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BackgroundIn February 2022, Russia began its invasion of Ukraine. War increases the demand for mental healthcare among affected populations, but with devastating losses across the nation, it is unclear if Ukrainian mental health services are able to meet the needs of the people.AimsWe aimed to evaluate the state of Ukrainian in-patient mental health services, which remains the backbone of the nation's psychiatric services, early in the 2022 Russian invasion.MethodWe conducted a nationwide cross-sectional study on Ukrainian in-patient mental health facilities during the 2022 Russian invasion. Using an online questionnaire, we obtained responses from the heads of 32 in-patient mental health facilities across Ukraine, representing 52.5% of all in-patient mental health facilities in the nation. We gathered information on hospital admissions, staff, humanitarian aid received and the additional needs of each facility.ResultsHospital admissions were reduced by 23.5% during the war (April 2022) compared with before the war (January 2022). Across facilities, 9.6% of hospital admissions in April 2022 were related to war trauma, with facilities reporting percentages as high as 30.0%. Facilities reported reductions in staff, with 9.1% of total medical workers displaced and 0.5% injured across facilities. One facility reported that 45.6% of their total medical workers were injured. Although facilities across Ukraine have received humanitarian aid (such as medical supplies, food, volunteers), they reported additionally needing equipment as well as more staff.ConclusionsThe mental health service structure in Ukraine has been severely damaged during the 2022 invasion, with staff shortages despite a significant number of hospital admissions related to war trauma.

Microplastics are emerging pollutant found in many ecosystems including soil. Within them, polyvinyl chloride (PVC) is one of the most toxic polymers and is known for its remarkable resistance to degradation. The recalcitrant nature of PVC and the improper waste disposal could cause serious environmental concerns. In addition, the possible fragmentation and accumulation of small plastic particles in agricultural soils might have impacts on soil chemical and microbiological properties. Based on these considerations, a microcosm experiment was set up to investigate the effects of PVC microplastics (0.021% w/w) on soil chemical properties and soil bacterial and fungal communities at different incubation times (from 3 to 360 days).Among chemical parameters, soil CO2 emissions, fluorescein diacetate hydrolysis (FDA), total organic C (TOC), total N, water extractable organic C (WEOC), water extractable N (WEN) and SUVA254 were investigated, while the structure of soil microbial communities was studied at different taxonomic levels (phylum and genus) by sequencing bacterial 16S and fungal ITS2 rDNA (Illumina MiSeq). The number and the dimensions of PVC particles were also evaluated after one year of experiment.The results showed that the presence of PVC particles in soil caused significant (p < 0.05) variations in chemical parameters in short- and medium-term, thus suggesting that the presence of this polymer in soil can affect the turnover of organic matter. In the long period, instead, an increase of the soil enzymatic activity (FDA) was observed.The analysis of microbiological parameters showed that PVC microplastics significantly affected (p < 0.05) the structure of soil microbial communities changing the abundances of specific bacterial and fungal taxa: Acidobacteria, Actinobacteria, Bacteroides, Candidatus_Saccharibacteria, and Proteobacteria, , among bacteria, and Ascomycota, Basidiomycota, and Mortierellomycota among fungi, suggesting that the impact of this polymer could be taxa-dependent.A significant (p < 0.05) decrease of the number and dimensions of PVC particles was also detected after one year of incubation, supposing a possible role of microbial community on polymer degradation.

The COVID-19 pandemic is an extraordinary challenge for all countries and affects the psychological wellbeing of healthcare professionals working with people suffering from COVID-19 and puts them at a high risk of mental health problems. The aim of the study was to identify stress-related factors that affect the mental health of healthcare workers during the COVID-19 pandemic in Ukraine.A total of 1098 Ukrainian healthcare workers were surveyed using an online questionnaire consisting of questions relating to a) socio-demographic characteristics; b) perceptions of the COVID-19 related situation; and c) stress and protective factors. Respondents were divided into two groups, depending on whether they provided care to the patients with COVID-19 or not.Of the 1087 healthcare workers, 863 (79.4%) were found to have anxiety / fear caused by the COVID-19. No significant difference was detected between professionals who did and did not provide personal assistance to patients with COVID-19 concerning anxiety / fear related to COVID-19 (p=0.0776). Based on logistic regression model (χNegative risk perception, high consumption of COVID-19 news, and shortage of staff in health care facilities were significant predictors of anxiety / fear caused by the COVID-19.

Background IGF-1 is an essential neurotrophin produced peripherally and in the brain. Impairments in the brain IGF-1 concentrations might be responsible for some aspects of major depressive disorder (MDD) pathogenesis, whereas peripheral IGF-1 could have the marker value. We aimed: 1) to compare serum IGF-1 levels in MDD patients and healthy controls (HC); 2) to elucidate possible associations between changes in IGF-1 expression and crucial characteristics of the current depressive episode, MDD course; 3) to evaluate IGF-1 dynamics after 8 weeks` vortioxetine treatment. Methods Seventy-eight MDD patients (according to DSM-5) and 47 HC were enrolled. Serum IGF-1, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST) were analyzed in all subjects at admission and 48 patients after 8 weeks` vortioxetine treatment. AUC-ROCs were calculated to determine if the value of serum IGF-1 could separate MDD patients from HC. Multiple regression models were performed to explore relationships between IGF-1 and depressive episode’s symptoms. Results MDD patients had significantly higher serum IGF-1 levels than HC (228 (183–312) ng/ml vs 153 (129–186) ng/ml, p p Conclusions Significant associations between IGF-1 levels and hypothymia, anxiety, and cognitive disturbances may indicate a pathogenic role of IGF-1 for the mentioned symptoms. We assume that the activity of the cerebral-hepatic axis increases in response to insufficient IGF-1 brain expression in MDD patients, whereas, vortioxetine treatment restores cerebral IGF-1 concentrations and, consequently, decreases its compensatory production by the liver. Trial registration registered at ClinicalTrials.gov (NCT03187093). First posted on 14th June 2017.

The aim: To study the emotional impact of the COVID-19 pandemic on healthcare workers in Ukraine. Materials and methods: 1087 healthcare workers across all regions of Ukraine completed an online questionnaire. Respondents were divided into two groups: A – 863 (79.4%), В – 224 (20.6%), according to whether or not they experienced anxiety/fear related to COVID-19. Results: Such factors as risk of contracting COVID-19, news of new cases, insufficient staff in healthcare facilities, risk of transmission of COVID-19 to family or friends, risk of death from COVID-19, the threat of the spread of the COVID-19 pandemic were associated with high level of anxiety/fear among healthcare workers. Factors that facilitate coping with stress included absence of Covid-19 cases among staff, recovering patients, availability of gear and protective equipment and absence of COVID-19 infected among loved ones, relieving stress (relaxation, going info sports and so on), communication with family and friends to relieve stress and get support, avoidance of COVID-19 media reports in particular on deaths connected cases, getting information about the spread of Covid-19 only from legitimate sources. Conclusions: The data obtained in this study indicate an urgent need for the development and implementation of preventive and rehabilitation measures aimed at stabilizing the psycho-emotional state of health workers and improving the quality of care in the special conditions of the COVID-19 pandemic. Achieving these goals will be facilitated by taking into account the specifics of the response to COVID-19 and measures to reduce the effects of stress while enhancing the effects of stressors among health care workers.

Background: Virtually every biological system is governed by the complex relations among its components. Identifying such relations requires a rigorous or heuristics-based search for patterns among variables/features of a system. A number of algorithms have been developed to identify two-dimensional (involving two variables) patterns employing correlation, covariation, mutual information, etc. It seems obvious, however, that comprehensive descriptions of complex biological systems may also include more complicated multidimensional relations, which can only be described using patterns that simultaneously embrace 3, 4, and more variables. The main challenges in the search for such multidimensional patterns include: (a) computational complexity of the search; (b) distinction of statistically significant patterns from false patterns which can be observed in large data sets simply by chance; and (3) integration of heterogeneous data types (numerical, Boolean, categorical, etc.) in a single pattern.Results: This manuscript presents an attempt to address some of these challenges by defining multidimensional Boolean patterns in a way permitting to: (a) accommodate heterogeneous multi-omics data, (b) formulate criteria for separating trivial from non-trivial patterns, and (c) identify conditions, required for a given pattern to predict the values of selected feature(s). Additionally, the proposed definition of the pattern’s strength (pattern’s score) and minimal population threshold permits estimation of the statistical significance of detected patterns using scores distributions of artificial datasets created by randomizing original data.Conclusion: To test the proposed approach we performed a search for all possible 2-, 3-, and 4-dimensional patterns in historical data from the Human Microbiome Project (15 body sites) and collection of H. pylori genomes associated with gastric ulcers, gastritis, and duodenal ulcers. In all datasets under consideration, we were able to identify hundreds of statistically significant multidimensional patterns. These results suggest that such patterns may dominate the landscape of microbial genomics/microbiomics systems.

INTRODUCTION AND HYPOTHESIS Mesenchymal cells known as myo-/fibroblasts (MFs) are critical immunosuppressors under gut mucosal homeostasis. Expression of immune checkpoint PD-L1 by MFs plays a key role in the control of T cell inflammatory responses. In Crohn’s disease (CD), MFs switch their activity from immunosuppressive to pro-inflammatory, where they are also known as Inflammatory Fibroblasts. However, the mechanisms responsible for these pathological changes in MF activity are unknown. Map-kinase-activated protein kinase 2 (MK2) is a major regulator of inflammation in the gut. MK2 is downstream of p38 signaling, it evokes a sub-pathway that directly regulates the production of key inflammatory cytokines implicated in CD (such as TNF-α, IL-1, and IL-6). Thus, we hypothesized that activation of MK2 signaling is critical to the pathological changes in MFs during the immunopathogenesis of CD. METHODS Human normal and CD tissues and derived MFs, as well as animal models relevant to CD, were used in this study. MF signaling/activity was analyzed using RNAseq, qRT-PCR, western blot (WB), cytokine/chemokine multiplex arrays, and confocal microscopy. RESULTS In situ analysis demonstrated an increase in MK2 activity within the inflamed compared to the non-inflamed CD and healthy control intestinal tissues, which was confirmed by WB and multiplex signaling array analysis. In situ increase in MK2 activity in CD intestinal mucosa was greatly associated with mesenchymal stromal cells that bear a “myofibroblast” phenotype (positive for α-SMA expression). An increase in MK2 activity was also observed in primary MF cultures isolated from CD (CD-MFs) when compared to normal (N-) MFs. MK2 activity within CD-MFs was also associated with a significant decrease in the expression of the immunosuppressive checkpoint PD-L1 and an increase in the expression of inflammatory CCL2 and IL-6. Inhibition of MK2 activity within CD-MFs through using the MK2-specific inhibitor PF-3644022 (10 μM) reversed the inflammatory activity of MFs. Remarkably, we observed a differential role of p38 and MK2 in the regulation of PD-L1 expression in MFs: while p38 was required for basal expression of PD-L1, activation of MK2 downregulates PD-L1 expression. These data indicate a unique role of MK2 activation in pathological reprogramming of MFs in CD. Use of MK2 inhibitor in a therapeutic modality in chronic DSS and IL-10 KO murine models of CD also significantly reduce MF-linked inflammatory responses in vivo. CONCLUSION Our data suggest that an increase in MK2 activity in CD is critical to the reprogramming of the MF from immunosuppressive toward pathological Inflammatory fibroblasts. Targeting MK2 activity within MFs could be a desirable strategy for improving the efficacy of current IBD therapeutic approaches.

Following the growing global focus on deinstitutionalisation in the past 50 years, accessible community mental health services was a highlighted commitment in the European Mental Health Action Plan 2013–2020 to improve well-being of patients and families. The progress of transition has been uneven in some Eastern European countries. This paper aims to update and reflect on the examples of five countries across the region.

In Ukraine, mental health problems are common yet the mental health services available are still old fashioned and based on healthcare approaches used in the Soviet Union, providing mainly inpatient services and rudimentary community services. The World Health Organization (WHO) introduced the Mental Health Gap Action Programme (mhGAP) to reduce the mental health treatment gap all over the world and 2 years later introduced the WHO mhGAP-Intervention Guide (mhGAP-IG), version 2.0 (2016) as not only an educational tool, but also an evidence based guideline to scale up services for mental, neurological and substance use (MNS) conditions with an objective to reduce gap between available health systems capacity and resources for mental health. The main aim of this paper is to describe reforms of undergraduate psychiatry training in Ukraine using Kyiv Medical University as a case example. Kyiv Medical University (KMU) is the first university in Ukraine to introduce the mhGAP-IG in Ukraine. The revised psychiatry curricula in KMU aims to strengthens the evidence based teaching practices, to put emphasis on community orientated mental health care, and to use interactive teaching methods that the university hopes will attract more future doctors to psychiatry and ideally contribute towards the reduction of the mental health treatment-gap in Ukraine.

INTRODUCTION Fibrosis is the major aggressive complication of Crohn’s disease (CD), causing intestinal obstruction. No targeted therapies are currently available to revert CD-associated fibrosis. While inflammatory mechanisms in CD have been extensively investigated, understanding the pathogenesis of fibrosis is relatively limited. Mesenchymal cells are believed to be the major effectors in profibrotic processes in CD. There is a dramatic increase in α-SMA expressing subsets of mesenchymal cells, also known as myofibroblasts (MF), and this is considered to be among the main hallmarks of profibrotic changes in CD. Thus, targeting the profibrotic reprogramming/increase of α-SMA+ MFs and/or fibrosis-driving signaling could lead to the development of novel anti-fibrotic approaches in CD. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream substrate of p38 and is known to regulate pro-inflammatory cytokines. Moreover, MK2 is a regulator of downstream signaling in the profibrotic non-canonical TGF-β1/p38 pathway. However, the role of MK2 in CD-associated fibrosis and profibrotic reprogramming of MFs is not known. We hypothesize that hyperactivation of MK2 is critical to the profibrotic reprogramming of MF in CD and has potential as an anti-fibrotic therapeutic target. METHODS Human normal- and CD-derived MFs were analyzed using RNAseq, cytokine/chemokine multiplex array, FACS, and confocal microscopy. Chronic IL-10 KO colitis murine models relevant to CD were used in this study. RESULTS Increased expression of MK2 within α-SMA+ mesenchymal cells was observed in stricturing CD. Ex vivo treatment of the CD tissues with MK2 inhibitor PF-3644022 (10 μM) abrogated MK2 activity and decreased expression of fibrosis-related genes. An increase in MK2 activity within intestinal MFs was observed in vivo in IL-10KO murine colitis. Therapeutic use of the MK2 inhibitor PF-3644022 (0.2 mg/kg, daily for 10 days) in vivo significantly decreased the degree of intestinal fibrosis as measured by collagen deposition and reduced the expression of fibrosis-related genes. When compared to the WT murine-derived MFs, MK2-/- MFs showed low basal and TGF-β1 induced levels of pro-fibrotic genes expression in vitro. Using primary human MFs, we found that MK2 activity was associated with hallmark profibrotic genes in CD-MFs. Inhibition of MK2 activity with PF-3644022 reduced TGF-β1-induced overexpression of Col1α2, α-SMA, TNC, Fn1, and TGF-β1 genes. Profibrotic responses in MFs through SMAD2/3 and p38, but not MAPK signaling were mediated by MK2. CONCLUSIONS Our data provide evidence that activation of MK2 drives profibrotic reprogramming of mesenchymal cells in CD and it may be an attractive therapeutic target for the development of novel targeted strategies against CD-associated fibrosis.

BACKGROUND & AIMS Intestinal fibrosis is a major serious complication of Crohn’s disease (CD). Gut microbiota-reactive Th17 cells have been established as crucial in the pathogenesis of CD, however, how Th17 cells induce fibrosis is still not completely understood. METHODS Wild-type Th1 cells and Th17 cells, or amphiregulin (Areg)-/- Th17 cells, were transferred into Tcrbxd-/- mice to induce colitis and intestinal fibrosis. CD4+ T cell expression of Areg was determined by qRT-PCR and ELISA. Intestinal fibroblasts were isolated from normal and CD patients and used to determine the effects of Areg on cell proliferation and migration in vitro. Video microscopy and single-cell tracking were used to assess cell migration kinetically. Areg expression was compared in peripheral blood CD4+ T cells, intestinal biopsy tissues, and lamina propria lymphocyte (LPL) from healthy controls and CD patients with or without intestinal fibrosis. RESULTS When transferred into TCRβ/δ-/- mice, although Th1 and Th17 cells induced intestinal inflammation at similar levels, Th17 cells induced more severe intestinal fibrosis than Th1 cells. RNA-seq analysis showed higher levels of AREG expression in Th17 cells compared to Th1 cells, which was further confirmed by qRT-PCR. Transfer of Areg-/- Th17 cells induced less severe fibrosis in TCRβ/δ-/- mice compared with WT Th17 cells. IL-6 but not IL-23 promoted Areg expression in Th17 cells in a time and dose-dependent manner. Treatment with Th17 signature cytokine IL-21, but not IL-17, upregulated T cell expression of Areg. Consistently, IL-21R-/- T cells produced lower levels of Areg. Mechanically, STAT3 mediates Areg expression in Th17 cells, in that IL-6 promoted STAT3 activation, and IL-6 did not induce AREG expression in STAT3-/- T cells. Areg expression was lower in STAT3-/- T cells compared with WT T cells under Th17 conditions. Treatment with RORgt inhibitor, which inhibits Th17 differentiation, suppressed Th17 cell Areg expression, indicating that higher Areg expression requires fully Th17 differentiation. Areg promoted human intestinal fibroblast proliferation and motility, which was mediated by activation of mTOR, and mTOR inhibitors inhibited Areg-induced human intestinal fibroblast proliferation and motility. Finally, Areg expression is increased in peripheral blood CD4+ T cells, intestinal biopsy tissues, and lamina propria lymphocytes of CD patients with fibrosis. CONCLUSION Collectively, these findings reveal that Th17-derived Areg promotes fibrotic responses in both experimental colitis and human CD patients. Thereby, Areg could serve as a potential therapeutic target for fibrosis in CD.

Rationale Long-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia. Objective This study aimed to explore the safety, tolerability, and treatment response of paliperidone palmitate once-monthly in non-acute but symptomatic adult patients switched from previously unsuccessful monotherapy with frequently used oral atypical antipsychotics. Methods This was a post hoc analysis of a prospective, interventional, single-arm, international, multicenter, open-label, 6-month study. Results The patients (N = 472) were switched to paliperidone palmitate once-monthly (PP1M) from daily oral treatment with either aripiprazole (n = 46), olanzapine (n = 87), paliperidone extended-release (n = 104), quetiapine (n = 44), or risperidone (n = 191). In all groups, mean Positive and Negative Syndrome Scale total (p

An intact T cell compartment and IFN-γ signaling are required for protective immunity against Chlamydia. In the mouse model of Chlamydia pneumoniae (Cpn) infection, this immunity is critically dependent on CD8+ T cells. Recently we reported that Cpn-infected mice generate an MHC class I-restricted CD8+ Tc1 response against various Cpn Ags, and that CD8+ CTL to multiple epitopes inhibit Cpn growth in vitro. Here, we engineered a DNA minigene encoding seven H-2b-restricted Cpn CTL epitopes, the universal pan-DR epitope Th epitope, and an endoplasmic reticulum-translocating signal sequence. Immunization of C57BL/6 mice with this construct primed IFN-γ-producing CD8+ CTL against all seven CTL epitopes. CD8+ T cell lines generated to minigene-encoded CTL epitopes secreted IFN-γ and TNF-α and exhibited CTL activity upon recognition of Cpn-infected macrophages. Following intranasal challenge with Cpn, a 3.6 log reduction in mean lung bacterial numbers compared with control animals was obtained. Using a 20-fold increase in the Cpn challenging dose, minigene-vaccinated mice had a 60-fold reduction in lung bacterial loads, compared with controls. Immunization and challenge studies with β2-microglobulin−/− mice indicated that the reduction of lung Cpn burdens was mediated by the MHC class I-dependent CD8+ T cells to minigene-included Cpn CTL epitopes, rather than by pan-DR epitope-specific CD4+ T cells. This constitutes the first demonstration of significant protection achieved by immunization with a CD8+ T cell epitope-based DNA construct in a bacterial system and provides the basis for the optimal design of multicomponent anti-Cpn vaccines for humans.

Helicobacter pylori (H. pylori) infects >50% of the world’s population and is linked to peptic ulcers and gastric cancer. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation and induction of Treg cells in vitro, but the mechanism was unknown. Herein, we investigated the underlying mechanisms behind H. pylori-mediated upregulation of B7-H1 expression by GEC and its functional relevance to chronic infection. Using H. pylori wild type and isogenic mutant strains we showed that H. pylori requires its type 4 secretion system (T4SS) component cytotoxin associated gene A (CagA) and peptidoglycan for B7-H1 upregulation in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, containing a functional T4SS, but not with H. pylori SS1 strain lacking this delivery system, led to upregulation of B7-H1 expression, increased bacterial load, induction of Treg cell in the stomach and increased IL-10 in the serum. Interestingly, B7-H1 knock out mice showed less Treg cells and reduced bacterial loads. We also showed that H. pylori uses p38 MAPK pathway to upregulate B7-H1 expression in GEC. Our observations suggest that H. pylori T4SS contributes to the ability to evade immune-mediated clearance by modulating expression of B7-H1 in GEC. These observations may have important implications in vaccine efforts directed at H. pylori.