relative increase in the total scattered intensity, a partial smearing and a shift of the match point in the SANS contrast variation data. The analysis shows an increase in the polydispersity of the proteins and a corresponding effective increase in the relative content of magnetic material against the protein moiety of the shell with the LF growth. At LFs above ∼150, the apoferritin shell undergoes structural changes, which is strongly indicative of the fact that the shell stability is affected by iron oxide presence.

On the origin of C60 fullerene solubility in aqueous solution.

In this work, we report that the surface hydroxylation of C60 molecules is the most likely mechanism for pristine C60 fullerenes/C60 fullerene aggregate stabilization in water, being independent of the method of C60 fullerene aqueous solution preparation.

[The reagents kit to detect Metyorchis biis, Opisthorchis viverrini and Clonorchis sinensis, Opisthorchis felineus--agents of opisthorchiasis using technique of polymerase chain reaction in real-time].

The helminths Opisthorchis felineus, Opisthorchis viverrini, Clonorchis sinensis, Metorchis bilis are the agents of opisthorchiasis. The actual diagnostic of parasitic diseases based on microscope analysis of samples of human feces to detect presence of ova of parasites suffers of many shortcomings, in particular low sensitivity especially at earlier stages. The purpose of this study was to compare results of detection of parasites using both classical technique and technique of specific differentiation based on extraction of nucleic acids from samples of human feces and implementation of reaction of amplification of the chosen fragment of DNA with detection of products of polymerase chain reaction in the real time. The study detected 150 out of 165 positive samples and also 6 out of 37 negative samples both validated by coproovoscopy.

Phage protein-targeted cancer nanomedicines.

Nanoencapsulation of anticancer drugs improves their therapeutic indices by virtue of the enhanced permeation and retention effect which achieves passive targeting of nanoparticles in tumors. This effect can be significantly enhanced by active targeting of nanovehicles to tumors. Numerous ligands have been proposed and used in various studies with peptides being considered attractive alternatives to antibodies. This is further reinforced by the availability of peptide phage display libraries which offer an unlimited reservoir of target-specific probes. In particular landscape phages with multivalent display of target-specific peptides which enable the phage particle itself to become a nanoplatform creates a paradigm for high throughput selection of nanoprobes setting the stage for personalized cancer management. Despite its promise, this conjugate of combinatorial chemistry and nanotechnology has not made a significant clinical impact in cancer management due to a lack of using robust processes that facilitate scale-up and manufacturing. To this end we proposed the use of phage fusion protein as the navigating modules of novel targeted nanomedicine platforms which are described in this review.

[PARTICULARITIES OF CARBOHYDRATE METABOLISM IN PATIENTS WITH PULMONARY TUBERCULOSIS WITH PRECLINICAL DISORDERS GLICEMIA].

Studied concentration of lactate and pyruvate in patiens with lung tuberculosis with disorders of tolerance to glucosis and glukemic disorders on an empty stomach and in patiens, wich had not such disorders. In patiens with preclinical disorders glicemia discovered increasing to concentrations of lactate and pyruvate in blood. This is indicative of more deep breaches of quality to oxidation the glucose in energetic aerobic reaction, in particular, in tricarboxylic acids cycle. Effect this is a deterioration energy status of the cells. Excess of the formation lactate and pyruvate on background of the effect anty-insulin hormone prevalence and relative insufficiency of the insulin realizes the independent contribution to development hyperglicemia disorders.

[Treatment of drug resistant destructive pulmonary tuberculosis: gemifloxacin and other fluoroquinolones clinical efficiency and tolerance at the end of initial phase of treatment].

Gemifloxacin efficiency and tolerance in comparison to the ofloxacin, levofloxacin and gatifloxacin during the intensive phase of the antituberculosis therapy for drug resistant cases was evaluated. 156 drug resistant TB patients were examined in the open, prospective, randomized research, being divided into 2 groups with similar drug resistance profile. The 1st group received gemifloxacin, the 2nd--other fluoroquinolones. Gemifloxacin efficiency in the treatment regimen for the drug resistant TB patients did not differ from the efficiency of the use of other fluoroquinolones of the 4th generation and was significantly higher in comparison to ofloxacin. At the same time the identical level of side effects was registered in the course of treatment with mentioned drugs. Gemifloxacin is effective and safe at treatment of tuberculosis in comparison to other fluoroquinolones that allows considering it as the drug of choice among fluoroquinolones for treatment of drug resistant TB, including multidrug-resistant TB.

Generation and characterization of phage-GnRH chemical conjugates for potential use in cat and dog immunocontraception.

Overpopulation of cats and dogs is a serious worldwide problem that demands novel, safe and cost-effective solutions. The objective of this study was to generate and characterize phage-peptide conjugates with gonadotropin-releasing hormone (GnRH) for potential use as an immunocontraceptive. A filamentous phage vector f5-8 with wild-type phage coat proteins was used as a carrier for construction of chemical conjugates with GnRH, a peptide that acts as a master reproductive hormone. In such conjugates, the phage body plays the role of a carrier protein, while multiple copies of GnRH peptide stimulate production of neutralizing anti-GnRH antibodies potentially leading to contraceptive effects. To generate the constructs, four different GnRH-based peptides were synthesized and conjugated to phage particles in a two-step procedure: (i) peptides were reacted with phage to form a conjugate using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride chemistry (EDC) and (ii) the conjugates were separated from remaining free peptides by dialysis. Formation and specificity of phage-GnRH conjugates were confirmed by three independent methods: spectrophotometry, electron microscopy and ELISA. When the conjugates were tested for interaction with sera collected from cats and dogs immunized with GnRH-based vaccines in independent studies, strong specific ELISA signals were obtained, suggesting the potential use of the conjugates for cat and dog immunosterilization. The ability of the conjugates to stimulate production of anti-GnRH antibodies in vivo was evaluated in mice. While optimization of dose, immunization route and adjuvant still requires investigation, our preliminary results demonstrated the presence of anti-GnRH antibodies in sera of mice immunized with such conjugates. Fertility trials in cats and dogs will be needed to evaluate contraceptive potentials of the phage-GnRH peptide chemical conjugates.