Serum Levels of VEGF-A and Its Receptors in Patients in Different Phases of Hemorrhagic and Ischemic Strokes.

Vascular endothelial growth factors (VEGFs) are important regulators of angiogenesis, neuroprotection, and neurogenesis. Studies have indicated the association of VEGF dysregulation with the development of neurodegenerative and cerebrovascular diseases. We studied the changes in serum levels of VEGF-A, VEGFR-1, and VEGFR-2 in patients at various phases of ischemic and hemorrhagic strokes. Quantitative assessment of VEGF-A, VEGFR-1, and VEGFR-2 in serum of patients with hemorrhagic or ischemic stroke was performed by enzyme immunoassay in the hyper-acute (1−24 h from the onset), acute (up to 1−7 days), and early subacute (7 days to 3 months) phases of stroke, and then compared with the control group and each other. Results of our retrospective study demonstrated different levels of VEGF-A and its receptors at various phases of ischemic and hemorrhagic strokes. In ischemic stroke, increased VEGFR-2 level was found in the hyper-acute (p = 0.045) and acute phases (p = 0.024), while elevated VEGF-A and reduced VEGFR-1 levels were revealed in the early subacute phase (p = 0.048 and p = 0.012, respectively). In hemorrhagic stroke, no significant changes in levels of VEGF-A and its receptors were identified in the hyper-acute phase. In the acute and early subacute phases there was an increase in levels of VEGF-A (p < 0.001 and p = 0.006, respectively) and VEGFR-2 (p < 0.001 and p = 0.012, respectively). Serum levels of VEGF-A and its receptors in patients with hemorrhagic and ischemic stroke indicate different pathogenic pathways depending on the phase of the disease.

Pneumonia and Related Conditions in Critically Ill Patients-Insights from Basic and Experimental Studies.

Pneumonia is an acute infectious disease with high morbidity and mortality rates. Pneumonia's development, severity and outcome depend on age, comorbidities and the host immune response. In this study, we combined theoretical and experimental investigations to characterize pneumonia and its comorbidities as well as to assess the host immune response measured by TREC/KREC levels in patients with pneumonia. The theoretical study was carried out using the Columbia Open Health Data (COHD) resource, which provides access to clinical concept prevalence and co-occurrence from electronic health records. The experimental study included TREC/KREC assays in young adults (18-40 years) with community-acquired (CAP) (n = 164) or nosocomial (NP) (n = 99) pneumonia and healthy controls (n = 170). Co-occurring rates between pneumonia, sepsis, acute respiratory distress syndrome (ARDS) and some other related conditions common in intensive care units were the top among 4170, 3382 and 963 comorbidities in pneumonia, sepsis and ARDS, respectively. CAP patients had higher TREC levels, while NP patients had lower TREC/KREC levels compared to controls. Low TREC and KREC levels were predictive for the development of NP, ARDS, sepsis and lethal outcome (AUCTREC in the range 0.71-0.82, AUCKREC in the range 0.67-0.74). TREC/KREC analysis can be considered as a potential prognostic test in patients with pneumonia.

Optically transparent electrodes to study living cells: A mini review.

The use of electrochemical methods to study living systems, including cells, has been of interest to researchers for a long time. Thus, controlling the polarization of the electrode contacting living cells, one can influence, for example, their proliferation or the synthesis of specific proteins. Moreover, the electrochemical approach formed the basis of the biocompatibility improvement of the materials contacting with body tissues that use in carbon hemosorbents and implants development. It became possible to reach a fundamentally new level in the study of cell activity with the introduction of optically transparent electrodes in this area. The advantage of the using of optically transparent electrodes is the possibility of simultaneous analysis of living cells by electrochemical and microscopic methods. The use of such materials allowed approaching to the study of the influence of the electrode potential on adhesion activity and morphology of the different cell types (HeLa cells, endothelial cell, etc.) more detailed. There are a negligible number of publications in this area despite the advantages of the usage of optically transparent electrodes to study living cells. This mini-review is devoted to some aspects of the interaction of living cells with conductive materials and current advances in the use of optically transparent electrodes for the study of living cells, as well as the prospects for their use in cellular technologies.

Long-Term Outcomes after Sepsis.

Sepsis is one of the most serious problems in modern medicine. Long-term outcomes in septic shock patients are very discouraging: 75% individuals who survived sepsis and septic shock demonstrate signs of organ failure and experience persistent functional deficit. Acute sepsis and its management in an intensive care unit (ICU) to a great extent determine the pathogenesis of further complications. We believe that the concept of phenoptosis proposed by Prof. Skulachev deserves a special attention from anesthesiologists and ICU doctors. According to this concept, septic shock is a suicidal mechanism of programmed organism death, which protects human population from dangerously infected individuals. The article suggests a potential approach to the sepsis treatment based on the notion that septic shock can be prevented by identification and blockade of receptors involved in the processing of phenoptotic signal induced by lipopolysaccharide and other substances that initiate septic shock. In view of this, the search for agents that can block molecular mechanisms of the phenoptotic signal transmission seems very promising.

Prevalence and Impact of Malnutrition Risk on Outcomes in Critically Ill Patients with Traumatic Brain Injury and Stroke: A Retrospective Cohort Study Using Electronic Health Records.

BACKGROUND: Malnutrition is a critical concern in ICU settings. It is associated with increased morbidity and mortality, yet its prevalence and impact on clinical outcomes in patients with stroke and traumatic brain injury (TBI) remain underexplored. OBJECTIVE: To evaluate the prevalence and impact of malnutrition risk on clinical outcomes in ICU patients with TBI, ischemic stroke, and hemorrhagic stroke, and to identify key risk factors associated with malnutrition risk. METHODS: This retrospective cohort study utilized electronic health records encompassing ICU admissions from 2017 to 2023. Patients with either stroke or TBI were included, with malnutrition risk assessed using the prognostic nutritional index. Data were extracted and analyzed to determine patient characteristics, clinical and laboratory parameters, and outcomes. RESULTS: This study included 1352 patients (267 TBI, 825 ischemic stroke, and 260 hemorrhagic stroke patients, >30% with pneumonia at admission). Severe malnutrition risk at admission was observed in over 60% of patients. Stroke patients, particularly those with hemorrhagic stroke, exhibited a higher risk of malnutrition compared to TBI patients. Malnutrition risk was associated with significantly higher hospital mortality and increased need for mechanical ventilation. Predictive factors for malnutrition risk included advanced age, higher SOFA scores, lower FOUR and GCS scores, and the presence of pneumonia at admission. CONCLUSIONS: Risk of malnutrition is highly prevalent among ICU patients with TBI, ischemic, and hemorrhagic stroke, significantly impacting mortality and other clinical outcomes. Identifying and managing malnutrition early in the ICU setting is crucial for improving patient outcomes. Further prospective, multicenter studies are needed to validate these findings and develop effective interventions.

The Tri-Steps Model of Critical Conditions in Intensive Care: Introducing a New Paradigm for Chronic Critical Illness.

Background: The prevailing model for understanding chronic critical illness is a biphasic model, suggesting phases of acute and chronic critical conditions. A major challenge within this model is the difficulty in determining the timing of the process chronicity. It is likely that the triad of symptoms (inflammation, catabolism, and immunosuppression [ICIS]) could be associated with this particular point. We aimed to explore the impact of the symptom triad (inflammation, catabolism, immunosuppression) on the outcomes of patients hospitalized in intensive care units (ICUs). Methods: The eICU-CRD database with 200,859 ICU admissions was analyzed. Adult patients with the ICIS triad, identified by elevated CRP (>20 mg/L), reduced albumin (<30 g/L), and low lymphocyte counts (<0.8 × 109/L), were included. The cumulative risk of developing ICIS was assessed using the Nelson-Aalen estimator. Results: This retrospective cohort study included 894 patients (485 males, 54%), with 60 (6.7%) developing ICIS. The cumulative risk of ICIS by day 21 was 22.5%, with incidence peaks on days 2-3 and 10-12 after ICU admission. Patients with the ICIS triad had a 2.5-fold higher mortality risk (p = 0.009) and double the likelihood of using vasopressors (p = 0.008). The triad onset day did not significantly affect mortality (p = 0.104). Patients with ICIS also experienced extended hospital (p = 0.041) and ICU stays (p < 0.001). Conclusions: The symptom triad (inflammation, catabolism, immunosuppression) during hospitalization increases mortality risk by 2.5 times (p = 0.009) and reflects the chronicity of the critical condition. Identifying two incidence peaks allows the proposal of a new Tri-steps model of chronic critical illness with acute, extended, and chronic phases.

Adductor Canal Block Versus Femoral Nerve Block in Total Knee Arthroplasty: Network Meta-Analysis.

OBJECTIVES: The quality of postoperative analgesia in total knee arthroplasty is crucial for patient recovery, rehabilitation, and hospital stay duration. In line with the above, а single-shot adductor canal block has been considered as an improved method over continuous femoral nerve block. However, continuous adductor canal block and single-shot femoral nerve block have been not adequately addressed in the discussion. This study aimed to compare the effectiveness of various types of adductor and femoral nerve blocks on clinically relevant outcomes in patients following total knee arthroplasty. METHODS: A systematic review and network meta-analysis were conducted following "PRISMA-NMA" and Cochrane Handbook guidelines. The eligibility criteria included randomized trials and, where these were lacking for a comparison, nonrandomized studies involving adults undergoing primary total knee arthroplasty, comparing single-shot adductor canal block, continuous adductor canal block, single-shot femoral nerve block, and continuous femoral nerve block. RESULTS: A total of 36 studies involving 3308 patients were included. Single-shot adductor canal block showed higher pain scores and opioid consumption but better functional recovery at 24 h compared with continuous femoral nerve block. However, this trend vanishes by the 48 h assessment postsurgery. Continuous adductor canal block required higher opioid consumption but better functional recovery and shorter hospital stay compared with continuous femoral nerve block. Single-shot adductor canal block showed higher pain scores but comparable opioid consumption and functional recovery to continuous adductor canal block. DISCUSSION: The shift from continuous femoral nerve block to single-shot adductor canal block as the preferred method for pain relief after total knee arthroplasty may be premature. While the latter improves mobility, it falls short in pain control and does not shorten hospital stays. Continuous adductor canal block shows promise but is currently underappreciated, and single-shot femoral nerve block is often overshadowed by other techniques in regional anesthesia. Further high-quality, multicenter randomized controlled trials are needed to validate these findings.

Effects of Lithium Ions on tPA-Induced Hemorrhagic Transformation under Stroke.

Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li+ on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood-brain barrier. We demonstrate that poststroke treatment with Li+ improves neurological status and increases blood-brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li+ on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression.

Intraoperative electroencephalogram patterns as predictors of postoperative delirium in older patients: a systematic review and meta-analysis.

Background: Postoperative delirium (POD) significantly affects patient outcomes after surgery, leading to increased morbidity, extended hospital stays, and potential long-term cognitive decline. This study assessed the predictive value of intraoperative electroencephalography (EEG) patterns for POD in adults. Methods: This systematic review and meta-analysis followed the PRISMA and Cochrane Handbook guidelines. A thorough literature search was conducted using PubMed, Medline, and CENTRAL databases focusing on intraoperative native EEG signal analysis in adult patients. The primary outcome was the relationship between the burst suppression EEG pattern and POD development. Results: From the initial 435 articles identified, 19 studies with a total of 7,229 patients were included in the systematic review, with 10 included in the meta-analysis (3,705 patients). In patients exhibiting burst suppression, the POD incidence was 22.1% vs. 13.4% in those without this EEG pattern (p=0.015). Furthermore, an extended burst suppression duration associated with a higher likelihood of POD occurrence (p = 0.016). Interestingly, the burst suppression ratio showed no significant association with POD. Conclusions: This study revealed a 41% increase in the relative risk of developing POD in cases where a burst suppression pattern was present. These results underscore the clinical relevance of intraoperative EEG monitoring in predicting POD in older patients, suggesting its potential role in preventive strategies. Systematic Review Registration: This study was registered on International Platform for Registered Protocols for Systematic Reviews and Meta-Analyses: INPLASY202420001, https://doi.org/10.37766/inplasy2024.2.0001.

Spectrum of Thrombotic Complications in Fatal Cases of COVID-19: Focus on Pulmonary Artery Thrombosis In Situ.

COVID-19-related thrombosis affects the venous and arterial systems. Data from 156 autopsies of COVID-19 patients were retrospectively analyzed to investigate the pattern of thrombotic complications and factors associated with pulmonary artery thrombosis and thromboembolism. Thrombotic complications were observed in a significant proportion (n = 68, 44%), with pulmonary artery thrombosis the most frequently identified thrombotic event (42, 27%). Multivariate analysis revealed that the length of hospital stay (OR 1.1, p = 0.004), neutrophil infiltration in the alveolar spaces (OR 3.6, p = 0.002), and the absence of hyaline membranes (OR 0.1, p = 0.01) were associated with thrombotic complications. Neutrophil infiltration in the alveolar spaces (OR 8, p < 0.001) and the absence of hyaline membranes (OR 0.1, p = 0.003) were also independent predictors of pulmonary artery thrombosis. The association of pulmonary artery thrombosis with an absence of hyaline membranes suggests it occurs later in the course of COVID-19 infection. As neutrophil infiltration in the alveolar spaces may indicate bacterial infection, our studies suggest the consideration of bacterial infections in these critically ill patients.

Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19.

The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein-protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe (n = 9) and non-severe COVID-19 (n = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.

Serial Changes in Blood-Cell-Count-Derived and CRP-Derived Inflammatory Indices of COVID-19 Patients.

The aim of the study was to investigate the serial changes in inflammatory indices derived from blood cell counts and C-reactive protein (CRP) levels in COVID-19 patients with good and poor outcomes. We retrospectively analyzed the serial changes in the inflammatory indices in 169 COVID-19 patients. Comparative analyses were performed on the first and last days of a hospital stay or death and serially from day 1 to day 30 from the symptom onset. On admission, non-survivors had higher CRP to lymphocytes ratio (CLR) and multi-inflammatory index (MII) values than survivors, while at the time of discharge/death, the largest differences were found for the neutrophil to lymphocyte ratio (NLR), systemic inflammation response index (SIRI), and MII. A significant decrease in NLR, CLR, and MII by the time of discharge was documented in the survivors, and a significant increase in NLR was documented in the non-survivors. The NLR was the only one that remained significant from days 7-30 of disease in intergroup comparisons. The correlation between the indices and the outcome was observed starting from days 13-15. The changes in the index values over time proved to be more helpful in predicting COVID-19 outcomes than those measured on admission. The values of the inflammatory indices could reliably predict the outcome no earlier than days 13-15 of the disease.

Morphologic Findings in the Cerebral Cortex in COVID-19: Association of Microglial Changes with Clinical and Demographic Variables.

Despite the enormous interest in COVID-19, there is no clear understanding of the mechanisms underlying the neurological symptoms in COVID-19. Microglia have been hypothesized to be a potential mediator of the neurological manifestations associated with COVID-19. In most existing studies to date, morphological changes in internal organs, including the brain, are considered in isolation from clinical data and defined as a consequence of COVID-19. We performed histological immunohistochemical (IHC) studies of brain autopsy materials of 18 patients who had died from COVID-19. We evaluated the relationship of microglial changes with the clinical and demographic characteristics of the patients. The results revealed neuronal alterations and circulatory disturbances. We found an inverse correlation between the integral density Iba-1 (microglia/macrophage-specific marker) IHC staining and the duration of the disease (R = -0.81, p = 0.001), which may indicate a reduced activity of microglia and do not exclude their damage in the long-term course of COVID-19. The integral density of Iba-1 IHC staining was not associated with other clinical and demographic factors. We observed a significantly higher number of microglial cells in close contact with neurons in female patients, which confirms gender differences in the course of the disease, indicating the need to study the disease from the standpoint of personalized medicine.

COVID-19 severity: does the genetic landscape of rare variants matter?

Rare variants affecting host defense against pathogens may be involved in COVID-19 severity, but most rare variants are not expected to have a major impact on the course of COVID-19. We hypothesized that the accumulation of weak effects of many rare functional variants throughout the exome may contribute to the overall risk in patients with severe disease. This assumption is consistent with the omnigenic model of the relationship between genetic and phenotypic variation in complex traits, according to which association signals tend to spread across most of the genome through gene regulatory networks from genes outside the major pathways to disease-related genes. We performed whole-exome sequencing and compared the burden of rare variants in 57 patients with severe and 29 patients with mild/moderate COVID-19. At the whole-exome level, we observed an excess of rare, predominantly high-impact (HI) variants in the group with severe COVID-19. Restriction to genes intolerant to HI or damaging missense variants increased enrichment for these classes of variants. Among various sets of genes, an increased signal of rare HI variants was demonstrated predominantly for primary immunodeficiency genes and the entire set of genes associated with immune diseases, as well as for genes associated with respiratory diseases. We advocate taking the ideas of the omnigenic model into account in COVID-19 studies.

Genes and Diseases: Insights from Transcriptomics Studies.

Results of expression studies can be useful to clarify the genotype-phenotype relationship. However, according to data from recent literature, there is a large group of genes that are revealed as differentially expressed (DE) in many studies, regardless of the biological context. Additional analyses could shed more light on the relationships between genes, their differential expression, and diseases. We generated a set of 9972 disease genes from five gene-phenotype databases (OMIM, ORPHANET, DDG2P, DisGeNet and MalaCards) and a report of the International Union of Immunological Societies. To study transcriptomics of disease and non-disease genes in healthy tissues, we obtained data from the Human Protein Atlas (HPA) website. We analyzed the dependency between expression in healthy tissues and gene occurrence in Gene Expression Omnibus series using tools within the Enrichr libraries. The results of expression studies were annotated with Gene Ontology (GO) and Human Phenotype Ontology (HPO) terms. Using transcriptomics analysis of healthy tissues, we validated the previous findings of higher expression levels of disease genes in pathologically linked tissues compared to other tissues. Preferentially DE genes were generally highly expressed in one or multiple tissues and were enriched for disease genes. According to the results of GO enrichment analyses, both down- and up-regulated DE genes most often took part in immune response, translation and tissue-specific processes. A connection between DE-related pathology and the diversity of HPO terms was found. Investigating a link between expression and phenotype contributes to understanding the mode of development and progression of human diseases.

The Role of Von Willebrand Factor in the Pathogenesis of Pulmonary Vascular Thrombosis in COVID-19.

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies of the lungs of 29 patients who died from COVID-19. We found a significant increase in the intensity of immunohistochemical reaction for VWF in the pulmonary vascular endothelium when the disease duration was more than 10 days. In the patients who had thrombotic complications, the VWF immunostaining in the pulmonary vascular endothelium was significantly more intense than in nonsurvivors without thrombotic complications. Duration of disease and thrombotic complications were found to be independent predictors of increased VWF immunostaining in the endothelium of pulmonary vessels. We also revealed that bacterial pneumonia was associated with increased VWF staining intensity in pulmonary arterial, arteriolar, and venular endothelium, while lung ventilation was an independent predictor of increased VWF immunostaining in arterial endothelium. The results of the study demonstrated an important role of endothelial VWF in the pathogenesis of thrombus formation in COVID-19.

Bacteriophage Cocktails in the Post-COVID Rehabilitation.

Increasing evidence suggests that gut dysbiosis is associated with coronavirus disease 2019 (COVID-19) infection and may persist long after disease resolution. The excessive use of antimicrobials in patients with COVID-19 can lead to additional destruction of the microbiota, as well as to the growth and spread of antimicrobial resistance. The problem of bacterial resistance to antibiotics encourages the search for alternative methods of limiting bacterial growth and restoring the normal balance of the microbiota in the human body. Bacteriophages are promising candidates as potential regulators of the microbiota. In the present study, two complex phage cocktails targeting multiple bacterial species were used in the rehabilitation of thirty patients after COVID-19, and the effectiveness of the bacteriophages against the clinical strain of Klebsiella pneumoniae was evaluated for the first time using real-time visualization on a 3D Cell Explorer microscope. Application of phage cocktails for two weeks showed safety and the absence of adverse effects. An almost threefold statistically significant decrease in the anaerobic imbalance ratio, together with an erythrocyte sedimentation rate (ESR), was detected. This work will serve as a starting point for a broader and more detailed study of the use of phages and their effects on the microbiome.

TREC/KREC Levels in Young COVID-19 Patients.

COVID-19 patients with acute respiratory distress syndrome (ARDS) have an immune imbalance when systemic inflammation and dysfunction of circulating T and B cells lead to a more severe disease. Using TREC/KREC analysis, we studied the level of mature naive T and B cells in peripheral blood of COVID-19 patients and its relationship with clinical and laboratory data. TREC/KREC analysis was performed by multiplex real-time quantitative PCR on a sample of 36 patients aged 45 years or younger. The reduced TREC/KREC level was observed in ARDS patients compared with non-ARDS patients, and similar results were found for the deceased patients. During days 6 to 20 of hospitalization, a higher neutrophil-to-lymphocyte ratio (NLR) was detected in ARDS patients compared with non-ARDS patients. TREC/KREC negatively correlated with NLR; the highest correlation was recorded for TREC per 100,000 cells with the coefficient of determination R2 = 0.527. Thus, TREC/KREC analysis is a potential prognostic marker for assessing the severity and outcome in COVID-19.

Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

Dysregulation in cytokine production has been linked to the pathogenesis of various immune-mediated traits, in which genetic variability contributes to the etiopathogenesis. GWA studies have identified many genetic variants in or near cytokine genes, nonetheless, the translation of these findings into knowledge of functional determinants of complex traits remains a fundamental challenge. In this study we aimed at collection, analysis and interpretation of data on cytokines focused on their tissue-specific expression, eQTLs and GWAS traits. Using GO annotations, we generated a list of 314 cytokines and analyzed them with the GTEx resource. Cytokines were highly tissue-specific, 82.3% of cytokines had Tau expression metrics ≥ 0.8. In total, 3077 associations for 1760 unique SNPs in or near 244 cytokines were mapped in the NHGRI-EBI GWAS Catalog. According to the Experimental Factor Ontology resource, the largest numbers of disease associations were related to 'Inflammatory disease', 'Immune system disease' and 'Asthma'. The GTEx-based analysis revealed that among GWAS SNPs, 1142 SNPs had eQTL effects and influenced expression levels of 999 eGenes, among them 178 cytokines. Several types of enrichment analysis showed that it was cytokines expression variability that fundamentally contributed to the molecular origins of considered immune-mediated conditions.

Genetic dissection of host immune response in pneumonia development and progression.

The role of host genetic variation in pneumonia development and outcome is poorly understood. We studied common polymorphisms in the genes of proinflammatory cytokines (IL6 rs1800795, IL8 rs4073, IL1B rs16944), anti-inflammatory cytokines (IL10 rs1800896, IL4 rs2243250, IL13 rs20541) and toll-like receptors (TLR2 rs5743708 and rs4696480, TLR4 rs4986791, TLR9 rs352139, rs5743836 and rs187084) in patients with community-acquired pneumonia (CAP) (390 cases, 203 controls) and nosocomial pneumonia (355 cases, 216 controls). Experimental data were included in a series of 11 meta-analyses and eight subset analyses related to pneumonia susceptibility and outcome. TLR2 rs5743708 minor genotype appeared to be associated with CAP/Legionnaires' disease/pneumococcal disease. In CAP patients, the IL6 rs1800795-C allele was associated with severe sepsis/septic shock/severe systemic inflammatory response, while the IL10 rs1800896-A allele protected against the development of these critical conditions. To contribute to deciphering of the above results, we performed an in silico analysis and a qualitative synthesis of literature data addressing basal and stimulated genotype-specific expression level. This data together with database information on transcription factors' affinity changes caused by SNPs in putative promoter regions, the results of linkage disequilibrium analysis along with SNPs functional annotations supported assumptions about the complexity underlying the revealed associations.