Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

The emergence of drug-resistant mycobacteria has rendered many clinical drugs and regimens ineffective, imposing significant economic and healthcare burden on individuals and society. Repurposing drugs intended for treating other diseases is a time-saving, cost-effective, and efficient approach for identifying excellent anti-mycobacterial candidates or lead compounds. This study is the first to demonstrate that rupatadine (RTD), a drug used to treat allergic rhinitis, possesses excellent activity against mycobacteria without detectable resistance, particularly Mycobacterium tuberculosis and Mycobacterium marinum, with a minimal inhibitory concentration as low as 3.13 µg/mL. Furthermore, RTD exhibited moderate activity against nonreplicating M. tuberculosis with the minimal inhibitory concentrations lower than drugs targeting the cell wall, suggesting that RTD has the great potential to be modified and used for the treatment of nonreplicating M. tuberculosis. Additionally, RTD exhibits partial synergistic effects when combined with clofazimine, pretomanid, and TB47 against M. tuberculosis, providing the theoretical foundation for the development of treatment regimens. Transcriptomic profiling leads us to speculate that eight essential genes may be the targets of RTD or may be closely associated with the mycobacterial resistance to RTD. In summary, RTD may be a promising hit for further anti-mycobacterial drug or regimen optimization, especially in case of nonreplicating mycobacteria.

Extracellular vesicles (EVs) hold enormous potential in the diagnosis and treatment of diseases, benefit from their roles in intercellular signaling, as well as their plentiful presence and stability in body fluids. However, conventional EV isolation methods are labor-intensive, and harvest EVs with low purity and compromised recovery. In addition, the drawbacks, such as limited sensitivity and specificity of traditional EV analysis methods hinder the application of EVs in clinical use. Therefore, it is urgent to develop effective and standardized methods for isolating and detecting EVs. Microfluidics technology is a powerful and rapidly developing technology that has been introduced as a potential solution for the above bottlenecks. It holds the advantages of high integration, short analysis time, low consumption of samples and reagents. In this review, we summarize the traditional techniques alongside microfluidic-based methodologies for the isolation and detection of EVs. We emphasize the separation advantages of microfluidic technology in enhancing EV capture efficiency and precise targeting, while summarizing its analytical role in targeted detection and discussing the significance of EV detection in the tumor microenvironment, providing a direction for achieving automated and high-throughput EV detection in clinical samples.

Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained through an extensive review of the literature, and additionally included target genes identified by the COVID-19 Host Genetic Initiative, as well as the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with severe COVID-19 outcome.

Darier disease (DD) is an autosomal dominant disorder due to mutation of ATP2A2 gene causing an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far although a high incidence of neuropsychiatric syndromes suggest an involvement of central nervous system. A Novel ATP2A2 Gene Mutation c.118G>A, causing keratinocyte and cardiomyocyte disconnection in Darier disease, is reported. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsy because of cardiac dilatation and dysfunction appeared several decades after skin manifestations.Keratinocyte disconnection was paralleled by cardiomyocyte separation at lateral junction. Cardiomyocyte separation was associated to cell disarray, sarcoplasmic reticulum dilatation and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules were associated to chest pain, severe muscle exhaustion and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation.Specific mutations of ATP2A2 gene may cause cardiac involvement in patients with DD. Cardiac pathologic changes are similar to those documented in the skin including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors, enhancing SERCA2 protein phosphorylation may substantially attenuate the symptoms.

The superfamily of Acid proteases has two catalytic aspartates for proteolysis of their peptide substrates. Here, we show a minimal structural scaffold, the Structural Catalytic Core (SCC), which packs all conserved substructure elements around the catalytic machinery, and which can be found in all enzymes of the Acid proteases superfamily. The SCC is a dimer of several structural blocks, such as the DD-link, the D-loop and the G-loop, around two catalytic aspartates in each protease subunit or within an individual chain. The dimer of two D-loop/DD-link substructures makes a DD-zone, and the dimer of two D-loop/G-loop substructures makes a psi-loop. These structural markers are useful for protein comparison, structure identification, protein family separation and protein engineering.

Summary— Introduction: HIV (human immunodeficiency virus) is a virus that attacks and destroys one type of white blood cell, in particular, the CD4 lymphocytes, which are responsible for the body's immune response. This weakens the immune system to such an extent that it can no longer fight other viruses, bacteria, protozoa, fungi, and tumors. Methods: We investigated the potential biological role of the natural compound Polydatin (or piceid) using SwissDock, a web service to predict the molecular interactions that can occur between a target protein and a small molecule. Discussion: For the first time, we have investigated the role of polydatin against HIV-1 protease and HIV-2 protease through a computational approach by comparing their estimated ΔG values (kcal/mol) and the nature of the interactions between the residues in the catalytic center of the HIV proteases.Conclusion: From these simulations, Polydatin has excellent physical properties and an excellent estimated ΔG value (kcal/mol) of about -9.9 kcal/mol against HIV-2 protease and ΔG value (kcal/mol) of about -9.5 kcal/mol against HIV-1 protease. In addition, Polydatin was able to bind to two key amino acids of the catalytic triad sequence common to asparagine proteases (Asp25 and Gly27)

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

Idiopathic pulmonary fibrosis (IPF) is a difficult to treat condition to treat with a high mortality rate. While preclinical models such as Bleomycin (Bleo)-induced fibrosis recapitulate some aspects of IPF, new models that more closely mimic the disease are warranted. We have developed and characterized a novel model in BALB/c mice using a transient overexpression of IL-6 combined with Bleo. This model’s transcriptomic signature was compared to published human IPF datasets. BALB/c females were treated with AdIL-6 in combination with Bleo (AdIL-6+Bleo) or control comparators, and underwent assessments of histopathology (ECM, α-SMA accumulation), collagen content and lung physiology (Elastance, EST). Flow cytometry was used to characterize T cell and Macrophage subsets, and T cell depletion studies (anti-CD4/CD8) were completed to assess T cells role in fibrosis. Bulk RNA sequencing generated gene signatures were compared to that of other rodent fibrosis models and published human datasets of IPF datasets. The AdIL-6+Bleo treatment resulted in robust fibrosis measures (day21), sustained fibrosis until at least day 50, a unique cytokine profile at day 7, and increased activated CD4+Tcells, CD8+Tcells, and CD16+MHChi/Clec7a/iNOS-/Arg1-/CD206- macrophages. T cell depletion markedly decreased fi-brotic responses and this population of macrophages. The Day 21 AdIL-6+Bleo transcriptome shared more genes with each of two human IPF datasets than Bleo alone in C57Bl/6 mice or other rodent models. We conclude that AdIL-6+Bleo in BALB/c mice offers a superior preclinical model for studying IPF mechanisms and potential therapeutic intervention.

Following the detection of highly pathogenic avian influenza (HPAI) virus in countries bordering Kenya to the west, we conducted surveillance among domestic and wild birds along the shores of Lake Victoria. In addition, between 2018 and 2020, we conducted surveillance among poultry and poultry workers in live bird markets and among wild migratory birds in various lakes that are resting sites during migration to assess introduction and circulation of avian influenza viruses in these populations. We tested 7,464 specimens (oropharyngeal and cloacal swabs) from poultry and 6,531 fresh fecal specimens from wild birds for influenza A viruses by real-time RT-PCR. Influenza was detected in 3.9% (n=292) of specimens collected from poultry and 0.2% (n=10) of fecal specimens from wild birds. On hemagglutinin subtyping, most of the influenza A positives from poultry (274/292, 93.8%) were H9. Of 34 H9 specimens randomly selected for further subtyping, all were H9N2. On phylogenetic analysis, these viruses were genetically similar to other H9 viruses detected in East Africa. Only two of the ten influenza A positive specimens from the wild bird fecal specimens were successfully subtyped; sequencing analysis of one specimen collected in 2018 was identified as low pathogenicity avian influenza H5N2 virus of the Eurasian lineage and the second specimen, collected in 2020, was subtyped as H11. A total of 18 OP/NS swabs from poultry workers with ARI (12%) were collected; none were positive for influenza A virus. We observed significant circulation of H9N2 influenza viruses in poultry in live bird markets in Kenya. During the same period, low pathogenic H5N2 virus was detected in a fecal specimen collected in a site hosting a variety of migratory and resident birds. Although HPAI H5N8 was not detected in this survey, these results highlight the potential for introduction and establishment of highly pathogenic avian influenza viruses in poultry populations and the associated risk of spillover to human populations.

Background: Features of post-traumatic stress disorder and anxiety may be present in Pulmonary Embolism (PE) patients along with impaired Quality of Life (QoL). We aim to evaluate health related QoL, anxiety and satisfaction with life, during the pandemic, in patients with a PE. Methods: Patients with PE were enrolled during their follow-up. All participants completed the Short Form 36 (SF-36) questionnaire, the State Trait Anxiety Inventory (STAI) X1 and X2 form, and the Satisfaction with Life Scale (SWLS). Results: 92 PE patients were included (mean age±SD=62.50±15.33 years, 56.5% males). Most of the mean values of the SF36 subscales were above the normative value except for “physical role functioning”) (45.92±42.41). “Emotional role functioning” (51.26±43.31) and “general health perceptions” (GH) (54.02±18.79) were slightly above the normative value of 50. Mean STAIX1 levels were 37.05±11.17 and mean STAIX2 levels were 39.80±10.47. Mean SWLS levels were 23.31±6.58. According to multiple linear regression analysis, mental healthscore (MH) and GH were predictive of SWLS(F (10,76) = 10.576, p

Background: The secretion of alarmin cytokines by epithelial cells, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, heralds the onset of the inflammatory cascade and immune effector infiltration in asthma. However, alarmin cytokine expression in the upper airways in asthma remains largely unknown. Methods: We recruited 40 participants with asthma who were categorized into four severity groups as per the Global Initiative for Asthma (GINA) classifications (10 in each group of GINA-1/2, -3, -4, and -5). Cells were derived from buccal, nasal and throat brushings, and intracellular alarmin cytokine expression (TSLP, IL-25, and IL-33) was assessed in cytokeratin 8+ (Ck8+) epithelial cells immediately after collection using flow cytometry with fluorescence minus one (FMO) controls. We assessed differences in alarmin cytokine expressions across asthma severity using quantile regression adjusted for age and sex. Results: Of all patients, 24 (60%) were females with a mean (standard deviation [SD]) age of 41 (16) years. TSLP levels in Ck8+ epithelial cells in nasal samples of GINA-5 patients were significantly (p=0.03) higher than other GINA groups after adjusting for age and sex but did not differ between patients with and without nasal comorbidities. However, we did not find any significant changes in TSLP levels in Ck8+ epithelial cells in buccal and throat samples across GINA groups. IL-25 or IL-33 (obtained from nasal, buccal, and throat epithelial cell samples) were not significantly different across GINA groups. Conclusions: Our study demonstrates for the first time that Ck8+ nasal epithelial cells from GINA-5 asthmatics express elevated levels of TSLP.

Chronic obstructive pulmonary disease (COPD) patients are particularly susceptible to respiratory infections like influenza, which exacerbate symptoms and increase healthcare utilization. While smoking cessation and influenza vaccination are recommended preventive measures, their combined impact on healthcare resource utilization is underexplored. The Charlson Comorbidity Index (CCI) assesses comorbidity burden in COPD patients and may influence healthcare outcomes. We conducted a retrospective analysis of 357 COPD patients, evaluating smoking cessation success over one year and influenza vaccination receipt, stratifying patients by CCI scores. Healthcare utilization outcomes included emergency room visits, hospitalizations, and medical expenses. Results showed that 51.82% of patients quit smoking and 59.66% received influenza vaccination, with higher comorbidity prevalence in advanced COPD stages (p=0.002). Both smoking cessation and influenza vaccination independently correlated with decreased emergency room visits, hospital admissions, days, and costs. Patients who both quit smoking and received influenza vaccination exhibited the lowest healthcare utilization rates. In conclusion, smoking cessation and influenza vaccination significantly reduce healthcare resource utilization in COPD patients, with the combination yielding synergistic benefits, particularly in those with lower CCI scores. Integrating these interventions and comorbidity management in COPD strategies is essential for optimizing patient outcomes and healthcare efficiency.

Exogenous proteases are well established for hydrolysing proteins and improving the digestibility of amino acids, which, in animal production, enhances growth performance and diet formulation flexibility. Attention has now turned to the wider, or ‘extra-proteinaceous’, benefits of proteases. Both host and (gut) microbiome utilise amino acids for diverse functions beyond just cellular growth and proliferation. For example, the host produces a diverse array of proteinaceous secretions that seek to modulate the activity of the intestinal microbiome and opportunities to interact with host (e.g., epithelial) receptors. Reciprocally, the microbiome utilises various protein-based components to perform individual lifestyle traits, such as colonising gut niches, production of virulence traits, etc., which can be influenced by protease activity and amino acid availability. In addition, microbial fermentation of proteins and amino acids produces metabolites that may be considered undesirable (e.g., toxic) for the host’s cells or, for example, can act as signalling molecules, shaping the secretion of gut hormones and function. Parallels may also exist between various antibiotic growth promoters and proteases, in that both can target/impact microbial proteins (synthesis and degradation, respectively). There are many aspects to consider, such as determining optimal intestinal levels and spectra of proteolytic activity under various scenarios, but great potential exists.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

Proteases are integral enzymes of the plant immune system. Multiple aspects of defence are regulated by proteases, including the hypersensitive response, pathogen recognition, priming and peptide hormone release. These processes are regulated by unrelated proteases residing at different subcellular locations. In this review we discuss ten prominent plant proteases contributing to the plant immune system, highlighting the diversity of roles they perform in plant defence.

Medication non-adherence remains a substantial obstacle in asthma care, prompting the exploration of novel therapeutic modalities that prioritize rapid symptom relief, anti-inflammatory activity and facilitate patients’ compliance. This task is well served by a new form of therapy - inhaled triple-combination medications ICS/LABA/LAMA (inhaled glucocorticosteroid/long-acting beta2-agonist/long-acting muscarinic antagonist). The integration of three medications within a singular inhalation device culminates in the reduction of the effective dose of the principal therapeutic agent for asthma management, namely, ICS. This consolidation yields a dual benefit of minimizing the likelihood of adverse effects typically linked with ICS while concurrently optimizing bronchodilator efficacy. The accumulated evidence suggests that adding LAMA to a medium- or high-dose ICS/LABA results in a decrease of asthma exacerbations compared to medium- or high-dose ICS/LABA alone, accompanied by sustained enhancements in lung function parameters. We propose in adult patients experiencing suboptimal asthma control despite medium/high-dose ICS/LABA treatment - regardless of adherence to GINA-recommended strategies, such as MART therapy as a first-line approach or alternative second-line strategies - the preferred course for intensifying asthma therapy involves the addition of a LAMA, ideally in the form of SITT.

The objective of this study was to investigate the impact of athletes' respiratory muscle strength, as assessed through maximal inspiratory (MIP) and expiratory pressure (MEP), on aerobic endurance, as indicated by maximal oxygen consump-tion (Max VO2) kinetics. Respiratory muscle strength was assessed using a digital spirometer (Pony FX Cosmed, Italy), while maximal oxygen utilization capacity was measured using a breath-by-breath automatic portable gas analysis system (Cosmed K5, Italy). Statistical analysis was conducted utilizing SPSS 22.0. Based on the standardized regression coefficients (β), it was found that MEP (mean ± SD: 130.95 ± 42.82) and inspiratory diaphragmatic circumference values significantly influenced ventilatory equivalent (VE), oxygen consumption (VO2), and carbon dioxide pro-duction (VCO2). Conversely, the remaining predictor variables did not exhibit a sig-nificant effect on VE (mean ± SD: 134.80 ± 36.69), VO2 (mean ± SD: 3877.52 ± 868.47 ml), and VCO2 (mean ± SD: 4301.27 ± 1001.07 ml). In contrast, measurements of chest circumference (mean ± SD: 91.40 ± 10.72 cm), MEP, and diaphragmatic cir-cumference during inspiration (mean ± SD: 95.20 ± 10.21 cm) were found to signifi-cantly impact Max VO2 (mean ± SD: 58.52 ± 10.74 ml/kg/min), while the other pre-dictor variables did not demonstrate a significant effect on Max VO2. Conclusively, the study revealed that measured values of diaphragmatic circumference during inspiration and MEP exerted a notable influence on Max VO2, VE, VO2, and VCO2. Our findings underscore the importance of considering respiratory muscle strength in assessing and enhancing athletes' aerobic performance. These insights contribute to a deeper understanding of the interplay between respiratory function and exercise capacity, offering potential avenues for optimizing training regimens and perfor-mance outcomes in athletic contexts.

Idiopathic pulmonary fibrosis, a chronic and fatal condition with no effective cure, is a challenging disease within the group of interstitial lung diseases. The pathogenic mechanisms of this disease are still not fully understood. In this context, the research on miRNAs, which are small non-coding RNAs that regulate messenger RNAs, is of utmost importance. These miRNAs, released into the circulation outside the cell through exosomes, play a crucial role in the pathogenic pathways and mechanisms involved in IPF development. The analysis of miRNAs in the serum/plasma of IPF patients has opened up new possibilities in the search for biomarkers. This review focuses on circulating miRNAs validated by real-time PCR in IPF and the evidence reported about the pulmonary fibrotic process.

Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.

In this review, we present several extracellular proteases, enzymes, membrane permeases, and transporters as essential accessories proteins for nutrient assimilation, conservation, and transportation as determined by nutrient repletion or depletion. As an obligate aerobic pathogen, it is crucial for invading Cryptococcus (C.) neoformans to negotiate its adaptation to human internal organs like the brain and spinal cord, where the oxygen level is low compared to peripheral organs. Besides, essential metals like copper and iron are important cofactors to functional proteins; however, these metals are not usually freely available to invading human pathogens. Again, the phagolysosome low pH with glucose paucity, internal temperature, immune response, and complex extracellular matrixes are challenging environments that must be circumvented by C. neoformans in the systemic tissues for survival, adaptation, and infection in humans. We review extensive works on several extracellular proteases, enzymes, membrane permeases and transporters orchestrated by different transcription factors and present these proteins as weapons needed to outwit systemic resistance to invading pathogens. Lastly, we examine the extracellular secretory vesicles of C. neoformans as “an exosomal virulence bag” that harbours urease, laccase, phosphatase, and capsular components as additional secretory weapons for tissue invasion and persistence.

Penicillium digitatum is the major postharvest pathogen of citrus fruit under Mediterranean climate conditions. In the present work, we have addressed the study of the role of P. digitatum’s proteases in virulence following two complementary approaches. In a first approach, we have undertaken the functional characterization of the P. digitatum prtT gene, which codes for a transcription factor previously shown to regulate extracellular proteases in other filamentous fungi. Deletion of prtT caused a significant loss in secreted protease activity during in vitro growth assays. However, there was no effect on virulence. Gene expression of the two major secreted acid proteases was barely affected in the ΔprtT deletant during infection of citrus fruit. Hence, no conclusion could be drawn on the role of these secreted acidic proteases on the virulence of P. digitatum. In a second approach, we have studied the effect of different protease inhibitors and chelators in virulence. Co-inoculation of citrus fruit with P. digitatum conidia and a cocktail of protease inhibitors resulted in almost a complete absence of disease development. Analysis of individual inhibitors revealed that the metalloprotease inhibitor 1,10-phenanthroline was responsible for the observed effect. The application of metal ions reverted the protective effect caused by the metallopeptidase inhibitor. These results may set the basis for the development of new alternative treatments to combat this important postharvest pathogen.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without changing the saturation of percutaneous oxygen. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptive area of respiration (the postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores.

The persistence of symptoms following COVID-19 infection represents a significant challenge in healthcare management. During the outbreak, tele-rehabilitation emerged as a new tool to support healthcare structures in providing rehabilitation services. This study assessed the effectiveness and the feasibility of a 3-week home-based motor and respiratory rehabilitation program for long COVID-19 individuals after traditional rehabilitation. Twenty-three patients completed the program and underwent functional tests at different time points (i.e. baseline, after hospital discharge, and after tele-rehabilitation). Motor function was evaluated using the instrumented Six-Minutes Walking Test (i6MWT), with monitored heart rate and oxygen saturation. Conversely, respiratory function was measured via forced vital capacity (FVC) and maximal voluntary ventilation (MVV) tests. Significant improvements (p < 0.05) in motor and respiratory function were observed throughout the intervention, including an 18.3% increase in walked distance from the baseline. The findings suggest that a home-based tele-rehabilitation can enhance motor and respiratory function in post-COVID patients. Despite limitations such as sample size and lack of control group, the positive outcomes seem to support the feasibility of the proposed tele-rehabilitation program in managing long COVID symptoms and promoting functional recovery. Further research is needed to validate these findings and explore tele-rehabilitation’s potential in broader patient populations.

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the con-comitant release of granule contents that damage surrounding tissues into sharp focus. Neutro-phil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. In-terestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promote lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and increase the risk of allergic responses. Recent observations point to the fact that re-duced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19

Background: RSV, or respiratory syncytial virus, is a deadly condition that is present all over the world today. The infection is initially contained in the lower respiratory tract without systemic transmission. The objective of the study: Bioinformatics was used in Egypt to create an mRNA vaccine against the Respiratory syncytial virus (RSV). Methodology: In the present screening experimental study, a lipid nanoparticles vaccine of mRNA of the surface fusion protein of Respiratory syncytial virus was manufactured. The present vaccine delivery system was lipid nanoparticles with a particle size of approximately 90 nanometres, manufactured by the hot micro-emulsion method. In stages 1 and 2 of clinical trials, the immunogenicity of the current mRNA RSV vaccine was evaluated. Results: The current vaccine demonstrated 81% immunogenicity in animal testing, but only 69% in stages 1 and 2 of clinical trials. Its side effects were manageable. The results persisted for a while. In the current trial, the vaccination proved effective as a preventative measure against RSV infection. The current vaccination lacked antibody-dependent enhancement, which causes non-protective antibodies to develop. These non-neutralizing antibodies exacerbate infection by activating cytokines and complement cascade through the formation of immune complexes or enhancement of the virus entry and replication in the host cells. On the other hand, the current RSV mRNA vaccine of the surface fusion protein consequent on the production of powerful neutralizing antibodies with prolonged immunity especially to infants and elderly candidates who received the optimal dosage regimen.

Background: Respiratory syncytial virus[ RSV] is a lethal overwhelming defectiveness that influences people all over the world. The infection gets down in the lower respiratory tract and does not disperse to the remainder of the body. The objective of the study: Bioinformatics was used to create an mRNA vaccine against the Respiratory syncytial virus( RSV). Methodology: Lipid nanoparticle vaccines containing the Respiratory syncytial virus's surface fusion protein's mRNA were created for the current screening experimental investigation. Lipid nanoparticles[ LNP] with a particle size of around 90 nanometres that were created using the hot micro-emulsion process comprise the current vaccine delivery system. In stages 1 and 2 of clinical trials, the immunogenicity of the current mRNA RSV vaccine was evaluated. Results: The current vaccine demonstrated 81% immunogenicity in animal testing, but only 69% in stages 1 and 2 of clinical trials. Its side effects were manageable. The results persisted for a while. In the current trial, the vaccination proved effective as a preventative measure against RSV infection. The current immunization lacks antibody-dependent enhancement, which causes non-protective antibodies to develop. These non-neutralizing antibodies worsen infection by enhancing viral entrance and replication in the host cells, activating cytokines and the complement cascade through the production of immunological complexes, or both. However, the current LPN-RSV mRNA vaccine of the surface fusion protein resulted in the formation of potent neutralizing antibodies with persistent protection, especially for newborns and elderly individuals who get the ideal dose regimen. Conclusion: The invention of the LNP-mRNA RSV vaccine, which might prevent RSV-caused bronchiolitis and fatal pneumonia, made the current study promising

More than 20 years after the discovery of the first anelloviruses (AVs), they still remain a mysterious group of viruses. To date, there is no clear understanding of their impact on the host organism, although information is emerging about their participation in various pathologies. However, it is well known that AVs are an important component of the human virome. In the current study we assessed the abundance of AVs in viromes from four nasal and pharyngeal samples from children with respiratory symptoms using a metagenomic approach. It is worth noting that three patients had known respiratory viruses and one did not have any. Regarding AVs, they were detected in all samples, namely Torque teno mini virus (TTMV). The greatest abundance and diversity of AVs (Torque teno virus (TTV), TTMV and Torque teno midi virus (TTMDV)) were shown in a diseased patient with an absence of respiratory viruses, which may indicate the potential involvement of AVs in the maintenance of respiratory symptoms. An activated immune system to combat the main pathogens, against the background of which the number of AVs decreases, is discussed as a possible reason for the reduced diversity of anellome in other patients. We also compared the results of the metagenomic approach and qPCR for major respiratory viruses, which were in agreement. In addition, metagenomic sequencing made it possible to obtain additional data on viral genomes in order to establish their taxonomic identification and characterize individual viral profiles in patients from the Siberian part of Russia.

According to many research groups, high glucose induces over production of superoxide anions, and reactive oxygen species (ROS) in general is the link between high glucose levels and the toxicities seen at cellular levels. Respiratory complex anomalies could lead to the production of ROS. Calcium [Ca2+], at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production which could be lethal to the mitochondria through various mechanisms. The F1F0-ATPase (ATP syn-thase or complex V) is the enzyme that is responsible for catalyzing the final step of oxidative phosphorylation. It does so by coupling the translocation of protons in the mitochondrial in-termembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space thereby blocking ATP synthesis leading to Neuropathy, Ataxia and Retinitis Pigmentosa Syndromes (NARP). This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain mediated mitochondrial stress. The NARP cybrids are the in vitro experimental models for the cells with F1FO-ATPase defects, these cells harbor 98% of mtDNA T8993G mutation. Their coun-terparts 143B osteosarcoma cell lines are the parental cell lines used for comparisons. We uncov-ered that, NARP cells mediated and enhanced the death of the cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose respectively as depicted by the MTT assay of cell viability. Furthermore, using the fluorescence probe-coupled laser scanning confocal imag-ing microscopy, NARP cells significantly enabled mitochondrial reactive oxygen species (mROS) formation and enhanced the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar enhanced toxicity on mitochondria would help in the fu-ture to alleviate the symptoms of patients associated with (NARP) syndromes.

Eosinophils are key therapeutic targets in severe asthma as they accumulate in tissues, resulting in local damage through the release of toxic mediators. Benralizumab is a monoclonal antibody with a direct anti-eosinophilic activity that has proved significant clinical efficacy in patients with severe eosinophilic asthma, and its use in real-life went well beyond what we had expected from the pivotal trials, especially in the reduction of asthma exacerbations and oral steroids usage. Benralizumab induces eosinophil apoptosis due to a mechanism of antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells. Within this review, we will discuss benralizumab pharmacological and pharmacokinetic aspects in the treatment of severe asthma, with an emphasis on the novel immunological effects of benralizumab on NK cells. Overall, these findings account for the clinical efficacy and safety profile of benralizuamb, previously described in patients with an eosinophilic phenotype of the disease.

Global public health systems have continuously faced challenges from the advent of novel infectious illnesses, necessitating quick and efficient actions to stop their spread.First discovered in Saudi Arabia in 2012, Middle East respiratory syndrome (MERS) is a viral respiratory disorder caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). Since then, the nation has reported most cases and fatalities related to this sickness, with occasional outbreaks happening in other nations and regions. Severe sickness and high mortality are caused by MERS-CoV, especially in older persons and those with underlying chronic conditions. Through intimate contact, the virus can spread from people to dromedary camels and vice versa. It has sparked multiple epidemics both domestically and abroad in the Middle East, raising the possibility of fatalities and widespread transmission, especially in susceptible groups. The Riyadh region was the main target of the most current MERS-CoV outbreak in Saudi Arabia, which began in 2023 and ended on September 1, 2023, with 312 confirmed cases and ninety-seven fatalities. With the use of published studies and their contributions to the field, we hope to present a thorough overview of the MERS-CoV outbreak in Saudi Arabia in this review of the literature, including its epidemiological investigation, public health response, impact, and lessons learned. In addition to highlighting the importance and continued relevance of this problem, our work suggests ways to lower the risk of MERS-CoV transmission and avert further outbreaks.

Kidney fibrosis is a complex polyetiological progressive disease manifesting as an intraorgan proliferation of the connective tissue with the appearance of cicatricial changes. However, pathogenetic mechanisms of renal fibrosis remain poorly understood. The paper highlights features of the protease phenotype and histotopography of mast cells (MCs) found in the kidney, as the key players in extracellular matrix remodeling in nephrofibrosis, detected in a patient diagnosed with "nephrosclerosis with the non-functioning upper pole of the duplex right kidney in the junction of refluxing megaureter of the upper pole of the duplex right kidney". The highest content of MCs was found in the kidney areas with fibrotic changes. MCs were actively involved in the development of inflammatory and fibrotic changes in limited loci of the specific tissue microenvironment of the kidney through targeted secretion of tryptase, chymase, and carboxypeptidase A3 to the vascular endothelium, nephron epithelium, interstitium cells, and components of the intercellular substance. The formation of a profibrotic environment in the kidney interstitium was facilitated by epigenetic effects of tryptase promoting epithelial-mesenchymal transition (EMT) of the nephron epithelium. A selectively increased number and targeted secretory activity of MCs in limited loci of the kidney parenchyma without visible pathological changes evidence a trigger pathogenetic role of specific proteases in the formation of a local microenvironment with a profibrogenic metabolic profile. Thus, MCs are actively involved in the mechanisms of formation and evolution of fibrogenic niches in the kidney; this fact can be used to develop new strategies for therapeutic options of tubulointerstitial fibrosis resulted from chronic kidney injury. Further study of the molecular phenotype of mast cells reveals new fundamental mechanisms of fibrosis pathogenesis being a significant tool for personalized therapy in nephrology.

The novel coronavirus SARS-CoV2 (CoV2) emerged in December 2019. This virus has 88% genomic similarity with SARS-CoV (CoV), and both viruses largely depend on their main protease (M^pro) to regulate infection. M^pro thus represents an attractive target for anti-SARS drug design. The CoV and CoV2 M^pro are 97% identical at the sequence level, with 12 variable residues, and their X-ray structures appear similar. We thus structurally analysed how these variable residues affect the intra-molecular interactions between key residues in the CoV2 M^pro active-site. Compared to CoV M^pro, the 12 divergent residues in CoV2 M^pro exhibit modified intra-molecular interaction networks that ultimately restructure the molecular micro-environment. These altered networks also indirectly affect the networks of other active-site residues at the entrance (T26, M49 and Q192) and near the catalytic region (F140, H163, H164, M165 and H172) of the M^pro. This suggest CoV2 indirectly (via neighbours) reshape key molecular networks around the M^pro active-site. It seems that the CoV2 M^pro deceives us with its apparent structurally identical to the CoV M^pro while this viral system accumulates mass mutations (12 variable residues) at key positions. Some of these identified CoV2 M^pro networks at the active-site might guide design of efficient CoV2 M^pro inhibitors.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. The rise in airways epithelial barrier permeability alters the tissue homeostasis and allows the allergen and other external agents penetration. Different factors contribute to barrier impairment, such as eosinophilic infiltrate and allergens proteases action: the eosinophilic cationic proteins and the allergens' proteolytic activity have a central role in contributing to epithelial damage. In the airways, the allergens proteases degrade the epithelial junctional proteins allowing the allergen penetration and the uptake by dendritic cells. The increase in allergen-immune system interactions induce the release of the alarmins and the activation of type 2 inflammatory pathways causing, or worsening, the main symptoms at skin, bowel and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic proteases-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance and progression. We further will explore clinical and radiological potential biomarkers of airways remodeling in allergic asthma patients.

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is a continually advancing respiratory disorder, characterized by enduring airflow limitation along with long-lasting inflammation in the airways. An expanding pool of evidence is emphasizing how mitochondrial dysfunction directly impacts the development and progression of COPD. This comprehensive review delves deeper into the intricate cellular and molecular biology of mitochondria within the framework of COPD, spotlighting significant alterations in structure and function that accompany mitochondrial dysfunction. In this narrative, we delve into the observed changes in mitochondrial shape, behavior, and respiratory chain complex alterations seen in individuals afflicted with COPD. The discussion includes implications on cellular signaling pathways and how this affects the natural process of programmed cellular death (apoptosis) and cellular aging, particularly in reference to COPD. Additionally, we consolidate ongoing therapeutic strategies, honing in on the management of COPD through a focus on mitochondrial dysfunction. Prominent among these strategies is the potential role of antioxidants and mitochondrial biogenesis inducers, which are emerging as promising fields of intervention. Furthermore, we embark on an overview of the possible use of mitochondrial biomarkers as innovative tools in diagnosing COPD, evaluating disease progression, and monitoring the efficacy of COPD treatments. As we unravel the rather complex interplay between mitochondrial biology and COPD, this review highlights the critical importance of formulating treatments that target mitochondrial dysfunction. The ultimate goal of these strategic interventions is to slow down the rate of COPD progression and significantly improve patient outcomes. Lastly, though our understanding of the nexus between COPD and mitochondrial dysfunction has significantly enhanced, ample scope remains for further investigation. Improved insights into the mechanisms of mitochondrial dysfunction, discovered biomarkers, and targeted therapies could encompass a revolutionary step towards comprehensive disease management. The future of COPD treatment seems to lean towards a combination of strategies, prioritizing not only the management of symptoms but also focused on preserving and restoring lung function, improving physical capacity, and enhancing quality of life for COPD patients.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study TM9 was effective against three murine coronavirus strains, demonstrating the therapeutic window is large enough to allow use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

Lactic acid bacteria (LAB) have an extracellular proteolytic system that includes a multi-domain, cell envelope protease (CEP) with a subtilisin homologous protease domain. These CEPs have different proteolytic activities despite having similar protein sequences. Structural characterization has previously been limited to CEP homologs of dairy and human derived LAB strains, excluding CEPs of plant derived LAB strains. CEP structures are a challenge to determine experimentally due to their large size and attachment to the cell envelope. This study aims to clarify the prevalence and structural diversity of CEPs by using the structure prediction software AlphaFold 2. Domain boundaries are clarified based on a comparative analysis of 21 three-dimensional structures, revealing novel domain architectures of CEP homologs that are not necessarily restricted to specific LAB species or ecological niches. The C-terminal flanking region of the protease domain is divided into fibronectin type-III-like domains with various structural traits. The analysis also emphasizes the existence of two distinct domains for cell envelope attachment that are preceded by an intrinsically disordered cell wall spanning domain. The domain variants and their combinations provide CEPs with different stability, proteolytic activity and potentially adhesive properties, making CEPs targets for steering proteolytic activity with relevance for both food development and human health.

Background: Permanent tracheostomy because of total laryngectomy surgery entails great conse-quences for the patient regarding respiratory physiopathology such as the filtering, humidifying, and heating function of the air by the nose is lost. The use of special stomal filters can determine adequate protection of the trachea-broncho-pulmonary system with a reduction in respiratory pathologies. In fact, in most cases laryngectomee patients are first cigarette smokers who for this reason already have also respiratory diseases such as chronic obstructive pulmonary disease (COPD). Despite the availability of tracheal filters, multiple times, as reported in the literature, the patient tends to limit their use due to reported breathing difficulties, especially in conditions of intense breathing. Methods: The objective of this clinical study was to evaluate the most suitable stomal filter for the laryngectomee patient during physical activity. The filters studied were an INHEALTH device (Blom-Singer SpeakFree HME); two ATOS devices (Provox® Life™ Energy HME and Provox® Life™ Home HME); and an FAHL device (Laryvox HME Sport). Results: For this purpose, the performances of 31 laryngectomee patients, subjected to medi-um-high physical effort, were analyzed through a standardized pneumological test, the Six Minute Walking Test (6MWT) which involves a sustained walk lasting six minutes, with evaluation , every 60 seconds, heart rate, oxygen saturation and meters travelled; furthermore, it examines two sub-jective indices, namely, the basal and final dyspnea index and the initial and final muscular fatigue index.

In recent years, the prevalence of tobacco and electronic cigarette (e-cigarette) use among adolescents has raised significant public health concerns worldwide. This study aims to investigate respiratory symptoms among Polish adolescents. We conducted an online survey among Polish school students from all provinces, collecting data over two months in Spring 2021. Students voluntarily complete the anonymous survey, answering questions about respiratory symptoms, smoking habits (both traditional and electronic cigarettes), and demographic information. Analysis focused on four subgroups: non-tobacco users, traditional cigarette smokers, e-cigarette users, and dual users, totaling 10,388 pupils aged 12-18 years, predominantly attending secondary technical and comprehensive schools. A total of 10388 pupils participated in the study, 55.6 % (5778) of whom were girls and 44.4 % (4610) boys. Adolescents, who admitted using both e-cigarettes and traditional cigarettes experienced more frequent episodes of cough during the day (39.70%) and at night (18.40%) compared to their peers in other groups. Chest discomfort, including pain and pressure, was also reported more often by adolescents, who used e-cigarettes and traditional cigarettes concurrently (27.60%) compared to their peers in other groups. Chest pressure was experienced less commonly by non-smoking adolescents (14.40%) than by smokers (18.90%). Higher severity of cough during the day and at night was observed in the group of adolescents using traditional cigarettes and e-cigarettes concurrently compared to the other groups. The adolescents in the dual user group experienced more severe dyspnoea and wheezing compared to the other groups included in the comparison. The results of this study confirm the correlation between the occurrence of respiratory symptoms in adolescents who smoke cigarettes, use e-cigarettes and in dual users. The respiratory symptoms occur most frequently and are the most severe in the group of adolescents who use e-cigarettes and traditional cigarettes

A case-crossover study examined how PM_2.5 from Asian Dust Storms (ADS) affects the number of emergency room (ER) admissions for cardiovascular diseases (CVDs) and respiratory diseases (RDs). Our data indicated that PM_2.5 concentration from ADS was highly correlated with ER visits for CVDs and RDs. The odds ratios (OR) increased by 2.92 (95% CI: 1.22-5.08) and 1.86 (95% CI: 1.30-2.91) per increase 10 µg/m³ in PM_2.5 levels, for CVDs and RDs, respectively. A 10 µg/m³ increase in PM_2.5 from ADSs was significantly associated with increase in ER visits for CVDs among those 65 years of age and older (an increase of 2.77 in OR) and for females (an increase of 3.09 in OR). In contrast, PM_2.5 levels had a significant impact on RD ER visits among those under 65 years of age (OR=1.77). The risk of ER visits for CVDs increased on the day when the ADS occurred in Taiwan and the day after (lag 0 and lag 1); the corresponding risk increase for RDs only increased on the fifth day after the ADS (lag 5). In Taiwan’s late winter and spring, the severity of ER visits for CVDs and RDs increases. Environmental protection agencies should employ an early warning system for ADS to reduce high-risk groups’ exposure to PM_2.5.

Bovine respiratory disease (BRD) is a major health problem within the global cattle industry. This disease has a complex aetiology, with viruses playing an integral role. In this study, metagenomics was used to sequence viral nucleic acids in the nasal swabs of BRD affected cattle. Viruses detected included those well known for their association with BRD in Australia (bovine viral diarrhea virus 1), as well as viruses known to be present but not fully characterised (bovine coronavirus) and viruses that have not been reported in BRD affect cattle in Australia (bovine rhinitis, bovine influenza D, and bovine nidovirus). Nasal swabs from a case control study were subsequently tested for 10 viruses and the presence of at least one virus was found to be significantly associated with BRD. Some of the more recently detected viruses had inconsistent association with BRD. Full genome sequences for bovine coronavirus, a virus increasingly associated with BRD, and bovine nidovirus were complete. Both viruses belong to the Coronaviridae family, which are frequently associated with disease in mammals. This study has provided greater insights into the viral pathogens associated with BRD and highlighted the need for further studies to elucidate more precisely the roles viruses play in BRD.

Patients who survived critical COVID-19 frequently reported post-acute sequelae of COVID-19 (PASC) such as psychosomatic and neurocognitive health problems. The goal of this study was to identify clinical risk factors and other predictors for such long-term consequences in severely ill COVID-19 patients. Adult COVID-19 intensive care unit (ICU) survivors from August 2020 to May 2021 were enrolled. A broad range of clinical, laboratory and chest computed tomography (CT) data was collected during ICU stay. The association between ICU predictors and psychosomatic, respiratory and neurocognitive assessments 12 months after ICU discharge was analyzed using univariate regression analysis. In 17 patients (mean age 58.9 ± 11.4 years), laboratory markers (CRP, lymphocytes, hemoglobin), ICU severity (SOFA, SAPS II, need for mechanical ventilation), complications (ARDS), and lung CT data (ground-glass opacity) were promising predictors of depressive and anxiety symptoms, fatigue, and sleep problems. Recovery of psychosomatic health such as fatigue, depression and anxiety correlated with lower levels of inflammation and high hemoglobin levels. ARDS, mechanical ventilation and worse SOFA and SAPS II scores were further risk factors for depressive and anxiety symptoms. Our study identified novel associations such as pulmonary ground-glass opacity being positively associated with depression, anxiety, fatigue, and insomnia levels.

Cell-to-cell distant mechanical communication has been demonstrated by using in-vitro and in-vivo models. However, the molecular mechanisms underlying long-range cell mechanoresponsive interactions remain to be more elucidated. This study further examined the roles of α-Catenin and Piezo in traction force-induced rapid branch assembly of airway smooth muscle (ASM) cells on Matrigel hydrogel containing type I collagen. Our findings demonstrate that siRNA-mediated downregulation of α-Catenin or chemical inhibition of Piezo activity significantly reduced both cell directional movement and branching assembly. In regarding the role of N-cadherin in regulating branch assembly but not directional migration, our results further confirmed that siRNA downregulation of α-Catenin caused a remarked reduction of focal adhesion formation, as assessed by focal Paxillin and Integrin α5 localization. These observations implied that mechanosensitive α-Catenin was involved in both cell-cell and cell-matrix adhesions. Additionally, Piezo showed partial localization with Paxillin in focal adhesions, which was inhibited by α-Catenin downregulation with siRNA. This provides a plausible clue for Piezo mechanosensing traction force in the hydrogel. Collectively, our findings highlight the significance of α-Catenin in regulating cell-matrix interactions along with possible interpretation for Piezo mechanosensation at focal adhesions during cell-cell distant mechanical communication.

Respiratory Syncytial Virus is a common respiratory pathogen known for causing respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and the elderly. This virus is responsible for one-third of pneumonia deaths in the pediatric population, but there are currently only a few effective vaccines and pharmacological treatments. The frac-talkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and a diversity of immune cells. Recent research has highlighted the role of CX3CR1 in the host immune response to RSV infection, and its potential role in the development of an efficient vaccine and novel treatments.

The serine proteases CAP1/Prss8 (prostasin) and CAP3/St14 (matriptase) are identified as ENaC channel-activating proteases in vitro highly suggesting that they are required for proteolytic activation of ENaC in vivo. The present study tested whether CAP3 is relevant for renal proteolytic ENaC activation and affects ENaC-mediated Na+ absorption following Na+-deprivation conditions. CAP3 knockout mice exhibit significant decrease in CAP1 protein expression with altered ENaC subunit and decreased pNCC protein abundances, but overall maintain sodium balance. RNAscope-based analyses reveal co-expression of CAP3 and CAP1 with alpha ENaC in distal tubules of the cortex from wildtype mice. Double CAP1/CAP3-deficiency maintained Na+ and K+ balance on Na+-deprived diet, restored ENaC subunit protein abundances but showed reduced NCC activity under Na+-deprivation. Overall, our data clearly show that CAP3 is not required for direct proteolytic activation of ENaC, but for its protein abundances. Our study reveal a complex regulation of ENaC by these serine proteases on the expression level rather than on its proteolytic activation.

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in cattle raised in North America. At the feedlot, cattle are subject to metaphylactic treatment with macrolides to prevent BRD, a practice that may promote antimicrobial resistance and has resulted in an urgent need for novel strategies. Mannheimia haemolytica is one of the major bacterial agents of BRD. The inhibitory effects of two amphipathic, α-helical (PRW4, WRL3) and one β-sheet (WK2) antimicrobial peptides were evaluated against multidrug-resistant (MDR) M. haemolytica isolated from Alberta feedlots. WK2 was not cytotoxic against bovine turbinate (BT) cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All three peptides inhibited M. haemolytica, with WK2, being the most efficacious against multiple isolates. At 8-16 µg/ml, WK2 was bactericidal against Mh 330 in broth and at 32 µg/ml in the presence of BT cells, reduced the population by 3 logs CFU/ml without causing cytotoxic effects. The membrane integrity of Mh 330 was examined using NPN (1-N-phenylnaphthylamine), and ONPG (o-Nitrophenyl β-D-galactopyranoside) with both the inner and outer membranes being compromised. Thus, WK2 may be a viable alternative to the use of macrolides as part of BRD prevention and treatment strategies.

Since the spread of the deadly virus SARS-CoV2 in late 2019, researchers have restlessly been seeking for unraveling how the virus factually enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: 1- the nano-machine Spike protein on behalf of the virus, 2- angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, 3- some host proteases and proteins exploited by SARS-CoV2, In this review, the complex process of SARS-CoV2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the Spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Besides, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.

Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by local and systemic inflammation independently of the risk factor; during the exacerbations, such inflammation is accentuated and amplified. A practical inflammatory marker and one with an applicable predictive value in the follow-up has been sought. FeNO has shown an excellent performance in that respect within the context of asthma and has also been studied in tobacco-smoke COPD (COPD-TS). In Biomass-smoke COPD (COPD-BS), this, to our knowledge, has not been evaluated. Objective: To measure FeNO levels in patients with COPD-BS and to compare these with those of patients with stable COPD-TS and in healthy controls. Methods: Transversal, observational, descriptive, comparative, and analytical study. A total of 57 patients, including 23 with COPD-BS, 17 with COPD-TS, and 17 healthy control subjects. The measurement of FeNO was carried out on all of these by means of the on-line chemiluminescence technique; the values were expressed in parts per billion (ppb) for their analysis. Results: It was observed that the FeNO values were similar between COPD-BS and COPD-TS and were significantly different between the healthy and stable COPD (both groups). No correlation was found between pulmonary function and symptoms with FeNO in any of the groups. Conclusions: The level of FeNO in stable COPD is found to be increased in a similar manner in COPD-BS and COPD-TS, with a significant difference on comparing it with that of the healthy subjects.

The study aimed to estimate the prevalence of respiratory symptoms and to assess respiratory health risks associated with Particulate Matter (PM) exposure among the residents of Windhoek, Namibia. Objectives: To measure particulate pollution concentration in Windhoek through monitoring of particulate matter concentration and to identify any associations between particulate pollution, individual location and respiratory health among the Windhoek resident’s. Methods: an adapted standardized self-administered questionnaire was used to collect respiratory health related data as well as previous exposure, while PM monitoring was done using ASTM D1739 reference method. Results: A high prevalence was observed for cough (43%), breathlessness (25%), and Asthma (11.2%). PM was found to be a significant risk factor for episode of cough and phlegm, while high PM exposure category had increased odds ratio for episode of phlegm and cough (OR: 2.5, 95% CI: 0.8-8.0). No association was observed between location and respiratory health outcomes. Conclusion: The study found high levels of PM concentration across all Windhoek suburbs which were above the German, American and EPA. Enactment of legislation relating to the control and monitoring of PM related emissions at point of generation is required at country and city level.

Coronavirus disease 2019 (COVID-19) has affected medical practice. More than 7,000,000 patients died worldwide after being infected with COVID-19; however, no specific laboratory markers have yet been established to predict death related to this disease. In contrast, electrocardiographic changes owing to COVID-19 include QT prolongation and ST-T changes; however, there have been no studies on ambulatory electrocardiographic markers of COVID-19. We encountered three patients diagnosed as having COVID-19 who did not have a prior history of significant structural heart diseases. All had abnormalities in ambulatory echocardiogram parameters detected by high-resolution 24-h electrocardiogram monitoring: positive late potentials (LPs) and T-wave alternans (TWA), abnormal heart rate variability (HRV), and heart rate turbulence (HRT). Case 1 involved a 78-year-old woman with a history of chronic kidney disease, Case 2 a 76-year-old man with hypertension and diabetes, and Case 3 a 67-year-old man with renal cancer, lung cancer, and diabetes. None of them had a prior history of significant structural heart disease. Although no significant consistent increases in clinical markers were observed, all three patients died, mainly because of respiratory failure with mild heart failure. LP, TWA, HRV, and HRT were all positive in three cases with no significant structural cardiac disease at the initial phase of admission. There is a possibility that LP, TWA, HRV, and HRT have the potential to be risk stratifiers of COVID-19 pneumonia in the early phase of admission. Further accumulation of data regarding ambulatory electrocardiographic markers in patients with COVID-19 is needed.

Bovine Respiratory Disease Complex, a complex respiratory ailment in cattle, results from a combination of viral and bacterial factors, compounded by environmental stressors such as overcrowding, transportation, and adverse weather conditions. Its impact extends beyond mere health concerns, posing significant economic threats to the cattle industry. This study presents an extensive investigation into viral pathogens associated with BRDC in Serbian cattle, utilizing serum samples and nasal swabs. A cross-sectional study was conducted in 2024 across 65 randomly selected dairy farms in Serbia, excluding vaccinated farms. Farms were categorized by livestock count: small (≤50 animals), medium-sized (51-200 animals), and large (>200 animals). Serum samples from adult cattle older than 24 months were tested for antibodies against BVDV, BHV-1, BRSV, and BPIV3. Nasal swab samples from animals with respiratory signs were tested using PCR for viral genome detection. Results showed seropositivity for all four viruses across all farms, with BPIV3 exhibiting universal seropositivity. Medium-sized and large farms demonstrated higher seropositivity for BRSV and BHV-1 compared to small farms (p<.05). True seroprevalence estimates at the animal level were 84.29% for BRSV, 54.08% for BVDV, 90.61% for BHV-1, and 84.59% for BPIV3. PCR analysis of nasal swabs revealed positive detections for BRSV (20%), BHV-1 (1.7%), BVDV (8%), and BPIV3 (10.9%). Influenza D virus was not found in any of samples. This study provides critical insights into the prevalence and circulation of viral pathogens associated with BRDC in Serbian cattle, emphasizing the importance of surveillance and control measures to mitigate the impact of respiratory diseases in cattle populations.

During the COVID-19 pandemic, the circulation of non–SARS-CoV-2 respiratory viruses changed throughout the world. This study aimed to analyze the effect of respiratory syncytial virus (RSV), metapneumovirus (MPV), rhinovirus (RV), and parainfluenza (PIV)-3 single infection, dual co-infection, and viral load on cytokine and chemokine expression in 300 Mexican patients with ARIs negative for SARS-CoV-2. Molecular detection and viral load were performed by RT-qPCR. Cytokine and chemokine expression was determined in samples positive for single RSV, MPV, RV, or PIV-3 infection, and in the most frequent dual co-infections, by a cytokine panel using a magnetic-bead-based multiplex immunoassay. Of the patients positive for viral infection, 91.7% had a single infection and 8.3% had dual co-infections. In this study, RSV was the respiratory virus with the highest prevalence, and the most common dual co-infection was RV+RSV. On the other hand, RV infections had the highest viral loads compared to the other viruses detected. FGF basic, MIP-1α IL-8, IP-10, MCP-1, IFN-γ, and RANTES showed differential expression between single infections and dual co-infections compared to healthy patients. We report, for the first time, the circulation of non-SARS-CoV-2 viruses in the south of Mexico and the cytokine and chemokine profiles associated with these viruses.

The extended cleavage specificities of two hematopoietic serine proteases originating from the ray-finned fish spotted gar (Lepisosteus oculatus) have been characterized using substrate phage display. The preference for particular amino acids at, and surrounding the cleavage site was further validated using a panel of recombinant substrates. For one of the enzymes, the gar granzyme G, a strict preference for the aromatic amino acid Tyr was observed at the cleavable P1 position. Using a set of recombinant substrates showed that the gar granzyme G had a high selectivity for Tyr, but also with lower activity cleaving after Phe but not after Trp. The second enzyme, gar DDN1, instead showed a high preference for Leu in the P1 position of substrates. This latter enzyme also showed high preference for Pro in the P2 position and Arg in both P4 and P5 positions. The selectivity for the two Arg residues in positions P4 and P5, suggest a highly specific substrate selectivity of this enzyme. Screening of the gar proteome with the consensus sequences obtained by substrate phage display for these two proteases resulted in a very diverse set of potential targets. Due to this diversity, a clear candidate for a specific immune function of these two enzymes cannot yet be identified. Antisera developed against the recombinant gar enzymes were used to study their tissue distribution. Tissue sections from juvenile fish showed expression of both proteases in cells in Peyer´s patch-like structures in the intestinal region, indicating they may be expressed in T or NK cells. However, due to the lack of antibodies to specific surface markers in the gar, it has not been possible to specify the exact cellular origin. A marked difference in abundance was observed for the two proteases where gar DDN1 was expressed at higher levels than gar granzyme G. However, both appear to be expressed in the same or similar cells, having a lymphocyte-like appearance.

Immunosenescence refers to age-related alterations of the immune system function affecting both the humoral and cellular arm of immunity. Understanding immunosenescence and its impact on vaccination of older adults is essential since primary vaccine responses in older individuals can fail to generate complete protection, especially vaccines targeting infections with increased incidence among the elderly, such as the respiratory syncytial virus. Here, we review the clinical trials of both candidate and approved vaccines against respiratory syncytial virus (RSV), which include adults aged ≥50 years, with an emphasis on the evaluation of immunogenicity parameters. Currently, there are 10 vaccine candidates and 2 vaccines approved for the prevention of RSV in the older adult population. The number of registered clinical trials for this age group amounts to 32. Our preliminary evaluation of published results and interim analyses of the RSV vaccine clinical trials indicates efficacy in older adult participants, demonstrating immunity levels that closely resemble those of younger adult participants.

Respiratory allergic diseases, affect over 500 million people globally and pose a substantial burden in terms of morbidity, mortality, and healthcare costs. Restrictive factors such as geographical disparities, infectious pandemics, limitations in resource, and shortage of allergy specialists in underserved areas, impede effective management. Moreover, the well-established suboptimal adherence in patients with respiratory allergies, contribute further to the accelerated loss of disease control. Telemedicine encompasses real-time visits, store-and-forward options triage, and computer-based technologies for establishing and efficient doctor-patient communication. Recent advances in digital technology, including designated applications, informative materials, digital examination devices, wearables, digital inhalers, and integrated platforms, facilitate personalized and evidence-based care delivery. The integration of telemonitoring in respiratory allergy care has shown beneficial effects in disease control, adherence, and quality of life. While the COVID-19 pandemic accelerated the adoption of telemedicine, certain concerns regarding technical requirements, platform quality, safety, reimbursement, and regulatory considerations remain unresolved. Challenges in telemonitoring implementation further include ensuring effective doctor-patient collaboration, addressing privacy concerns, and establishing cost-effective models. The integration of artificial intelligence (AI) in telemonitoring applications holds promise for data analysis, pattern recognition, and personalized treatment plans. Striking the balance between AI-enabled insights and human expertise is crucial for optimizing the benefits of telemonitoring. This overview reports the up- to- date telemedicine approaches in managing patients with respiratory allergies. While telemonitoring exhibits potential in enhancing patient care and healthcare delivery, critical considerations have to be addressed in order to ensure the successful integration of telemonitoring into the healthcare landscape.

Acute respiratory distress syndrome (ARDS) is caused by infectious insults, such as pneumonia from various pathogens or related to other noninfectious events. Clinical and histopathologic characteristics are similar across severely affected patients, suggesting that a common mode of immune reaction may be involved in the immunopathogenesis of ARDS. There may be etiologic substances that have an affinity for respiratory cells and induce lung cell injury in cases of ARDS. These substances originate not only from pathogens, but also from injured host cells. At the molecular level, these substances have various sizes and biochemical characteristics, classifying them as protein substances and non-protein substances. Immune cells and immune proteins may recognize and act on these substances, including pathogenic proteins and peptides, depending upon the size and biochemical properties of the substances (this theory is known as the protein-homeostasis-system hypothesis). The severity or chronicity of ARDS depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances. Therefore, treatment with early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) as soon as possible may reduce aberrant immune responses in the potential stage of ARDS.

Background/Objectives: The primary life-threatening complication in Spinal-bulbar muscular atrophy (SBMA) is ventilatory failure, which results from the weakening of the bulbar and respiratory muscles. However, systematic studies assessing respiratory function over the long-term have not been performed. The present study analyzes the longitudinal patterns of respiratory function tests over a follow-up of 11 years, aiming to identify any potential, sustained decline during this time. Furthermore, we explored possible correlations between respiratory function tests and clinical and biochemical serum indices. Methods: We collected data from 9 genetically confirmed SBMA patients and conducted spirometric measurements twice a year for eleven years. The spirometric data included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and forced vital capacity (FVC)]. Additionally, we measured serum biochemical indices and SBMA functional rating scale (SBMAFRS) for clinical analysis. Results: All three respiratory function tests showed a descending trend. A major decrease was observed for MEP (52%) and MIP (42%), while this was minor for FVC (25%). SBMAFRS score correlated with the three pulmonary function tests. MIP and MEP correlated with creatine phosphokinase and creatinine levels, and FVC correlated with serum level of transaminases. Conclusions: This longitudinal study shows a progressive decline of spirometric data throughout life in patients with SBMA. Spirometric measures relative to maximal strength of the respiratory muscles (MIP and MEP) may have a better predictive value for pulmonary and muscular decline than FVC.

Duchenne muscular dystrophy (DMD) is the most prevalent progressive muscular dystrophy, and the guidelines recommend the regular assessment of respiratory muscle function. This study aimed to assess the relationship between maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) and sniff nasal inspiratory pressure (SNIP) measurements and upright-supine spirometry parameters in children with DMD, predictability of upright-supine spirometry in terms of diaphragm involvement, and impact of nutrition on muscle strength. This prospective cross-sectional study examined patients with DMD by comparing upright and supine FVC, MIP, MEP, and SNIP measurements. Forty-four patients were included in the study. The mean patient age was 10.8±2.9 years. Twenty-five patients were ambulatory. A significant decrease in FVC, FEV1, and FEF25-75 values was detected in the supine position in both ambulatory and nonambulatory patients (p<0.05). All patients had low MIP, MEP, and SNIP measurements (less than 60 cm H2O). MIP, MEP, and SNIP values were significantly lower in patients with malnutrition than in those without (p<0.05). To accurately assess respiratory muscle strength, supine FVC should be combined with upright FVC, MIP, MEP, and SNIP measurements. It is crucial to regularly screen patients for malnutrition, as this can significantly affect respiratory muscle function during pulmonology follow-up.

Proteomics in respiratory allergic diseases has such a battery of techniques and programs that one would almost think that there is nothing impossible to find, invent or mold. All these resources that we document here, are involved in solving problems in allergic diseases, both diagnostic, prognostic, treatment and immunotherapy development. The main perspectives, according to this version, are in three strands and / or lockout immunological system: 1) In blocking the diapedesis of cells involved, 2) modifications and blocking of paratopes and epitopes being understood by modifications to antibodies, antagonism or blocking them and 3) blocking FcεR1 receptors to prevent specific IgEs from sticking to mast cells and basophils. These tools and targets in the allergic landscape are, in our view, the prospects in the field.

We propose an electrocardiogram (ECG) signal-based algorithm to estimate the respiratory rate is a significant informative indicator of physiological state of a patient. The consecutive ECG signals reflect the information about the respiration because inhalation and exhalation make transthoracic impedance vary. The proposed algorithm extracts the respiration-related signal by finding out the commonality between the frequency and amplitude features in the ECG pulse train. The respiration rate can be calculated from the principle components after the procedure of the singular spectrum analysis. We achieved 1.7569 breaths per min of root-mean-squared error and 1.7517 of standard deviation with a 32-seconds signal window of the Capnobase dataset, which gives notable improvement compared with the conventional Autoregressive model based estimation methods.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is an extremely rare type of vasculitis characterized by inflammation within small blood vessels or tissues that may cause damage to the lungs, heart, kidneys, and other organs. Here, we present a rare case of EGPA with cardiac involvement that presented with acute heart failure. Clinical findings: A 44-year-old woman with a history of bronchial asthma and sinusitis pre-sented with fever, shortness of breath, fatigue, unintentional weight loss, and polyarthritis. Physical examination revealed a fine basal crepitation and mononeuritis multiplex. Diagnosis: The peripheral film revealed dimorphic features, an elevated eosinophil count, low hemoglobin (Hb), and abnormally high lactate dehydrogenase levels. The cardiac enzyme levels were elevated upon admission. Cardiac magnetic resonance imaging (CMR) revealed global hypokinesia and features suggestive of myocarditis. Echocardiography showed a low ejection fraction of 25%. Thus, the patient diagnosed with EPGA and myocarditis presented with acute heart failure. Interventions: The patient was administered high-dose corticosteroids (intravenous bolus methylprednisolone 500 mg for three days, followed by 1 mg/kg of prednisolone) and cyclo-phosphamide 750 mg intravenously. Outcome: After one months, the patient showed a marked improvement in clinical and labora-tory parameters. The ejection fraction improved to 30-40%, the eosinophil count returned to normal, and the hemolytic anemia resolved. The patient was sent home with mycophenolate mofetil 1 g twice a day as maintenance therapy. Conclusion: Patients with EGPA have a higher morbidity and mortality rate when they have cardiac in-volvement. The pathophysiological mechanism of cardiac involvement in EGPA warrants con-sideration of immunosuppressive therapy in addition to standard heart failure treatment.

Acute respiratory viruses (ARVs) are leading cause of diseases in human worldwide. High risk individuals including children and elderly could potentially develop severe illness that could result in hospitalization or death in the worst case. Most common ARVs are Human respiratory syncytial virus, Human Metapneumovirus, Human Parainfluenza Virus, rhinovirus, coronaviruses (including SARS and MERS CoV), adenoviruses, Human Bocavirus, enterovirus (-D68 and 71), and influenza viruses. The olfactory deficits due to ARVs infection is a common symptom among patients. This mini review provides an overview of the role of SARS-CoV-2 and other common ARVs in the development of human olfactory pathophysiology. We highlight the critical need for understanding the signaling underlying the olfactory dysfunction and the development of therapeutics for this wide-ranging category of AVRs to restore the altered or loss of smell in affected patients.

This study evaluated the epidemiological and genetic susceptibility profile caused by coronavirus 2 (SARS-CoV-2) in children ≤3 years of age with acute gastroenteritis (AGE) or acute respiratory infection (ARI), living in the northwestern region of the Amazon (NWAR). Fecal and saliva sam-ples collected from 202 children (n=404) were subjected to detection of SARS-CoV-2 by RT-qPCR. Polymorphisms in the angiotensin-converting enzyme (ACE rs4646994) and ACE2 G8780A; rs2285666) genes were detected by SYBR GREEN real-time PCR and PCR/Alul digestion, respec-tively. Secretory and Lewis status of histo-blood group antigen (HBGA) was performed using phenotyping/ELISA. Frequencies for the AGE group: SARS-CoV-2; 8.9%; ARI group: SARS-CoV-2; 2.9%. The ACE I/I homozygous polymorphism gene was majority. Males with the ACE2 G8780A SNP were more susceptible to ARI symptoms than AGE (OR = 3.85; 95% CI-1.42-10.38; P 0.007). Most children were secretory FUT2 phenotype (92.6%). Surveillance of diarrhea and respiratory infections in children, along with understanding their causes, are crucial for identifying preven-tion and control strategies and for prioritizing and developing new vaccines. Clinical manifesta-tions of COVID-19 in children ≤3 years of age include AGE.

Obstructive sleep apnea (OSA) is a common sleep disorder that is associated with a wide variety of health conditions, including cardiovascular, cerebrovascular, metabolic, neoplastic, and neurocognitive manifestations. OSA as a chronic condition is mainly characterized by repeated upper airway obstructions during sleep that cause episodes of intermittent hypoxia (IH), resulting in tissue hypoxia-reoxygenation cycles. Decreased arterial oxygen pressure (PaO₂) and hemoglobin saturation (SatO₂) stimulate reflex responses to overcome the obstruction. The prevalence of OSA is significant worldwide, and an underrated problem when focusing on women during pregnancy. The physiological changes associated with pregnancy, especially during its latest stages, are related with a higher prevalence of OSA events in pregnant mothers, and associated with an increased risk of hypertension, pre-eclampsia and diabetes, among other deleterious consequences. Furthermore, OSA during pregnancy can interfere with normal fetal development and is associated with growth retardation, preterm birth, or low term weight. Carotid body overstimulation and hypoxia-reoxygenation episodes contribute to cardiovascular disease and oxidative stress, which can harm both mother and fetus and have long-lasting effects that can reach into adulthood. Because IH is the hallmark of OSA, this review examines the literature available about the impact of gestational intermittent hypoxia (GIH) on the respiratory system at maternal, fetal, and offspring levels. Offering the latest scientific data about OSA during pregnancy, we may help to tackle this condition with lifestyle changes and therapeutic approaches, that could influence the mothers, but also impact adult health problems, mostly unknown, inherited from these hypoxic episodes in the uterus.

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA) – a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease rodent models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts which characterize the respiratory phenotype of Pompe rodent models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease rodent models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, phrenic and hypoglossal motor nucleus, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle and higher order respiratory control centers. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

The objective of the study was to analyse the antimicrobial susceptibility trends of Spanish porcine bacteria to quinolones, cephalosporins and polymyxins. Isolates of Actinobacillus pleuropneumoniae, Pasteurella multocida, and Escherichia coli were isolated from sick pigs from 2019 to 2022. Antimicrobial susceptibility test was determined by minimal inhibitory concentration (MIC) following internationally accepted methodology. MIC categorization was based on distributing the range of MIC values in four categories being category one the most susceptible (lowest MIC value) and four the less susceptible one (highest MIC value). Moreover, clinical susceptibility (susceptible/resistant) was also determined according to CLSI and EUCAST clinical breakpoints. A logistic and multinomial logistic regression model was used to analyze the susceptibility data for dichotomized and categorized MIC data, respectively for any pair of antimicrobial/microorganism. In general terms, the antimicrobial susceptibility of pig bacteria to these antimicrobials remained stable or increased in the last four years in Spain. In the case of A. pleuropneumoniae and quinolones, it was observed a significant temporal trend where isolates from 2020 had significantly increased odds of being more susceptible than isolates from 2019. In the case of E. coli and polymyxins, a significant temporal trend was observed where isolates from 2020 and 2021 had significantly increased odds of being more susceptible than isolates from 2019 and 2020, respectively. Finally, a significant odd of being less susceptible was only observed for cephalosporins and E. coli for 2020 versus 2019, stagnating for the rest of study period. These results provide sound data on critical important antimicrobials in swine medicine.

Respiratory syncytial virus (RSV) is a common respiratory virus that can cause mild to severe illness in people of all ages. The most common symptoms of an RSV infection are cough, runny nose, and fever. However, RSV can also cause more serious complications, such as tracheobronchitis, bronchiolitis, pneumonia, and apnea. RSV is especially dangerous for infants, young children, and older adults. RSV is a seasonal virus, with peak incidence in the winter months. The virus spreads through respiratory droplets produced when an infected person coughs or sneezes. The virus can also be spread through contact with contaminated surfaces. Treatment is aimed at relieving symptoms and preventing complications. This review will provide an overview of the medical significance, virology, pathogenesis, immunity, epidemiology, symptoms, risk factors, and complications associated with RSV, and the diagnosis and management of RSV infections.

The history of saline nasal irrigation (SNI) is indeed a long one, beginning from the ancient Ayurvedic practices and starting to gain a foothold in the west at the beginning of 20th century. Today, there is a growing number of papers covering effects of SNI from in vitro studies to randomized clinical trials and literature overviews. Based on the recommendations of most of the European and American professional associations, seawater, alone or in combination with other preparations, has its place in treatment of numerous conditions of the upper respiratory tract (URT), primarily in chronic (rhino)sinusitis, allergic rhinitis, acute URT infections and postoperative recovery. Additionally, taking into account its multiple mechanisms of action and mounting evidence from recent studies, locally applied seawater preparations may have an important role in prevention of viral and bacterial infections of the URT. Therefore, in this review we discuss results published in the past years focused on the seawater preparations and their use in clinical and everyday conditions, since such products are superior to saline, have an excellent safety profile and are recommended by most professional associations in the field of otorhinolaryngology.

Life cycle assessment (LCA) is being included formally in EcoDesign regulations. Especially product carbon footprint will be mandatory in Europe. However, life cycle impact assessment including global warming potential (GWP) in LCA is hampered by several challenges. One of these is lack of water vapor characterization indexes for GWP. A life cycle inventory profile for air transport fuel including water vapor emissions is evaluated with state-of-the-art practice, i.e. EF Method and ILCD 2011 Midpoint+ and neglecting water vapors high altitude GWP compared to carbon dioxide. Then the characterization factor in GWP100 for water vapor and alternate normalization for particulates are introduced. The results are compared. The main findings are that the EF method and ILCD both generate rather realistic results for Particulate Matter and Respiratory Inorganics mid-point indicators, respectively, but the amount of premature deaths should be better allocated to different specific emissions, and that water vapor may dominate the GWP100 result over the usual carbon dioxide. LCIA mid-points need measurable and understandable bases. The common knowledge of water vapor’s GWP100 should not be neglected in LCIA for air transport and beyond where relevant.

Bovine respiratory disease is still a major concern in feedlots and has major economic impact. Another consequence of respiratory infections is the use of antimicrobial molecules to control bacterial pathogens. This can participate to the emergence and shedding of antimicrobial re-sistance that can threaten animal as well as human health. Appeasing pheromones with their capacity to reduce stress and thus their ability to preserve the functions of the immune system have been proposed to reduce the use of antimicrobial substances. In the current report we as-sessed the effect of appeasing pheromone administration on bovine health and performance during the fattening period. Zootechnical and health parameters as well as whole blood immune transcript expressions were measured over weeks in young bulls to determine the effect of the pheromone. We observed a reduction of clinical signs at day 30 in young bulls who received the pheromone and a higher expression of interleukin 8 transcripts in this group than in the control group. Our results are in line with previous reports in bovine and other mammals and ask for further studies to shed more light on the beneficial impact of appeasing pheromones and to de-cipher their exact mechanisms of action.

There are limited proven therapies for the treatment of COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects, make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19, supporting anti-inflammatory treatment. This literature review focuses on vitamin C deficiency in respiratory infections including COVID-19; the mechanism of action in infectious disease and adrenal function supporting the anti-inflammatory actions of glucocorticosteroids: its role in preventing and treating colds and pneumonia and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8g/d) may reduce incidence and duration of respiratory infections and intravenous vitamin C (2-24g/d) has been shown to reduce mortality, Intensive Care Unit and hospital stays, time on mechanical ventilation in severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and frequency of vitamin C deficiency in respiratory infections it may be worthwhile testing patients’ vitamin C status and treating accordingly with intravenous use within ICUs and orally with doses between 2 and 8g/day in hospitalised and infected persons.

The current Covid-19 pandemic has hugely disrupted the delivery of routine and established medical care. Patients can develop a wide range of clinical signs and symptoms from a cough and fever to severe respiratory failure. There is an ongoing argument on a concise investigative pathway to ensure the safety of all healthcare workers. The stethoscope can help with any clinical respiratory assessment but the risk of cross infection is high. Computer tomography should not be routinely performed. There is a potential place for lung ultrasound but outcomes are not yet determined.

Background: Generative artificial intelligence (Gen-AI) has emerged as a transformative tool in research and education. However, there is a mixed perception about its use. This study assessed the use, perception, prospect, and challenges of Gen-AI use in higher education. Methods: This is a prospective, cross-sectional survey of university students in the United Kingdom (UK) distributed online between January and April 2024. Demography and perception of Gen-AI and other AI tools were assessed and statistically analysed to assess the difference in perception between various subgroups. Results: A total of 136 students responded to the survey of which 59% (80) were male. The majority were aware of Gen-AI and other AI use in academia (61%) with 52% having personal experience of the tools. Grammar correction and idea generation were the two most common tasks of use, with 37% being regular users. Fifty-six percent of respondents agreed that AI gives an academic edge with 40% holding a positive overall perception about the use in academia. Comparatively, there was a statistically significant difference in overall perception between different age ranges (I² = 27.39; p = 0.002) and levels of education (I² = 20.07; p < 0.001). Also, 83% of students believe AI use will increase in academia with over half agreeing it should be integrated into learning. Plagiarism (33%), privacy issues (14%), and lack of clarity by the university (13%) remain the top concerns regarding the use of Gen-AI and other AI tools in academia. Conclusions: Gen-AI and other AI tools are being used and their use will continue to grow in higher education. While current use is challenging due mainly to plagiarism fear and lack of clarity by the university, most users believe AI should be integrated into the university curriculum.

Extracorporeal membrane oxygenation (ECMO) support for respiratory failure in the intensive care unit continues to have an expanded role in select patients. While acute respiratory distress syndrome remains the most common indication, ECMO may be used in other causes of refractory hypoxemia and/or hypercapnia. The most common configuration is veno-venous (V-V) ECMO, however in specific cases of refractory hypoxemia or right ventricular failure, some patients may benefit from veno-pulmonary (V-P) ECMO or veno-venoarterial (V-VA) ECMO. Patient selection and extracorporeal circuit management are essential to successful outcomes. This narrative review explores the physiology of ECMO, indications and contraindications, ventilator management, extracorporeal circuit management, troubleshooting hypoxemia, complications, and ECMO weaning in patients with respiratory failure. As the footprint of ECMO continues to expand it is essential that clinicians understand the underlying physiology and management of these complex patients.

Recurrent respiratory papillomatosis (RRP) is a non- malignant disease, characterized by the production of wart-like growths in respiratory tract, affecting both young and adults (Juvenile-Onset Recurrent Respiratory Papillomatosis, JORRP and Adult-Onset Recurrent Respiratory Papillomatosis, AORRP, respectively). Infection caused by Human Papillomavirus (HPV) is known as the main factors involved in RRP development. Complications of RRP may rarely occur, including lung involvement and malignant transformation. The present systematic review was aimed to evaluate the prevalence of severe complications, as lung involvement and lung tumor in JORRP and AORRP patients, following the guideline for reporting systematic reviews and meta-analysis (PRISMA Statement). Among the 378 studies were found on PubMed and Scopus using the following MESH terms “recurrent respiratory papillomatosis and lung tumor” and “pulmonary tumor and recurrent respiratory papillomatosis”. Basing on inclusion and exclusion criteria, a total of 11 studies were included in the systematic review. We found a pooled prevalence of 8% (95% CI:4%-14%; I2: 87.5%) for lung involvement in RRP patients. In addition, we found a pooled risk difference of 5% in lung involvement between JORRP and AORRP (95% CI: -7%-18%; I2 :85.6%, p-value: 0.41). Among patients with lung involvement, we observed a pooled prevalence of lung tumor of 4% (95% CI:1%- 7%; I2: 67.1%), and a pooled prevalence mortality for this group of 4% (95% CI:2%-6%; I2: 0%). Overall, the positivity rate for HPV-6 and -11 in patients with RRP was 91%. Considering only cases with pulmonary involvement, the pooled prevalence for HPV 11 was 21% (95% CI: 5%-45%; I2: 77.2%). Our results evidenced a low/middle risk of pulmonary involvement and lung tumor in JORRP and AORRP patients, with an increased risk for HPV-11 positive patients. Further studies should be performed to improve knowledge and adopt preventive measures to contrast the progression to severe diseases in RRP patients.

A Pediatric Sleep Questionnaire (PSQ) and a recording of the respiratory parameters with a noc-turnal home cardiorespiratory polygraphy (PG) are necessary to diagnose OSAS. Few researchers have studied how obesity could influence the respiratory parameters in OSAS children. The aim of the study was to investigate how obesity can influence sleep respiratory parameters in OSAS children. Methods: The study analyzes 56 Caucasian children and adolescents aged 11 ± 2.79 years with a BMI> 5th percentiles and PSQ value of 0.33. Children were divided into the Obesity Group (OG) with a BMI of  95th and the Control Group (CG) with a 5th<BMI> 95th percentile. All selected children underwent PG. Respiratory parameters were extracted to divide into levels of severity OSAS: snoring, mild, moderate, and severe. Results: The comparison analysis of AHI, SaO2, and Nadir between the OG and CG showed a statistical significance only for ODI (p = 0.02). The comparison analysis of PSQ between the OG and CG and of PSQ and respiratory parameters showed no significant result. A statistically significant correlation between BMI and AHI (r2=0.01), SaO2 (r2=0.09), and Nadir O2 (r2=0.00) was found. Conclusion: There was no strong correlation between Obesity and OSAS, but it was found between BMI increasing and AHI severity

Understanding microbial composition in upper respiratory infections (URIs) is critical for effective diagnosis and treatment. Precision Metagenomic next-generation sequencing p(mNGS) can provide a comprehensive yet clinically relevant profile of respiratory infection. The hybridization capture-based targeted sequencing generated a precision metagenomics profile of 29 patients with acute URIs. Nasopharyngeal samples were collected from the subjects suspected of respiratory infection, and p(mNGS) was performed using the Illumina®/IDbyDNA Respiratory Pathogen ID/AMR Panel (RPIP). The dataset obtained from the mNGS analysis contains a wealth of information on the composition of acute URI microbiota, including the relative abundance of known pathogens and potential clinical implications. The dataset represents a valuable resource for future research endeavors in respiratory medicine, infectious disease epidemiology, and therapeutic interventions. In addition, the dataset offers significant potential for reuse and integration with other omics datasets. The comprehensive nature of the mNGS data allows the exploration of associations between the respiratory microbiota and host factors such as clinical outcomes, immune responses, or genetic predisposition. Combining this dataset with other relevant datasets, such as transcriptomics or metabolomics, could provide a deeper understanding of the complex interactions between the microbiota and the host in acute URIs.

Nasal cavity is a primary checkpoint for the invasion of several respiratory pathogens. Numerous pathogens including SARS-CoV-2, S. pneumonia, S. aureus, etc., adhere to the nasal epithelium or mucus to invade and trigger an infection. IgA serves as the first line of defense against foreign antigens and pathogens. They exhibit cross-reactivity against a diverse variety of antigens through immune exclusion, which intercepts the invasion of pathogens through the mucosal lining. Advances in intranasal immunization technology underscore the elevated neutralizing IgA levels at local and distal mucosa in contrast to the parenteral vaccines. This review highlights the adjuvants that induce IgA class switching and the challenges of maintaining nominal IgA levels at the mucosal surface. Finally, the review features the paradigm-shifting of conventional immunization techniques to IgA-inducing vaccines to enhance protection against homologous and heterologous pathogens.

Some COVID-19 patients develop interstitial pneumonia that can evolve into Acute Respiratory Distress Syndrome (ARDS). This is accompanied by an inflammatory cytokine storm. SarS-CoV has proteins capable of promoting cytokine storm, especially in patients with comorbidities, including obesity. Since there is currently no resolutive therapy for ARDS and given the scientific literature regarding the use of adenosine, its application has been hypothesized. Adenosine through its receptors is able to inhibit the acute inflammatory process, increase the protection capacity of the epithelial barrier and reduce the damage due to an overactivation of the immune system, such as in cytokine storms. These features are known in ischemia / reperfusion models and could also be exploited in acute lung injury, with hypoxia. In light of these hypotheses, for compassionate use, a COVID-19 patient, with unresponsive respiratory failure, was treated with adenosine. The results showed a rapid and clear improvement in clinical conditions, with the negative effect of detection of SarS-CoV2.

Severe acute respiratory infection (SARI) is mainly caused by viral pathogens, with a high prevalence in high-risk populations such as infants and older adults. Co-infections by different viruses are frequent and, in some cases, associated with severe disease outcomes. Purpose: The main purpose of this study was to identify respiratory viruses circulating in Barranquilla during the COVID-19 pandemic peaks and estimate the prevalence of viral co-infections in samples from individuals with different degrees of respiratory infection. Methods: Between August and October 2021, 101 samples were collected from individuals with influenza-like illness (ILI) by the District Health Laboratory of Barranquilla and four local health care institutions and analyzed at Universidad Simón Bolívar. Eighteen respiratory viruses, including SARS-CoV-2, were analyzed via qRT-PCR using nasal swabs or nasopharyngeal aspirate samples. Results: Of the 101 study individuals, 56 were male and 45 were female (55.5% and 44.5%, respectively); 25.7% of individuals were infected with at least one of the evaluated viruses. Respiratory syncytial virus (RSV) and human rhinovirus (HRV) were the two most frequently detected viruses (30.7% and 15.4% of total positives, respectively). Co-infections with two or more respiratory viruses accounted for 42% of the total positive cases. Conclusion: Our findings indicate the presence of different respiratory viruses in swab or nasopharyngeal aspirate samples from individuals with ILI, including coinfection. These results reveal the circulation of several respiratory viruses in the city of Barranquilla, confirming their importance as potential causes of SARI in Colombia and the need for their active surveillance.

Leishmaniasis is a neglected tropical disease and affects more than 350 million people worldwide. However, there are no vaccines for humans, and current treatment is hampered due to its high cost, numerous side effects, and painful administration routes. Ending its epidemics by 2030 has become a United Nations goal, and the multitarget drug strategy emerges as a promising alternative. Flavonoids are an example of multitarget compounds and organic synthesis represents a tool to obtain high yields of these molecules. In our study, we synthesized 17 flavonoid analogs using a scalable, easy-to-reproduce, and inexpensive method. All compounds demonstrated an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b stood out as effective against all isoforms and intermolecular interactions were investigated through a molecular modeling study. The compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. The results were pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Furthermore, compounds have shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

Objective: To determine if higher weight-to-length z-scores after 32 weeks of gestation are associated with higher Pulmonary Scores (PS) in preterm infants requiring respiratory support using a prospective observational study. Methods: Infants born <30 weeks, with a post-menstrual age (PMA) of 30-33 weeks were enrolled. Weight, infant’s length, and head circumference were measured weekly. Data on calories/kg/d, protein g/kg/d, weight for length percentiles, z-scores, and BMI at 33 through 40 weeks PMA were collected. PS was calculated. Results: We analyzed 91 infants. The mean gestational age was 26.9 ± 1.7 weeks. There was a significant association between PS and W/L z scores(p<0.0001). For every one-unit increase in W/L z-scores, PS increased by 0.063. There was a significant association between PS and W/L percentiles (p = 0.0017) as well as BMI (p = <0.0001). For every unit increase in W/L percentiles, PS increased by 0.002, and for a unit increase in BMI, PS increased by 0.04. The association remained significant after postnatal steroids, sex, corrected, and birth gestational ages were included in the regression analysis. Nutrition did not affect anthropometric measurements. Conclusion: Our study is the first to demonstrate that higher BMI and W/L may adversely affect respiratory severity in infants.

Respiratory viral infections, including influenza, respiratory syncytial virus (RSV), and, more recently, the coronavirus disease 2019 (COVID-19) pandemic, continue to pose significant global health threats. Conventional treatments for these infections often face challenges such as limited efficacy, the emergence of drug-resistant strains, and the requirement for frequent administration. In recent years, nanobodies have emerged as a promising class of therapeutic agents due to their unique properties, including small size, high stability, and specific binding capabilities. This mini-review article focuses on the application of nanobodies as spray and aerosol particles for the treatment of respiratory viral infections. Furthermore, we highlight the remarkable efficacy of nanobodies in preclinical and clinical studies against respiratory viruses, including their ability to neutralize viral particles, inhibit viral replication, and modulate the host immune response. We discuss the potential advantages of using nanobodies as inhalable formulations, including their improved delivery to the respiratory tract, enhanced stability in aerosol form, and reduced systemic side effects. Additionally, we explore the various strategies employed to engineer nanobodies for optimal aerosol delivery, such as conjugation to carrier particles or formulation as dry powders. We also examine the potential challenges and limitations associated with the development of nanobody-based aerosol therapies, including production scalability, cost-effectiveness, and regulatory considerations.

Background and Objectives: Intramedullary spinal cord tumors (IMSCT) are rare entities. Especially, a location in the upper cervical spine as a highly eloquent region carries the risk of postoperative neurological deficits, such as tetraparesis or respiratory dysfunction. Evidence for respiratory dysfunction is scarce. The aim of this study was to describe the early and late postoperative clinical course of this highly eloquent tumours. Patients and Methods: This is a single-centre retrospective cohort study. We included 35 patients with IMSCT at levels of craniocervical junction to C4 who underwent surgical treatment between January 2008 and December 2022. The authors analysed the patients' preoperative status, tumour- and surgery-specific characteristics, and follow-up functional status. Results: The study cohort included 22 patients with grade II ependymoma (62.9%), 2 low-grade astrocytomas (5.7%), 2 glioblastomas (5.7%), 6 hemangioblastomas (17.1%), 2 metastases (5.7%), and 1 patient with partially intramedullary schwannoma (2.9%). Gross total resection was achieved in 76% of patients. Early dorsal column related symptoms and motor deterioration occurred in 64% and 44% of patients, respectively. At a follow-up of 3.27 ± 3.83 years, 43% and 33% of patients preserved postoperative sensory and motor deterioration, respectively. The median McCormick Scale grade was 2 in the preoperative and late postoperative periods, respectively (p=0.0897, α=0.05). Only two out of 35 patients (5.7%) developed new intermittent respiratory dysfunction, of whom two were transient. There were no surgery-related deaths. Conclusions: The surgery of IMSCT of the upper cervical spine could be performed without major procedure-related risk. Roughly a half of the patients develop new neurological deficit in the immediate postoperative period. However, most of the patients still maintain functional independence. The rate of respiratory insufficiency is low and is strongly influenced by the rapid neurological deterioration in high-grade tumours.

We aimed to provide a comprehensive assessment of exercise physiology of adult Fontan patients (FP) and factors limiting functional capacity (FC). A prospective single-centre study of 37 FP aged ≥16years and 19 healthy-controls (HC), who underwent CPET on cycle-ergometer in February-March 2022. Lung function was impaired in FP, mostly mild restrictive pattern (56.8%). Mean peakVO2 was 21±5.4ml/kg/min, 55% predicted. Morphologically left-single ventricle showed higher peakVO2%predicted (57.4±14.4% vs 43.4±8.1%, p=0.045). A lower peakVO2%predicted was observed in patients with an early flattened and/or descending O2 pulse at maximal exertion (52±14% vs 62±12.5, p=0.04 and 47.6±9% vs 60±14 respectively, p=0.018) and chronotropic insufficiency (53±12% vs 69.8±20%, p=0.008). Strong positive correlation was observed between %OUES and peakVO2%predicted (r=0.726, p>0.001). PeakVO2%predicted was progressively higher as the level of physical activity increased (low-level 49.5±14%, moderate-level 55±12%, intense-level 69±20%). FP showed lower inspiratory muscle strength compared to HC but it was no statistically associated with either peakVO2 or VE/VCO2 slope. In FP OUES is a useful submaximal parameter in those who fail to reach maximal exertion. Chronotropic insufficiency and early flattened or descending oxygen pulse slope were factors associated with low peakVO2. Regular intense physical activity improves FC. Although FP have inspiratory muscle weakness, its impact on FC is unclear.

Aim: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been in the past associated with adverse effects on human health among which belong also respiratory diseases. Our study is focused on the evaluation of PAH exposure by measuring the concentrations of their monohydroxylated metabolites (OH-PAHs) in urine and comparing their concentrations with the incidence of respiratory diseases in 2-year-old children from two locations of the Czech Republic – a control locality Ceske Budejovice and a previously highly contaminated mining district Most. Methods: The total number of 248 participants were sampled for urine samples that were analysed for the presence of 11 OH-PAHs using liquid-liquid extraction with ethyl acetate and clean-up employing dispersive solid phase extraction with a sorbent Z-Sep. Separation, identification and quantification of the target compounds was achieved by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The incidence of respiratory diseases was evaluated according to the questionnaires provided by the paediatricians. Results and discussion: The concentrations of measured OH-PAHs were higher in the urine samples collected from 2-year-old children living in Most compared to 2-year-old children from Ceske Budejovice. The same trend was observed also when the urine samples were analysed when these children were studied as newborns in our previous study. From all of the monitored respiratory diseases, only influenza due to unidentified influenza virus showed a difference between tested locations where the 2-year-old children living in Most were more frequently diagnosed with this disease. Conclusion: Even though the air pollution and lifestyle in both cities is very similar, we have observed higher incidence of respiratory diseases as well as higher concentration of OH-PAHs in urine of the 2-year-old children from Most. Therefore, we hypothesize that the population living in this previously highly contaminated location (in 1970s and 1980s) can carry some long-term health burden.

A short review of the important studies was conducted to evaluate the potential of aerosol transmission of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The minimum size of droplets potentially carrying the SARS-CoV-2 was newly estimated and discussed in this review.

Mutations in epidermal growth factor receptor (EGFR) occur in about 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) have been developed, targeting EGFR activity. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. These models are particularly effective in identifying optimal responders to specific treatments, thereby enhancing therapeutic efficacy. We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, representing two distinct generations of EGFR TKIs, to accurately simulate the drugs’ distribution within the primary tumor and metastatic sites following oral administration. These models were integrated with a pathophysiological mechanistic model of EGFR-mutant LUAD, enabling the representation of the effects of both gefitinib and osimertinib on EGFR activation-induced signaling pathways. This comprehensive model outputs detailed evolutions of the primary tumor and each metastatic site, facilitating the evaluation of patient progression in alignment with RECIST guidelines (version 1.1). Notably, the model encapsulates the heterogeneity within the tumor, through the representation of various subclones, each characterized by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002 and FLAURA clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. The model adeptly replicated the time to progression observed in real clinical trials in EGFR-mutant LUAD patients receiving gefitinib or osimertinib as first-line therapy. In addition, the model was able to reproduce the results from a retrospective study comparing gefitinib and osimertinib, a study that was not used to inform the model. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a vital investigational tool for deriving pertinent insights and informing treatment strategies, particularly in identifying optimal responders to various generations of EGFR TKIs. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the required patient cohort size in such trials, optimizing resource utilization.

Asthma is a significant public health concern. This study identified the provinces with the highest morbidity and mortality rates due to asthma among the working-age population (15-69 years) in the Republic of Ecuador. The secondary objective was to explain the possible differences attribut-able to occupational exposure. This nationwide ecological and exploratory study was conducted in 24 provinces between 2016 and 2019. Government databases were used as sources of infor-mation. Standardized rates were calculated for codes the J45 and J46. The hospitalization mor-bidity rate for asthma decreased from 6.51 to 5.76 cases per 100,000 working-age population, and the mortality rate has consistently been low and stable from 0.14 to 0.15 deaths per 100,000 working-age population. Geographic differences between the provinces were evident. The risk of hospitalization and death due to asthma was higher in the Pacific coast (five provinces) and the Andean region (two provinces). The high rates observed in provinces with greater agricultural and industrial development could be the main determinants of national heterogeneity and could act as occupational risk factors. The contribution of occupational hazards in each province should be examined in depth through ad hoc studies. These findings provide valuable information for creating public policies aimed at promoting and safeguarding the respiratory health of the popu-lation, particularly that of workers.

Background: The newly introduced COVID-19 vaccines have reduced disease severity and hospitalizations. However, they do not significantly prevent infection or transmission. In the same context, measuring IgM and IgG antibody levels is important, but it doesn't provide information about the status of the mucosal immune response. This article describes a comprehensive mapping of IgA epitopes of the S protein, its cross-reactivity, and the development of an ELISA-peptide assay. Methods: IgA epitope mapping was conducted using Spot-synthesis and sera from RT-qPCR COVID-19-positive patients. Specific and cross-reacting epitopes were identified, and an evolutionary analysis from the early Wuhan strain to the Omicron variant was performed using bioinformatics tools and a microarray of peptides. The selected epitopes were chemically synthesized and evaluated using ELISA-IgA. Results: 40 IgA epitopes were identified, with 23 in S1 and 17 in the S2 subunit. Among these, at least 23 epitopes showed cross-reactivity with DENV and other organisms and 24 with other associated coronaviruses. Three MAP4 polypeptides were validated by ELISA, demonstrating a sensitivity of 90-99.96% and a specificity of 100%. Among the six IgA-RBD epitopes, only the SC/18 epitope of the Omicron variants (BA.2 and BA.2.12.1) presented a single IgA epitope. Conclusions: This research unveiled the IgA epitome of the S protein and identified many epitopes that exhibit cross-reactivity with DENV and other coronaviruses. The S protein of variants from Wuhan to Omicron retains many conserved IgA epitopes, except for one epitope (#SCov/18). The cross-reactivity with DENV suggests limitations in using the whole S protein or the S1/S2/RBD segment for IgA serological diagnostic tests for COVID-19. The expression of these identified specific epitopes as diagnostic biomarkers could facilitate monitoring mucosal immunity to COVID-19, potentially leading to more accurate diagnoses and alternative mucosal vaccines.

Ever since the discovery of dendritic cells by Ralph Steinman and Zanvil Cohn in 1973, it is increasingly evident that dendritic cells are integral for adaptive immune responses, and there is an undeniable focus on them for vaccines development. Fungal infections, often thought in-nocuous, are becoming significant threats due to increased immunocompromised or im-mune-suppressed population and climate change. Further, the recent COVID-19 pandemic unraveled the wrath of fungal infections and devastating outcomes. Invasive fungal infections cause significant case fatality rates ranging from 20% to 90%. Regrettably, no licensed fungal vaccines exist, and there is an urgent need for preventive and therapeutic purposes. In this re-view, we discuss the ontogeny, subsets, tissue distribution, and functions of lung dendritic cells. In the latter part, we summarize and discuss the studies on the DC-based vaccines against pulmonary fungal infections. Finally, we highlight some emerging potential avenues that can be incorporated for DC-based vaccines against fungal infections.

Respiratory infections are usually characterized by mucus hypersecretion. This condition may worsen and prolong symptoms and signs. Mucoactive agents include different molecules with different mechanisms of action. Sobrerol is a monoterpene able to fluidify mucus, increase mucociliary clearance, and exert antioxidant activity. Sobrerol is available in various formulations (granules, syrup, nebulized, and suppository). Sobrerol has been on the market for over 50 years. Several studies investigated its efficacy and safety in acute and chronic respiratory diseases characterized by mucus hyperproduction. Seven pediatric studies have been conducted with favorable outcomes. Recently, regulatory agencies reduced the treatment duration to three days. Therefore, a future study will test the hypothesis that a combination of oral and topical sobrerol could benefit children and adults with frequent respiratory infections. The rationale considers that mucus accumulation could be a risk factor for increased susceptibility to have infections.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and is the leading cause of infection in patients with cystic fibrosis (CF). The ability of P. aeruginosa to evade host responses and develop into chronic infection causes significant morbidity and mortality. Several mouse models have been developed to study chronic respiratory infections induced by P. aeruginosa, with the bead agar model being the most widely used. However, this model has several limitations, including the requirement for surgical procedures and high mortality rates. Herein, we describe novel and adapted biologically relevant models of chronic lung infection caused by P. aeruginosa. Three methods are described, a clinical isolate infection model, utilizing isolates obtained from patients with CF, an incomplete antibiotic clearance model, leading to bacterial bounce-back and the establishment of chronic infection, and an adapted water bottle chronic infection model. These models circumvent the requirement for surgical procedure and importantly, can be induced with clinical isolates of P. aeruginosa and in wild-type mice. We also demonstrate successful induction of chronic infection in the transgenic βENaC murine model of CF. We envisage that the models described will facilitate the investigations of host and microbial factors, and the efficacy of novel antimicrobials, during chronic P. aeruginosa respiratory infections.

The COVID-19 pandemic exposed the vulnerability of current vaccine technologies characterized by a slow onset of action and antigen-specific immune response. Although parental vaccines offer long-term protection against homologous strains, they rely exclusively on adaptive immune memory to produce neutralizing antibodies that are ineffective against new vaccine variants. Moreover, growing evidence highlights the multifaceted functions of trained immunity to elicit a rapid and enhanced innate response against unrelated stimuli or pathogens to subsequent triggers. This review discusses the protective role of trained immunity against respiratory pathogens and the experimental models essential for evaluating novel inducers of trained immunity. We further elaborate on the potential of trained immunity to leverage protection against emerging pathogens via recognition of diverse antigens by pathogen recognition receptors (PPRs) on innate immune cells. We also propose integrating trained- with adaptive- immunity to shape next-generation vaccines by coupling each one's unique characteristics.

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for pre-sent and future pandemics of viral respiratory pathogens. We review the history of causality as-sessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierar-chy of evidence to integrate clinical, epidemiologic, molecular and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Intelligent systems are transforming the world, as well as our healthcare system. We propose a deep learning-based cough sound classification model that can distinguish between children with healthy versus pathological coughs such as asthma, upper respiratory tract infection (URTI), and lower respiratory tract infection (LRTI). In order to train a deep neural network model, we collected a new dataset of cough sounds, labelled with clinician's diagnosis. The chosen model is a bidirectional long-short term memory network (BiLSTM) based on Mel Frequency Cepstral Coefficients (MFCCs) features. The resulting trained model when trained for classifying two classes of coughs -- healthy or pathology (in general or belonging to a specific respiratory pathology), reaches accuracy exceeding 84\% when classifying cough to the label provided by the physicians' diagnosis. In order to classify subject's respiratory pathology condition, results of multiple cough epochs per subject were combined. The resulting prediction accuracy exceeds 91\% for all three respiratory pathologies. However, when the model is trained to classify and discriminate among the four classes of coughs, overall accuracy dropped: one class of pathological coughs are often misclassified as other. However, if one consider the healthy cough classified as healthy and pathological cough classified to have some kind of pathologies, then the overall accuracy of four class model is above 84\%. A longitudinal study of MFCC feature space when comparing pathologicial and recovered coughs collected from the same subjects revealed the fact that pathological cough irrespective of the underlying conditions occupy the same feature space making it harder to differentiate only using MFCC features.

Background: Natural environment inhalation topography provides useful information for toxicant exposure, risk assessment and cardiopulmonary performance. Commercially available Wearable Respiratory Monitors (WRM), which are currently used to measure a variety of physiological parameters such as heart rate and breathing frequency, can be leveraged to obtain inhalation topography, yet little work has been done. This paper assesses the feasibility of adapting these WRMs for measuring inhalation topography. Methods: Commercially available WRMs were compiled and assessed for the ability to report chest motion, data analysis software features, ambulatory observation capabilities, participant acceptability, purchasing constraints and affordability. Results: The following WRMs were found: LifeShirt, Equivital EQ02 LifeMonitor, Smartex WWS, Hexoskin Smart Garment, Zephyr BioHarness, Nox T3&amp;A1, BioRadio, SleepSense Inductance Band, and ezRIP &amp; zRIP Durabelt. None of the WRMs satisfied all six assessment criteria in a manner enabling them to be used for inhalation topography without modification and development. Conclusion: The results indicate that there are WRMs with core technologies and characteristics that can be built upon for ambulatory inhalation topography measurement in the NE.

Purpose: To assess the clinical safety and possible effectiveness of Vasoactive Intestinal Peptide in the treatment of Acute Respiratory Distress Syndrome (ARDS) related to sepsis. Methods: Under FDA Investigational New Drug clearance, 8 patients with ARDS related to sepsis were treated with 50 pmole/kg/hr – 100 pmole/kg/hr of Vasoactive Intestinal Peptide by intravenous infusion for 12 hours. All patients were on mechanical ventilation and full telemetery. Results: No drug-related serious adverse events were seen. Hypotension was seen in association with two infusions and diarrhea in association with one, but did not necessitate cessation of therapy. Bigeminy was seen in association with one infusion without sequelae. Seven of eight patients demonstrated a successful course during intensive care and were successfully removed from mechanical ventilation and discharged from intensive care. The eighth patient succumbed to purulent secretions in the lungs. Of those who were discharged from the ICU, six demonstrated successful 30 day survival. The seventh died from a cerebral infract at day 30, deemed unrelated to treatment with VIP. Serum levels of Tumor Necrosis Factor α were obtained in 6 patients at baseline and 24 hours and were seen to decrease with treatment in five patients. Conclusions: Initial clinical results of treatment with VIP in patients with ARDS demonstrated a safety profile consistent with previous studies in normal volunteers. The successful clinical course seen in 7 of 8 patients in the setting of an expected 50% survival may suggest that VIP shows promise in the treatment of other infectious conditions that damage the pulmonary epithelium, particularly COVID-19.

With the emergence of COVID-19 we are confronted with a new clinical picture of acute respiratory distress syndrome in the intensive care unit. In the majority of patients, the respiratory mechanics are very different from the “normal” ARDS patient. We measured transpulmonary pressure and dead space ventilation to assess the effects of high and low PEEP levels on lung compliance and ventilation-perfusion mismatching. Advanced respiratory mechanics were assessed in 14 patients. Compared to ARDS patients, lung compliance was relatively high (61 ± 5 mL/cmH₂O). COVID-19 patients had high dead space ventilation and gas exchange impairment (Bohr 52 ± 3%; Enghoff modification 67 ± 2%; ventilatory ratio 2.24 ± 0.23). we show that higher PEEP levels decrease lung compliance and in most cases increase dead space ventilation, indicating that high PEEP levels probably cause hyperinflation in patients with COVID-19. We suggest using prone position for an extended period of time, and apply lower PEEP levels as much as possible.