Amphibian skin bacteria display antifungal activity and induce plant defense mechanisms against Botrytis cinerea.

Botrytis cinerea is the causal agent of gray mold, which affects a wide variety of plant species. Chemical agents have been used to prevent the disease caused by this pathogenic fungus. However, their toxicity and reduced efficacy have encouraged the development of new biological control alternatives. Recent studies have shown that bacteria isolated from amphibian skin display antifungal activity against plant pathogens. However, the mechanisms by which these bacteria act to reduce the effects of B. cinerea are still unclear. From a diverse collection of amphibian skin bacteria, three proved effective in inhibiting the development of B. cinerea under in vitro conditions. Additionally, the individual application of each bacterium on the model plant Arabidopsis thaliana, Solanum lycopersicum and post-harvest blueberries significantly reduced the disease caused by B. cinerea. To understand the effect of bacteria on the host plant, we analyzed the transcriptomic profile of A. thaliana in the presence of the bacterium C32I and the fungus B. cinerea, revealing transcriptional regulation of defense-related hormonal pathways. Our study shows that bacteria from the amphibian skin can counteract the activity of B. cinerea by regulating the plant transcriptional responses.

Facilitadores y barreras para el uso de la práctica basada en evidencia / Facilitators and barriers to the use of evidence-based practice / Facilitadores e barreiras ao uso de práticas baseadas em evidências

Objetivo: Conocer los facilitadores y barreras para el uso de la práctica basada en evidencia (PBE) en profesionales de enfermería que laboran en el área clínica. Método: Estudio cuali-tativo de tipo exploratorio descriptivo, con análisis de discurso, se realizaron 6 grupos focales conformados por 3 a 7 participantes para un total de 32 personas, se utilizó un muestreo inten-cional; en promedio fueron grabados entre 60 a 90 minutos por grupo focal. Para el análisis se empleó la fragmentación, codificación y categorización de las entrevistas obteniendo categorías temáticas, subcategorías y códigos a partir del uso del programa Atlas Ti versión 8. Resultados: El 69 % de los entrevistados respondió que el pregrado o posgrado habían recibido algún tipo de formación en PBE, la principal fuente de información cuando tienen alguna duda en la práctica clínica son los protocolos institucionales o los compañeros con más experiencia. Los facilitado-res identificados en este estudio fueron: tiempo para investigar, formación en PBE, iniciativa, grupos de investigación y compañeros; las barreras fueron: falta de apoyo institucional, poca formación en PBE, falta de tiempo, idioma, desmotivación profesional y el rechazo frente al cambio. Conclusiones: Se describen los facilitadores y barreras que presentan los profesionales de enfermería que laboran en el área clínica. Sin embargo se requieren investigaciones adicion-ales que permitan reconocer el fenómeno desde otras perspectivas en el contexto Colombiano y latinoamericano

Objective: To find out the facilitators and barriers to the use of evidence-based practice (EBP) in nursing professionals working in the clinical area. Method: Qualitative descrip-tive exploratory study, with discourse analysis, 6 focus groups were carried out with 3 to 7 participants for a total of 32, a purposive sampling was used; an average of 60 to 90 minutes were recorded per focus group. For the analysis we used the fragmentation, coding and cate-gorisation of the interviews obtaining thematic categories, subcategories and codes from the use of Atlas Ti version 8. Results: 69 % of the interviewees responded that the undergraduate or postgraduate had received some kind of training in EBP, the main source of information when they have any doubt in clinical practice are the institutional protocols or colleagues with more experience. Facilitators identified in this study were: time to investigate, training in EBP, initiative, research groups and peers; barriers were: lack of institutional support, little training in EBP, lack of time, language, professional demotivation and rejection in the face of change. Conclusions: The facilitators and barriers presented by nursing professionals working in the clinical area are described. However, further research is needed to recognise the phenomenon from other perspectives in the Colombian and Latin American context.

Objetivo: Descobrir os facilitadores e as barreiras ao uso da prática baseada em evidências (PBE) em profissionais de enfermagem que atuam na área clínica. Método: Estudo exploratório descritivo qualitativo, com análise de discurso; foram realizados 6 grupos focais com 3 a 7 participantes, totalizando 32; foi usada uma amostragem intencional; foi registrada uma média de 60 a 90 minutos por grupo focal. Para a análise utilizou-se a fragmentação, codificação e categorização das entrevistas obtendo-se categorias temáticas, subcategorias e códigos a partir da utilização do Atlas Ti versão 8. Resultados: 69% dos entrevistados responderam que a grad-uação ou pós-graduação havia recebido algum tipo de treinamento em PBE, a principal fonte de informação quando têm alguma dúvida na prática clínica são os protocolos institucionais ou colegas com mais experiência. Os facilitadores identificados neste estudo foram: tempo para in-vestigar, treinamento em PBE, iniciativa, grupos de pesquisa e colegas; as barreiras foram: falta de apoio institucional, pouco treinamento em PBE, falta de tempo, idioma, desmotivação profis-sional e rejeição diante de mudanças. Conclusões: São descritos os facilitadores e as barreiras apresentados pelos profissionais de enfermagem que trabalham na área clínica. No entanto, são necessárias mais pesquisas para reconhecer o fenômeno de outras perspectivas no contexto co-lombiano e latino-americano

Advancements in Home-Based Devices for Detecting Obstructive Sleep Apnea: A Comprehensive Study.

Obstructive Sleep Apnea (OSA) is a respiratory disorder characterized by frequent breathing pauses during sleep. The apnea-hypopnea index is a measure used to assess the severity of sleep apnea and the hourly rate of respiratory events. Despite numerous commercial devices available for apnea diagnosis and early detection, accessibility remains challenging for the general population, leading to lengthy wait times in sleep clinics. Consequently, research on monitoring and predicting OSA has surged. This comprehensive paper reviews devices, emphasizing distinctions among representative apnea devices and technologies for home detection of OSA. The collected articles are analyzed to present a clear discussion. Each article is evaluated according to diagnostic elements, the implemented automation level, and the derived level of evidence and quality rating. The findings indicate that the critical variables for monitoring sleep behavior include oxygen saturation (oximetry), body position, respiratory effort, and respiratory flow. Also, the prevalent trend is the development of level IV devices, measuring one or two signals and supported by prediction software. Noteworthy methods showcasing optimal results involve neural networks, deep learning, and regression modeling, achieving an accuracy of approximately 99%.

Mechanistic Insights on Pd-Catalyzed Three-Component Reactions of Alkynols, Methyl Orthoformate, and Salicylaldehyde Derivatives. Application to the Synthesis of Steroid Chroman Ketals and Spiroketals with Antioxidant Activity.

Contrary to our previous report in which a Pd-catalyzed three-component reaction of a steroid alkynol, trimethyl orthoformate, and salicylaldehyde exclusively produced chroman ketals, the same reaction employing 2,5-dihydroxysalicylaldehyde led to a mixture of a chroman ketal and a spiroketal. Provided that both courses of the reaction imply a 4 + 2 inverse demand cycloaddition between an o-quinone methide and an enol ether, density functional theory calculations revealed that the chroman ketal/spiroketal selectivity is governed by both, the rate of the formation of the o-quinone methide and the isomerization of the initially produced exocyclic enol ether─that led to the spiroketal─to its endocyclic partner that produces the chroman ketal. Remarkably, Lewis catalysis is central to the observed reactivity, and the availability of plausible catalytic species controls the overall chemoselectivity. The methodology herein applied and scrutinized enriches the palette of reactions, leading to increased molecular complexity, as demonstrated in the obtained products, whose antioxidant activity and detailed NMR characterization are presented.

Exploring COX-2 inhibitors in tuberculosis: A whole-blood model approach for immune response and adjunt therapy evaluation.

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.

Serum pro-inflammatory biomarkers associated with improvement in quality of life in pulmonary tuberculosis.

Introduction: Pulmonary dysfunction is an underestimated complication in tuberculosis (TB) infection, affecting quality of life (QoL). Although respiratory function tests objectively reflect lung disturbances in a specific moment, predictors of illness severity at the time of diagnosis are still lacking. Methods: We measured serum pro-inflammatory cytokines (TNF-α and IL-8), eicosanoids (PGE2, LTB4, RvD1, Mar1, and LXA4), a marker of tissue damage (cell-free nucleosomes), and indicators of redox status (malonaldehyde, 8-isoprostane, total oxidants, and antioxidants), as well as a score of radiological abnormalities (SRA) and a QoL questionnaire, in 25 patients with pulmonary TB at the time of diagnosis (t0) and two months after the initiation of treatment (t2). Results: We found higher antioxidant levels in the patients with the worst QoL at t0, and all the indicators of the prooxidant state were significantly reduced at t2, while the total antioxidant levels increased. LTB4, a pro-inflammatory eicosanoid, was diminished at t2, while all the pro-resolutory lipids decreased substantially. Significant correlations between the SRA and the QoL scores were observed, the latter showing a substantial reduction at t2, ranking it as a reliable tool for monitoring disease evolution during TB treatment. Discussion: These results suggest that evaluating a combination of these markers might be a valuable predictor of QoL improvement and a treatment response indicator; in particular, the oxidation metabolites and eicosanoid ratios could also be proposed as a future target for adjuvant therapies to reduce inflammation-associated lung injury in TB disease.

Main Cardiac Histopathologic Alterations in the Acute Phase of Trypanosoma cruzi Infection in a Murine Model.

Symptoms in the acute phase of Chagas disease are usually mild and nonspecific. However, after several years, severe complications like dilated heart failure and even death may arise in the chronic phase. Due to the lack of specific symptoms in the acute phase, the aim of this work was to describe and analyze the cardiac histopathology during this phase in a CD1 mouse model by assessing parasitism, fibrotic damage, and the presence and composition of a cellular infiltrate, to determine its involvement in the pathogenesis of lesions in the cardiac tissue. Our results indicate that the acute phase lasts about 62 days post-infection (dpi). A significant increase in parasitemia was observed since 15 dpi, reaching a maximum at 33 dpi (4.1 × 106). The presence of amastigote nests was observed at 15-62 dpi, with a maximum count of 27 nests at 35 dpi. An infiltrate consisting primarily of macrophages and neutrophils was found in the cardiac tissue within the first 30 days, but the abundance of lymphocytes showed an 8 ≥ fold increase at 40-62 dpi. Unifocal interstitial fibrosis was identified after 9 dpi, which subsequently showed a 16 ≥ fold increase at 40-60 dpi, along with a 50% mortality rate in the model under study. The increased area of fibrotic lesions revealed progression in the extent of fibrosis, mainly at 50-62 dpi. The presence of perivasculitis and thrombus circulation disorders was seen in the last days (62 dpi); finally, cases of myocytolysis were observed at 50 and 62 dpi. These histopathological alterations, combined with collagen deposition, seem to lead to the development of interstitial fibrosis and damage to the cardiac tissue during the acute phase of infection. This study provides a more complete understanding of the patterns of histopathological abnormalities involved in the acute phase, which could help the development of new therapies to aid the preclinical tests of drugs for their application in Chagas disease.

Expression of Proteins, Glycoproteins, and Transcripts in the Guts of Fasting, Fed, and Trypanosoma cruzi-Infected Triatomines: A Systematic Review.

Chagas disease is caused by the hemoflagellate protozoan Trypanosoma cruzi. The main transmission mechanism for the parasite in endemic areas is contact with the feces of an infected triatomine bug. Part of the life cycle of T. cruzi occurs in the digestive tract of triatomines, where vector and parasite engage in a close interaction at a proteomic-molecular level. This interaction triggers replication and differentiation processes in the parasite that can affect its infectivity for the vertebrate host. With the aim of compiling and analyzing information from indexed publications on transcripts, proteins, and glycoproteins in the guts of fasting, fed, and T. cruzi-infected triatomines in the period 2000-2022, a systematic review was conducted following the PRISMA guidelines. Fifty-five original research articles retrieved from PubMed and ScienceDirect were selected; forty-four papers reported 1-26,946 transcripts, and twenty-one studies described 1-2603 peptides/proteins.

Biomodulation of Induced Tooth Movement by Three Methods, Corticopuncture, Photobiomodulation, and Their Combination: An Animal Study.

Objective: The aim of this study was to assess the effects of accelerated tooth movement (ATM) methods: corticopuncture (CP), photobiomodulation (PBM), and their combination (CP + PBM) by evaluating tooth displacement, alveolar bone changes, and molecular and cellular response compared with conventional induced tooth movement. Materials and methods: Tooth movement and bone changes were evaluated on days 1, 3, and 7 (9 animals per time point) using microtomography, histological, and immunohistochemical evaluation, at compression and tension sites. CP groups received two perforations in the palate and one mesial to the molars. PBM was performed using GaAlAs diode laser applied every other day for 7 days (λ = 808 nm, 100 mW) in two points for 15 sec/point and total energy of 3 J. Results: Tooth movement was significantly increased in all three ATM groups after 7 days compared with the control group (mean 0.24 mm) by 27% PBM (0.31 mm), 45% CP (0.35 mm), and 57% CP + PBM (0.38 mm) (p < 0.05). At the compression side, all ATM groups showed significant decrease in bone density on day 3 (p < 0.05) and significant less bone volume on day 7 compared with Control (p < 0.05). At the tension side, PBM group showed a significant increase in bone density and volume on day 3 (p < 0.05). Immunohistochemistry analysis showed that at the compression side, tartrate-resistant acid phosphatase-positive cells, RANKL, and tumor necrosis factor-alpha expression were highly marked of the PBM and the combined method groups (p < 0.05). PBM and CP + PBM groups showed a significant increase in expression Runt-related transcription factor 2 and osterix (p < 0.05) at the tension side. Conclusions: All ATM groups showed increase on tooth displacement with CP + PBM group showing greatest tooth displacement. CP method appears to stimulate bone catabolism, PBM has more effect on bone formation, and the combined method showing a synergistic effect on bone remodeling.

Interim safety and immunogenicity results from an NDV-based COVID-19 vaccine phase I trial in Mexico.

There is still a need for safe, efficient, and low-cost coronavirus disease 2019 (COVID-19) vaccines that can stop transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we evaluated a vaccine candidate based on a live recombinant Newcastle disease virus (NDV) that expresses a stable version of the spike protein in infected cells as well as on the surface of the viral particle (AVX/COVID-12-HEXAPRO, also known as NDV-HXP-S). This vaccine candidate can be grown in embryonated eggs at a low cost, similar to influenza virus vaccines, and it can also be administered intranasally, potentially to induce mucosal immunity. We evaluated this vaccine candidate in prime-boost regimens via intramuscular, intranasal, or intranasal followed by intramuscular routes in an open-label non-randomized non-placebo-controlled phase I clinical trial in Mexico in 91 volunteers. The primary objective of the trial was to assess vaccine safety, and the secondary objective was to determine the immunogenicity of the different vaccine regimens. In the interim analysis reported here, the vaccine was found to be safe, and the higher doses tested were found to be immunogenic when given intramuscularly or intranasally followed by intramuscular administration, providing the basis for further clinical development of the vaccine candidate. The study is registered under ClinicalTrials.gov identifier NCT04871737.

Immunopathological Mechanisms Underlying Cardiac Damage in Chagas Disease.

In Chagas disease, the mechanisms involved in cardiac damage are an active field of study. The factors underlying the evolution of lesions following infection by Trypanosoma cruzi and, in some cases, the persistence of its antigens and the host response, with the ensuing development of clinically observable cardiac damage, are analyzed in this review.

Mendelian Susceptibility to Mycobacterial Disease: Retrospective Clinical and Genetic Study in Mexico.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella, as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1) genes. Interleukin-12Rß1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection.

Parasitemia and Differential Tissue Tropism in Mice Infected with Trypanosoma cruzi Isolates Obtained from Meccus phyllosoma in the State of Oaxaca, Mexico.

Trypanosoma cruzi is a parasite transmitted by the feces of triatomines. Many triatomine species are found in Mexico, and various T. cruzi variants have been isolated from these species, each showing very different virulence and cell tropism. The isolates were obtained from Meccus phyllosoma specimens in three localities in the state of Oaxaca, Mexico: Tehuantitla, Vixhana, and Guichivere. The virulence of each isolate was assessed by quantifying parasitemia, survival, and histopathologic findings. The lineage of each isolate was identified using the mini-exon gene. The expression of the tssa gene during infection was detected in the heart, esophagus, gastrocnemius, and brain. Our results show that the maximum post-infection parasitemia was higher for the Tehuantitla isolate. On genotyping, all isolates were identified as T. cruzi I. The amastigotes in the heart and gastrocnemius were verified for all isolates, but in the brain only for Tehuantitla and Vixhana. The tssa expression allowed us to detect T. cruzi isolates, for Tehuantitla, predominantly in the heart. For Vixhana, a higher tssa expression was detected in gastrocnemius, and for Guichivere, it was higher in the esophagus. Results show that virulence, tropism, and tssa expression can vary, even when the isolates are derived from the same vector species, in the same region, and at similar altitudes.

Mycobacterium tuberculosis whiB3 and Lipid Metabolism Genes Are Regulated by Host Induced Oxidative Stress

The physiological state of the human macrophage may impact the metabolism and the persistence of Mycobacterium tuberculosis. This pathogen senses and counters the levels of O2, CO, reactive oxygen species (ROS), and pH in macrophages. M. tuberculosis responds to oxidative stress through WhiB3. The goal was to determine the effect of NADPH oxidase (NOX) modulation and oxidative agents on the expression of whiB3 and genes involved in lipid metabolism (lip-Y, Icl-1, and tgs-1) in intracellular mycobacteria. Human macrophages were first treated with NOX modulators such as DPI (ROS inhibitor) and PMA (ROS activator), or with oxidative agents (H2O2 and generator system O2•-), and then infected with mycobacteria. We determined ROS production, cell viability, and expression of whiB3, as well as genes involved in lipid metabolism. PMA, H2O2, and O2•- increased ROS production in human macrophages, generating oxidative stress in bacteria and augmented the gene expression of whiB3, lip-Y, Icl-1, and tgs-1. Our results suggest that ROS production in macrophages induces oxidative stress in intracellular bacteria inducing whiB3 expression. This factor may activate the synthesis of reserve lipids produced to survive in the latency state, which allows its persistence for long periods within the host.

Trastorno de depresión mayor e intento suicida en una paciente pediátrica víctima de abuso sexual / Major depressive disorder and suicidal attempt in a pediatric patient victim of sexual abuse

RESUMEN Introducción: el abuso sexual en la infancia se define como una experiencia traumática que puede llevar a la víctima a padecer complicaciones mentales, sexuales, físicas, interpersonales y comportamentales, nefastas para la salud. Además, constituye un factor de riesgo que desencadena el trastorno depresivo mayor en mujeres. Presentación del caso: se trata de una paciente femenina de 17 años de edad que sufrió abuso sexual a los siete años de edad. La paciente ingresa en una primera ocasión el 5 marzo de 2018 por intento suicida y trastorno depresivo al tener contacto con la persona que efectuó el acto. Pasados 17 días la paciente vuelve a ser ingresada por presentar un cuadro de trastorno depresivo mayor y egresa nueve días después por buena evolución. El 7 de agosto ingresa por tercera vez por trastorno depresivo mayor e intento suicida nuevamente. La paciente fue tratada con Imipramina de 25 mg dos veces al día y con tratamiento psicoterapéutico, al cual respondió adecuadamente. La paciente se encuentra psicológicamente estable. Conclusiones: el abuso sexual en la niñez constituye un factor de riesgo desencadenante del trastorno depresivo mayor. La atención especial mediante apoyo y estudios psicológicos de los pacientes, y el tratamiento de fármacos antidepresivos es de vital importancia para la recuperación de víctimas sometidas a acoso sexual con ideación e intento suicidas.

ABSTRACT Introduction: childhood sexual abuse is defined as a traumatic experience that can lead the victim to suffer mental, sexual, physical, interpersonal and behavioral complications harmful to health. It is also a risk factor for major depressive disorder in women. With this case, the authors aim to share experiences to the diagnosis; treatment and prevention of these health problems by disseminating them to the medical community. Case report: a 17-year-old female patient who was sexually abused at the age of 7 years. The patient is admitted on a first occasion on March 5, 2018 for suicide attempt and depressive disorder upon contact with the person who performed the act. After 17 days, the patient was admitted again for major depressive disorder and was discharged 9 days later due to good evolution. On August 7, she was admitted for a third time for major depressive disorder and another suicide attempt. The patient was treated with Imipramine 25 mg twice a day and psychotherapeutic treatment, responding satisfactorily. The patient is psychologically stable at present. Conclusions: sexual abuse in childhood constitutes a risk factor triggering major depressive disorder. Special attention through support and psychological studies of the patients and treatment with antidepressant drugs is of vital importance for the recovery of victims subjected to sexual harassment with suicidal ideation and attempt.

Sex-Dependent Differential Expression of Lipidic Mediators Associated with Inflammation Resolution in Patients with Pulmonary Tuberculosis.

There is a sex bias in tuberculosis's severity, prevalence, and pathogenesis, and the rates are higher in men. Immunological and physiological factors are fundamental contributors to the development of the disease, and sex-related factors could play an essential role in making women more resistant to severe forms of the disease. In this study, we evaluated sex-dependent differences in inflammatory markers. Serum samples were collected from 34 patients diagnosed with pulmonary TB (19 male and 15 female) and 27 healthy controls (18 male and 9 female). Cytokines IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα, and GM-CSF, and eicosanoids PGE2, LTB4, RvD1, and Mar1 were measured using commercially available immunoassays. The MDA, a product of lipidic peroxidation, was measured by detecting thiobarbituric-acid-reactive substances (TBARS). Differential inflammation patterns between men and women were observed. Men had higher levels of IL6, IL8, and TNFα than women. PGE2 and LTB4 levels were higher in patients than healthy controls, but there were no differences for RvD1 and Mar1. Women had higher RvD1/PGE2 and RvD1/LTB4 ratios among patients. RvD1 plays a vital role in resolving the inflammatory process of TB in women. Men are the major contributors to the typical pro-inflammatory profile observed in the serum of tuberculosis patients.

Circulating Levels of PD-L1, TIM-3 and MMP-7 Are Promising Biomarkers to Differentiate COVID-19 Patients That Require Invasive Mechanical Ventilation.

Background: COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many COVID-19 patients require invasive mechanical ventilation (IMV) while others, even with acute respiratory failure, do not (NIMV). Therefore, we aimed to evaluate serum levels of MMP-7 and molecules related to exhausted T-cells as potential biomarkers to differentiate between IMV and NIMV patients. Methods: 105 patients diagnosed with COVID-19 and confirmed by RT-PCR for SARS-CoV-2 were divided into two groups according to the requirement for IMV. Serum levels of sPD-L1, sPD-L2, sTIM-3, sGal-9 and sMMP-7 were quantified by ELISA and correlated with clinical data. Twelve patients were followed up after eight months to compare the levels of the biomarkers between acute disease and post-COVID-19. Results: IMV patients experienced a lower PaO2/FiO2 (p < 0.0001) and a longer hospital stay (p < 0.0001), and exhibited higher levels of sPD-L1 (p < 0.05), sTIM-3 (p < 0.01) and sMMP-7 (p < 0.0001) when compared with NIMV patients. According to a ROC analysis, sMMP-7 had the highest sensitivity (78%) and specificity (76%) with a cut point of 4.5 ng/mL, followed by sTIM-3 and sPD-L1. Eight months post-COVID-19, IMV patients displayed a significant decrease in the initially high levels of sPD-L1, sTIM-3 and sGal-9, while sPD-L2 was increased, and sMMP-7 was unchanged. Conclusion: Circulating levels of sPD-L1, sTIM-3 and sMMP-7 are potential biomarkers of disease severity to distinguish patients requiring IMV. MMP-7 could also be a marker for the persistence of lung lesions post-COVID-19.

Safety and immunogenicity of a live recombinant Newcastle disease virus-based COVID-19 vaccine (Patria) administered via the intramuscular or intranasal route: Interim results of a non-randomized open label phase I trial in Mexico.

There is still a need for safe, efficient and low-cost coronavirus disease 2019 (COVID-19) vaccines that can stop transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we evaluated a vaccine candidate based on a live recombinant Newcastle disease virus (NDV) that expresses a stable version of the spike protein in infected cells as well as on the surface of the viral particle (AVX/COVID-12-HEXAPRO, also known as NDV-HXP-S). This vaccine candidate can be grown in embryonated eggs at low cost similar to influenza virus vaccines and it can also be administered intranasally, potentially to induce mucosal immunity. We evaluated this vaccine candidate in prime-boost regimens via intramuscular, intranasal, or intranasal followed by intramuscular routes in an open label non-randomized non-placebo-controlled phase I clinical trial in Mexico in 91 volunteers. The primary objective of the trial was to assess vaccine safety and the secondary objective was to determine the immunogenicity of the different vaccine regimens. In the interim analysis reported here, the vaccine was found to be safe and the higher doses tested were found to be immunogenic when given intramuscularly or intranasally followed by intramuscular administration, providing the basis for further clinical development of the vaccine candidate. The study is registered under ClinicalTrials.gov identifier NCT04871737. Funding was provided by Avimex and CONACYT.

High Vitamin D Concentrations Restore the Ability to Express LL37 by M. tuberculosis-Infected Human Macrophages.

Vitamin D has an immunomodulatory function and is involved in eliminating pathogens. Vitamin D deficiencies reported in Type 2 diabetes mellitus (T2DM) patients make them more susceptible to developing tuberculosis (TB). The macrophages are the immune cells that control intracellular pathogens by producing the antimicrobial peptide cathelicidin-LL37. This pathway involves TLR activation by pathogens, vitamin D receptor (VDR) ligation, and the enzyme 1α-hydroxylase Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1). However, it is not clear whether the biological actions of vitamin D are affected by high glucose concentrations. This study aimed to evaluate the vitamin D contribution in the expression of VDR and CYP27B1, involved in the conversion of an inactive to an active form of vitamin D in the infected macrophages using M. tuberculosis as an infection model. The expression of LL37 and the nucleus translocation of VDR were evaluated as the readout of the response of vitamin D and determined if those processes are affected by glucose concentrations. Macrophages from healthy donors were cultured under glucose concentrations of 5.5, 15, or 30 mM, stimulated with vitamin D in inactive (25(OH)D3) or active (1,25(OH)2D3) forms, and infected with M. tuberculosis. The vitamin D-dependent induction of LL37 and the expression of VDR and CYP27B1 genes were analyzed by qPCR, and VDR translocation was analyzed in nuclear protein extracts by ELISA. M. tuberculosis downregulated the expression of LL37 regardless of the glucose concentration, whereas VDR and CYP27B1 upregulated it regardless of the glucose concentration. After evaluating two concentrations of vitamin D, 1 nM or 1 µM, the high concentration (1 µM) was necessary to restore the induction of LL37 expression in M. tuberculosis-infected macrophages. High concentrations of the inactive form of vitamin D restore the infected macrophages' ability to express LL37 regardless of the glucose concentration. This finding supports the idea that vitamin D administration in patients with T2DM could benefit TB control and prevention.

CD33 is downregulated by influenza virus H1N1pdm09 and induces ROS and the TNF-α, IL-1ß, and IL-6 cytokines in human mononuclear cells.

The influenza A virus (IAV) H1N1pdm09 induces exacerbated inflammation, contributing to disease complications. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), favor an inflammatory response that aids viral replication and survival. A pathway by which spontaneous TNF-α production occurs involves either the reduction of Siglec-3 (CD33) levels or the absence of its ligand, sialic acid. Influenza virus uses sialic acid to enter cells by reducing their expression; however, the role of CD33 in IAV H1N1pdm09 stimulation and its relationship with inflammation have not yet been studied. To evaluate the role of CD33 in proinflammatory cytokine production in IAV H1N1pdm09 stimulation, peripheral blood mononuclear cells from healthy subjects were incubated with IAV H1N1pdm09. We observed that the infection caused an increase in the mRNA expression of proinflammatory cytokines such as TNF-α, interleukin (IL)-1ß, and IL-6 and a significant reduction in CD33 expression by monocytes at an early stage of infection. Additionally, suppressor of cytokine signaling 3 (SOCS-3) mRNA expression was upregulated at 6 h, and reactive oxygen species (ROS) production increased at 1.5 h. Moreover, a significant reduction in CD33 expression on the cell surface of monocytes from influenza patients or of IAV H1N1pdm09-stimulated monocytes incubated in vitro was observed by flow cytometry. The results suggest that the decrease in CD33 and increase of SOCS-3 expression induced by IAV H1N1pdm09 triggered TNF-α secretion and ROS production, suggesting an additional way to exacerbate inflammation during viral infection.