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Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, and integrated stress response, that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate the expression of most genes but increase the expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in the repair of stress-induced damage to macromolecules and cellular structures. Sixty-one years after the discovery of the heat shock response by Ferruccio Ritossa, many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.

Abstract Background There is broad scientific evidence for the effectiveness of individual trauma-focused evidence-based treatments (EBTs) such as “trauma-focused cognitive behavioural therapy” (TF-CBT) for children and adolescents with posttraumatic stress symptoms. However, there is a significant research-to-practice gap resulting in traumatized children in high-income countries in Europe having only very limited access to these treatments. The aim of this study was, therefore, to identify common barriers and successful dissemination and implementation (D&I) strategies of evidence-based trauma-focused treatments (in particular TF-CBT) in seven European countries. Methods For this study, we chose a mixed-method approach: an online survey among certified European TF-CBT trainers (N = 22) and the collection of country-based narratives from TF-CBT experts in different European countries (Finland, Germany, Italy, Netherlands, Norway, Sweden). Results Common modifiable barriers to the implementation of TF-CBT were identified on different levels (e.g. government or treatment level), and successful D&I strategies were highlighted across all countries, such as translations of materials. Additionally, the experts from the country narratives put together a broad overview of TF-CBT research in Europe. Conclusions The results of this study revealed that especially learning collaborations and the development of joint European efforts in funding and researching D&I strategies are crucial for future implementation of trauma-focused EBTs in Europe.

Alzheimer’s disease is a brain disorder characterized by a gradual decline in memory, thinking, behavior, and social skills. Galantamine hydrobromide is a reversible competitive cholinesterase inhibitor used for managing Alzheimer’s disease. Its oral administration, however, is accompanied by unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. These side effects could be avoided by the incorporation of galantamine into nanoparticles. The present study describes the preparation and characterization of HPMC-based fast-dissolving oral films with galantamine-loaded chitosan nanoparticles. Galantamine-loaded chitosan nanoparticles were prepared using the ionotropic gelation method. High values for loading efficiency were established. DLS was used to evaluate the particle size and the Z-potential. The polymer used in this study for the preparation of the fast-dissolving oral films was HPMC, and PEG 400 was used as a plasticizer. The quality of the prepared films was evaluated based on the following criteria: flexibility, spreading ability, adhesiveness, non-sticky and easily peeled, and appearance. The thickness, folding endurance, and disintegration times of the prepared films were determined. In vitro dissolution studies were conducted in order to establish the drug release rate from the films.

Introduction: Parametric mapping is a non-invasive method to quantify tissue changes in the myocardium by measuring T1, T2 and T2* relaxation times and extracellular volume, requiring a pre-established range of normal values. Purpose: To establish reference values for native T1 and T2 myocardial relaxation times in healthy subjects on 1.5 T magnetic resonance imaging and to assess changes in their values according to left ventricular segments, age, sex, heart rate, and myocardial thickness. Material and Methods: A prospective 1.5 T magnetic resonance imaging study was performed with the voluntary participation of 50 healthy individuals in different age groups. Image analysis was performed by a radiologist with 5 years of experience in the field of CMRT and further coordinated with a radiologist with more than 20 years of expe-rience in the field. Siemens ARGUS integrated software was used to calculate the volumes and function of both cameras. Global and segmental T1 and T2 values were measured in the shortaxis midlevel section by manually delineating the region of interest. Myocardial thickness of the mid septum was measured for each patient. Results: The distribution of volunteers was 25 men and 25 women. Significantly higher global T1 values were observed in women (1027.7 ± 25.4 ms) compared to men (992.9 ± 24.4 ms), at p < 0.001. The same correlation was observed in individual segments, with a significant difference between genders. Examination of the correlation between T1 and other parameters demonstrated a negative linear relationship only with myocardial thickness. Global T2 in women (48.6 ± 2.49 ms) was also significantly higher than in men (44.6 ± 2.06 ms), with an observed difference of 3.95, p < 0.001. Global T2 showed a very strong negative correlation with myocardial thickness (r = -0.769; p < 0.001). There was no sig-nificant correlation between T2 times and heart rate and age of patients. Conclusion: A statistically significant difference in native T1 and T2 values by sex was demonstrated. The use of sex-specific reference values to distinguish healthy from pathologically affected myocardium is recommended.

A new amorphous alloy (Al74Cu16Mg10)99,7Zr0.3 was prepared the applying a melt-spinning technique. Temperature dependence of viscosity of the alloy was determined using data from a PerkinElmer TMS2 thermo-mechanical analyzer processed according to a methodology based on the Free Volume Model (FVM). The strength of the alloy was calculated according to the Yang equation and the glass-forming ability was calculated according to the values of the Angell index mA. The activation energy of crystallization and the activation energy of the glass transition were computed using data from differential scanning calorimetry and thermomechanical experiments respectively. The activation energy of crystallization Еx = 168 ± 3.7 kJ/mol, was found to be higher than the activation energy of the glass transition Еg = 156 ± 1.4 kJ/mol, which means a dominant contribution of the atomic transport barrier, compared to the nucleation barrier. The relatively high temperature interval of the supercooled melt state Tx-Tg = 32 K and the low viscosity values in the same range ƞ(Тg) = 3.40E + 11 Pa.s and ƞ(Тx) = 1.87E + 10 Pa.s would allow thermomechanical treatment of the alloy in the temperature range of supercooled melt.

Cellular processes require precise and specific gene regulation, in which continuous mRNA degradation is a major element. The mRNA degradation mechanisms should be able to degrade a wide range of different RNA substrates with high efficiency, but should at the same time be limited, to avoid killing the cell by elimination of all cellular RNA. RNase Y is a major endoribonuclease found in most Firmicutes, including Bacillus subtilis and Staphylococcus aureus. However, the molecular interactions that direct RNase Y to cleave the correct RNA molecules at the correct position remain unknown. In this work we have identified transcripts that are homologs in S. aureus and B. subtilis, and are RNase Y targets in both bacteria. Two such transcript pairs were used as models to show a functional overlap between the S. aureus and the B. subtilis RNase Y, which highlighted the importance of the nucleotide sequence of the RNA molecule itself in the RNase Y targeting process. Cleavage efficiency is driven by the primary nucleotide sequence immediately downstream of the cleavage site and base-pairing in a secondary structure a few nucleotides downstream. Cleavage positioning is roughly localised by the downstream secondary structure and fine-tuned by the nucleotide immediately upstream of the cleavage. The identified elements were sufficient for RNase Y-dependent cleavage, since the sequence elements from one of the model transcripts were able to convert an exogenous non-target transcript into a target for RNase Y.

Abstract Protein–protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.

The conservation and research of genetic resources of key crops and their use in the global farming system present the main trends for developing sustainable agriculture and producing healthy food products. This study aims to investigate the available genetic resources of (Phaseolus spp. L.) landraces and breeding lines/varieties to identify promising genotypes with a view to their further use for breeding as a source of new germplasm. Investigation and evaluation of 18 accessions of Phaseolus spp. L. from Bulgaria for economically important agronomic traits and molecular approaches using ISSR and SCAR marker systems were carried out. The genetic characterization by seven SCAR markers was applied to the selected genotypes to determine the genes associated with the resistance to economically important diseases. The population structure of Phaseolus spp. L. was determined using the grouping method based on Bayesian models based on six ISSR markers and STRUCTURE software. Based on a comparison between the ISSR molecular marker and descriptors results and the higher Q value, the no admixture ancestry model and correlated allele frequencies were the parameters combination selected for describing the population structure of the selected genotypes. The correspondence between the ISSR-based analysis and the descriptors showed that 14 (77.78%) of the 18 Phaseolus accessions groups were in the same cluster in both methods. Promising genotypes have been identified based on the applied integrated research approach - phenotypic and

The present study fills a knowledge gap in the distribution and genetic variation of Morimus populations in the Balkans, by studiyng the representatives of the genus in Bulgaria – M. asper funereus Mulsant, 1862, M. verecundus bulgaricus Danilevsky, 2016 and M. orientalis Reitter, 1894. Additional information is provided for Albania and northern Greece. The mitochondrial cytochrome C oxidase subunit I (COI) marker and the nuclear internal transcribed spacer 2 (ITS2) were used for the genetic analyses. Three of the previously-defined mitochondrial lineages (Lb/HgA, L2 and L3) were detected in Bulgaria, as well as a new lineage (Str) from the Strandzha Mountains (south-eastern Bulgaria). A total of 24 distinct haplotypes, 20 of them in Bulgaria, were found. Bulgarian populations of Morimus demonstrated relatively high nucleotide diversity. The L3 COI lineage was confirmed as the most diverse and frequent in the Balkans. The L3 lineage is dominant in most of Bulgaria, but was not identified in the easternmost parts near the Black Sea coast, where the L2 and Str lineages were found. New data highlighted two dispersal routes of the L2 mitochondrial lineage on the Balkan Peninsula: 1) northwards along the Black Sea coast and 2) westwards, across the Balkans where only disjunct populations remain. North-western Bulgaria seems to be the eastern limit of the basal lineage Lb/HgA distribution. Our results show high levels of genetic exchange between most of the mitochondrially defined lineages, yet some of the easternmost populations probably remained isolated for comparatively longer periods.

AbstractAnise hyssop (Agastache foeniculum (Pursh) Kuntze) is a perennial plant belonging to the Lamiaceae family mainly used in folk medicine to treat various ailments. This study determined the chemical composition of the essential oil and evaluated its antimicrobial and antioxidant activity. The essential oil was obtained from plants cultivated in the experimental field at the Institute of Roses, Essential and Medical Plants, Kazanlak, Bulgaria. The plants were processed by steam distillation, with the essential oil yielding 0.37%, and its main components being methyl chavicol (82.03%) and limonene (9.90%). The most potent antimicrobial action was observed against the gram-positive bacteria Staphylococcus aureus (25.7 mm inhibition zone) and Bacillus cereus (12.3 mm), the yeast Saccharomyces cerevisiae (16.3 mm) and Candida albicans (16.5 mm). The remaining gram-positive bacteria (Staphylococcus epidermidis and Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Salmonella ebony), and fungi (Aspergillus brasiliensis and Fusarium moniliforme) were resistant to the action of the essential oil. The antioxidant activity of the essential oil was ABTS (32.36 µmol TE/mL), DPPH (21.61 µmol TE/mL), CUPRAC (19.94 µmol TE/mL), and FRAP (29.56 µmol TE/mL) in vitro. Overall, the results from this study revealed the biological potential of anise hyssop as a source in pharmaceutical, food, and cosmetic applications.

Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause of beta cell dysfunction and apoptosis in diabetes. NRF2 (NF-E2 p45-related factor-2) regulates the adaptation to oxidative stress, and its activity is negatively regulated by the redox-sensitive CUL3 (cullin-3) ubiquitin ligase substrate adaptor KEAP1 (Kelch-like ECH-associated protein-1). Additionally, NRF2 is repressed by the insulin-regulated Glycogen Synthase Kinase-3 (GSK3). We have demonstrated that phosphorylation of NRF2 by GSK3 enhances β-TrCP (beta-transducin repeat-containing protein) binding and ubiquitylation by CUL1 (cullin-1), resulting in increased proteasomal degradation of NRF2. Thus, we hypothesise that inhibition of GSK3 activity or β-TrCP binding upregulates NRF2 and so protects beta cells against oxidative stress. We have found that treating the pancreatic beta cell line INS-1 832/13 with the KEAP1 inhibitor TBE31 significantly enhanced NRF2 protein levels. The presence of the GSK3 inhibitor CT99021 or the β-TrCP-NRF2 protein-protein interaction inhibitor PHAR, along with TBE31, resulted in prolonged NRF2 stability and enhanced nuclear localisation (P

This work analyzes spontaneous cooperation between children who participated in Automata for STEM, European Union funded Erasmus+ project workshops. Taking into account the characteristics of automata, that involve a narrative part and a mechanism, the project used them to implement contextualized and interdisciplinary STEM activities. The pedagogical method involved the presentation of automata, and children being challenged to plan and construct their own. Although no cooperative learning strategies were imposed during the workshops, this research aimed to identify types of spontaneous cooperation that could emerge among children. Data was gathered through participant observation and a questionnaire. Core dimensions of spontaneous cooperation were identified as well as specific dimensions, pointing to a divergent type, characterized by involvement between pairs of children in different projects, and to another type, convergent, involving work between pairs of children in the same project. Spontaneous cooperation also varied according to the children's age or the workshop structure. During workshops with children aged 6-7 years, the class teacher was present and provided guidance, the children were seated in pairs or in a presentation arrangement. During workshops for older children of 8-9 years of age, there was less guidance and the class teacher sometimes was not even in the room the children worked at round tables.

Abstract Background The cellular tumor protein p53 (TP53) is a tumor suppressor gene that is frequently mutated in human cancers. Among various cancer types, the very aggressive high‐grade serous ovarian carcinoma (HGSOC) exhibits the highest prevalence of TP53 mutations, present in >96% of cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved to rescue p53 function. In this study, our primary objective was to administer in vitro‐transcribed (IVT) wild‐type (WT) p53‐mRNA to HGSOC cell lines, primary cells, and orthotopic mouse models, with the aim of exploring its impact on inhibiting tumor growth and dissemination, both in vitro and in vivo. Methods To restore the activity of p53, WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system. Moreover, IVT WT p53 mRNA was delivered into different HGSOC model systems (primary cells and patient‐derived organoids) using liposomes and studied for proliferation, cell cycle progression, apoptosis, colony formation, and chromosomal instability. Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR‐8 and primary HGSOC cells, followed by ingenuity pathway analysis. In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models. Results Reactivation of the TP53 tumor suppressor gene was explored in different HGSOC model systems using newly designed IVT mRNA‐based methods. The introduction of WT p53 mRNA triggered dose‐dependent apoptosis, cell cycle arrest, and potent long‐lasting inhibition of HGSOC cell proliferation. Transcriptome analysis of OVCAR‐8 cells upon mRNA‐based p53 reactivation revealed significant alterations in gene expression related to p53 signaling, such as apoptosis, cell cycle regulation, and DNA damage. Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells, underscoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double‐strand breaks arising from replication stress. Furthermore, in various mouse models, treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose‐dependent manner. Conclusions The IVT mRNA‐based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC, providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.

Abstract Background The management of sludge from municipal wastewater treatment plants (WWTPs) is a global issue, but also an opportunity for circular reuse. Recent data show that sludge reuse in agriculture has the highest share of all utilization routes in the EU. Council Directive 86/278/EEC on the spreading of sludge in agriculture, adopted more than 35 years ago, is still relevant, notwithstanding the discussion on the need to update it. Extracting critical, strategic, and precious metals and metalloids from sludge is an alternative for sludge reuse, which offers several benefits, such as avoiding the high environmental and health risks associated with using sludge directly in agriculture. Additionally, it allows for the recovery of metals, including those listed as Critical Raw Materials by the European Commission. To implement this alternative, it is necessary to first assess the metal content in the sludge and then develop economically and technically viable technologies. In this study, the content of chemical elements in the sludge of eight full-scale WWTPs in Bulgaria is analysed with focus on: (1) assessing the suitability for agricultural application by evaluating the content of macro- and micronutrients and hazardous metals; (2) assessing the possibility of using the sludge as a source of critical and precious metals. Results For the main nutrients, the following contents as a percentage of the sludge dry weight (DW) were recorded—2.06% to 6% for N, 1.52% to 2.67% for P and 0.47% to 0.81% for K, which are in line with case studies of successful sludge application in agriculture. Only sludge samples from two WWTPs exceeded the permitted limit for hazardous metals and metalloids. On the other hand, of the 21 metal and metalloid constituents listed in the EU Critical and Strategic Material (CRM) list, at least one of the examined samples has a content above 10 mg/kg for 15 elements. The average contents in mg/kgDW of Au (1.1), Al (19,272.9), Mg (6677.6), Ti (1730.9), Ga (20.9) and As (16.6) measured in the investigated WWTPs are among the highest or second highest reported in other countries. Conclusions The results of the study show prospects for optimising and improving the reuse of sewage sludge in Bulgaria. Sewage sludge from most WWTPs has potential for agricultural application due to its high nutrient content. Large amounts of accumulated critical and strategic metals, gold and silver are trapped in Bulgarian sewage sludge, indicating that sewage sludge could be considered an alternative source with high potential for these valuable elements.

Prosthetic valve thrombosis is one of the life-threatening complications in patients with prosthetic heart valves. It is more common in mechanical prosthetic valves in the setting of inadequate or missing anticoagulation. Besides optimization of anticoagulation urgent surgery or thrombolytic therapy should be considered but both are associated with an increased risk for complications and mortality. We report a case of a patient with imaging data for mechanical prosthetic mitral valve thrombosis. Considering the individual patient’s characteristics and the published guidelines we decided to perform systemic thrombolysis with ultra-slow low-dose infusion of tissue-type plasminogen activator. The therapy was successful without any bleeding or thromboembolic complications.

This study aims to determine the level of satisfaction with professional work among teachers of physical education and sport and those teaching other general subjects. Methods: The following scientific research methods were applied: a questionnaire on satisfaction with the pedagogical work, variation, and comparative analysis. Results: a tendency towards high levels of satisfaction among teachers in physical education and sport and those teaching general educational subjects, the empirical research results showed high satisfaction with the time commitment. It is indisputable that teachers’ professional work is with a cause aimed at building students’ mental, physical, intellectual, and emotional development, which inevitably places the teaching profession among those of high social importance. Therefore, for teachers to fully fulfill their work commitments, they must feel satisfied with their professional work in all aspects and dimensions. Conclusion: Based on the analyzed data, it was possible to outline the main characteristics of professional work satisfaction among teachers (men and women) and to look for differences depending on the subject they teach.

The rational design of novel bioactive molecules is a critical but challenging task in drug discovery [...]

Key Clinical Message High‐dose intravenous immunoglobulin exhibits great potential in the treatment of Netherton syndrome. Abstract Netherton syndrome (NS) is a rare autosomal recessive genodermatosis (OMIM #256500) characterized by superficial scaling, atopic manifestations, and multisystemic complications. It is caused by loss‐of‐function mutations in the SPINK5 gene, which encode a key kallikrein protease inhibitor. There are two subtypes of the syndrome that differ in clinical presentation and immune profile: ichthyosiform erythroderma and ichthyosis linearis circumflexa. NS is a multisystemic disease with numerous extracutaneous manifestations. Current therapy for patients with NS is mainly supportive, as there is no curative or specific treatment, especially for children with NS, but targeted therapies are being developed. We describe an 8‐year‐old boy with genetically proven NS treated with intravenous immunoglobulin for recurrent skin and systemic infections from infancy, growth retardation, and associated erythroderma. Under this therapy, his skin status, infectious exacerbations, and quality of life all improved. Knowledge of the cytokine‐mediated pathogenesis of NS and the development of new biologic drugs open new possibilities for NS patients. However, the different therapeutic options have been applied in a limited number of cases, and variable responses have been shown. Randomized controlled trials with a sufficient number of patients stratified and treated according to their specific immune profile and clinical phenotype are needed to evaluate the safety and efficacy of treatment options for patients with NS.

Objective Estimate the incremental costs and benefits of scaling up hypertension care in adults in 24 select countries, using three different systolic blood pressure (SBP) treatment cut-off points—≥140, ≥150 and ≥160 mm Hg.Intervention Strengthening the hypertension care cascade compared with status quo levels, with pharmacological treatment administered at different cut-points depending on the scenario.Target population Adults aged 30+ in 24 low-income and middle-income countries spanning all world regions.Perspective Societal.Time horizon 30 years.Discount rate 4%.Costing year 2020 USD.Study design Data sources Institute for Health Metrics and Evaluation’s Epi Visualisations database—country-specific cardiovascular disease (CVD) incidence, prevalence and death rates. Mean SBP and prevalence—National surveys and NCD-RisC. Treatment protocols—WHO HEARTS. Treatment impact—academic literature. Costs—national and international databases.Outcome measures Health outcomes—averted stroke and myocardial infarction events, deaths and disability-adjusted life-years; economic outcomes—averted health expenditures, value of averted mortality and workplace productivity losses.Results of analysis Across 24 countries, over 30 years, incremental scale-up of hypertension care for adults with SBP≥140 mm Hg led to 2.6 million averted CVD events and 1.2 million averted deaths (7% of expected CVD deaths). 68% of benefits resulted from treating those with very high SBP (≥160 mm Hg). 10 of the 12 highest-income countries projected positive net benefits at one or more treatment cut-points, compared with 3 of the 12 lowest-income countries. Treating hypertension at SBP≥160 mm Hg maximised the net economic benefit in the lowest-income countries.Limitations The model only included a few hypertension-attributable diseases and did not account for comorbid risk factors. Modelled scenarios assumed ambitious progress on strengthening the care cascade.Conclusions In areas where economic considerations might play an outsized role, such as very low-income countries, prioritising treatment to populations with severe hypertension can maximise benefits net of economic costs.

Objective To assess the effects of COVID-19 vaccines in women before or during pregnancy on SARS-CoV-2 infection-related, pregnancy, offspring and reactogenicity outcomes.Design Systematic review and meta-analysis.Data sources Major databases between December 2019 and January 2023.Study selection Nine pairs of reviewers contributed to study selection. We included test-negative designs, comparative cohorts and randomised trials on effects of COVID-19 vaccines on infection-related and pregnancy outcomes. Non-comparative cohort studies reporting reactogenicity outcomes were also included.Quality assessment, data extraction and analysis Two reviewers independently assessed study quality and extracted data. We undertook random-effects meta-analysis and reported findings as HRs, risk ratios (RRs), ORs or rates with 95% CIs.Results Sixty-seven studies (1 813 947 women) were included. Overall, in test-negative design studies, pregnant women fully vaccinated with any COVID-19 vaccine had 61% reduced odds of SARS-CoV-2 infection during pregnancy (OR 0.39, 95% CI 0.21 to 0.75; 4 studies, 23 927 women; I2=87.2%) and 94% reduced odds of hospital admission (OR 0.06, 95% CI 0.01 to 0.71; 2 studies, 868 women; I2=92%). In adjusted cohort studies, the risk of hypertensive disorders in pregnancy was reduced by 12% (RR 0.88, 95% CI 0.82 to 0.92; 2 studies; 115 085 women), while caesarean section was reduced by 9% (OR 0.91, 95% CI 0.85 to 0.98; 6 studies; 30 192 women). We observed an 8% reduction in the risk of neonatal intensive care unit admission (RR 0.92, 95% CI 0.87 to 0.97; 2 studies; 54 569 women) in babies born to vaccinated versus not vaccinated women. In general, vaccination during pregnancy was not associated with increased risk of adverse pregnancy or perinatal outcomes. Pain at the injection site was the most common side effect reported (77%, 95% CI 52% to 94%; 11 studies; 27 195 women).Conclusion COVID-19 vaccines are effective in preventing SARS-CoV-2 infection and related complications in pregnant women.PROSPERO registration number CRD42020178076.

An integrative approach is presented to understand the transmission mechanisms of attachment trauma and the quality of the internal working model through manifestations of bodily symptoms concerning physical and mental health. A case of dissociative symptomatology is described in a woman whose ancestors experienced individual and collective trauma related to the political regime. The approach allows for an analytical view beyond the standard complaints of anxiety, depression, post-traumatic symptoms, eating disorders, etc. A brief description of the transgenerational transmission of trauma is presented.

Data collected from the German national resistance monitoring program GERM-Vet showed slowly increasing prevalence of macrolide resistance among bovine respiratory disease (BRD)-associated Pasteurellacae from cattle over the last decade. The focus of this study was to analyze the genetic basis of antimicrobial resistance (AMR) and the prevalence of multidrug-resistance (MDR)-mediating integrative and conjugative elements (ICEs) in 13 German BRD-associated Mannheimia haemolytica isolates collected between 2009 and 2020 via whole-genome sequencing. Antimicrobial susceptibility testing (AST) was performed via broth microdilution according to the recommendations of the Clinical and Laboratory Standards Institute for the macrolides erythromycin, tilmicosin, tulathromycin, gamithromycin, tildipirosin, and tylosin as well as 25 other antimicrobial agents. All isolates either had elevated MICs or were resistant to at least one of the macrolides tested. Analysis of whole-genome sequences obtained by hybrid assembly of Illumina MiSeq and Oxford Nanopore MinION reads revealed the presence of seven novel Tn7406-like ICEs, designated Tn7694, and Tn7724- Tn7729. These ICEs harbored the antimicrobial resistance genes erm(T), mef (C), mph(G), floR, catA3, aad(3“)(9), aph(3‘)-Ia, aac(3)-IIa, strA, strB, tet(Y), and sul2 in different combinations. In addition, mutational changes conferring resistance to macrolides, nalidixic acid or streptomycin, respectively, were detected among the M. haemolytica isolates. In addition, four isolates carried a 4,613-bp plasmid with the β-lactamase gene blaROB − 1. The detection of the macrolide resistance genes erm(T), mef (C), and mph(G) together with other resistance genes on MDR-mediating ICEs in bovine M. haemolytica may explain the occurrence of therapeutic failure when treating BRD with regularly used antimicrobial agents, such as phenicols, penicillins, tetracyclines, or macrolides. Finally, pathogen identification and subsequent AST is essential to ensure the efficacy of the antimicrobial agents applied to control BRD in cattle.

Coumarin (2H-1-benzopyran-2-one) presents the fundamental structure of an enormous class of biologically active compounds of natural, semi-synthetic, and synthetic origin. Extensive efforts are continually being put into the research and development of coumarin derivatives with medicinal properties by the broad scientific community. Transition metal coordination compounds with potential biological activity are a “hot topic” in the modern search for novel drugs. Complexation with transition metals can enhance the physiological effect of a molecule, modify its safety profile, and even imbue it with novel attributes of interest in the fields of medicine and pharmacy. The present review aims to inform the reader of the latest developments in the search for coumarin transition metal complexes with biological activity, their potential applications, and structure-activity relationships, where such can be elucidated. Each section of the present review addresses a certain kind of biological activity (antiproliferative, antioxidant, antimicrobial, etc.), explores the most recent discoveries in the field, and, at the same time, tries to offer useful perspectives for potential future investigations.