High-dimensional analysis of 16 SARS-CoV-2 vaccine combinations reveals lymphocyte signatures correlating with immunogenicity.

The range of vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) provides a unique opportunity to study immunization across different platforms. In a single-center cohort, we analyzed the humoral and cellular immune compartments following five coronavirus disease 2019 (COVID-19) vaccines spanning three technologies (adenoviral, mRNA and inactivated virus) administered in 16 combinations. For adenoviral and inactivated-virus vaccines, heterologous combinations were generally more immunogenic compared to homologous regimens. The mRNA vaccine as the second dose resulted in the strongest antibody response and induced the highest frequency of spike-binding memory B cells irrespective of the priming vaccine. Priming with the inactivated-virus vaccine increased the SARS-CoV-2-specific T cell response, whereas boosting did not. Distinct immune signatures were elicited by the different vaccine combinations, demonstrating that the immune response is shaped by the type of vaccines applied and the order in which they are delivered. These data provide a framework for improving future vaccine strategies against pathogens and cancer.

Professionalization of Clinical Ethics Consultants: A Need for Liability Protection?

Clinical Ethics Consultation (CEC) has grown significantly in the last decade, and efforts are being made to professionalize the practice. The American Society for Bioethics and Humanities (ASBH) has been instrumental in this process, having published the Code of Ethics and Professional Responsibilities for Healthcare Ethics Consultants and founded and endorsed the creation of the Healthcare Ethics Consultant Certified (HCEC) Certification Commission. The ASBH also published "core competencies" for healthcare ethics consultants and has delineated a clear identity and role of such consultants distinct from that other healthcare professionals. In addition, more enter the field armed with advanced degrees (MA and PhD) or certification in clinical ethics consultation. While some have questioned the trend toward professionalization, the momentum is clearly in its favor. This paper explores three questions: Does the professionalization of healthcare ethics consultation expose those engaged in the field to the types of liability claims faced by professionals in other fields? What specific liabilities could affect a healthcare ethics consultant? And finally, what should healthcare ethics consultants do to protect themselves against liability claims? We conclude that while the risk of liability remains low, those engaged in the field should accept that risk just as part of their status as professionals and, like those in allied professions, seek appropriate protection in the form of liability insurance.

[Invasive candidiasis: A view to central nervous system infection]. / Candidiasis invasora: un enfoque a la infección en el sistema nervioso central.

Candidemia is the most frequent invasive mycosis in hospitalized patients worldwide. Fungal infection in central nervous system is a life-threatening complication which aggravates patients' prognosis. This article summarizes relevant aspects on the clinical characteristics of this pathology, mechanisms of fungus invasion, local immune response to Candida albicans and the impact of genetic defects on innate immune receptors that increase susceptibility to the acquisition of this form of mycosis.

Moral Distress Entangled: Patients and Providers in the COVID-19 Era.

Moral distress is defined as the inability to act according to one's own core values. During the COVID-19 pandemic, moral distress in medical personnel has gained attention, related to the impact of pandemic-associated factors, such as the uncertainty of treatment options for the virus and the accelerated pace of deaths. Measures to provide aid and mitigate the long-term pandemic effect on providers are starting to be designed. Yet, little has been said about the moral distress experienced by patients and the relational and additive effect on provider moral distress. Pandemic-associated factors affecting moral distress in patients include the constraining effects of isolation on spiritual and religious traditions as well as the intentional separation of patients from their families. This paper will explore the idea that patients are suffering their own moral distress and further how this impacts the intensity of moral distress experienced by the providers-nurses and physicians. The paucity of research in this area with the implications on patient's distress, decision making, and distress experienced by providers compels further investigation and analysis.

[Mucinous cystadenoma of the ileocecal valve. Uncommon intestinal tumor in a oneyear-old boy. Case report]. / Cistoadenoma mucinoso de la vá lvula ileocecal: tumoración intestinal infrecuente en un niñ o de 1 añ o. Reporte de caso.

Mucinous cystadenoma is usually found in the ovary, pancreas and appendix but its presentation in the intestine is extremely rare. In this case report we present an infant with partial intestinal occlusion due to a mucinous cystadenoma of the ileocecal valve. We performed an excision of the terminal ileum, ileocecal valve, cecum and appendix, followed by ileocolic anastomosis. The patient did well after the procedure and recovered uneventfully. To our knowledge, this is the first case report of this tumor in this location.

Strangers in a Strange Land: How Our Founding Principles and a Bitter Pill Undo the Assimilation of US Catholics.

Most Catholic physicians work with the comfortable assumption that we can practice our profession and our faith, fully assimilated into modern American culture and society. Increasingly, we have come to realize that to be a Catholic Christian is by nature to be countercultural. American culture, ordered by the founding fathers in concepts of liberty and freedom, has been profoundly affected by the introduction and reliance on a contraceptive pill. This has changed the mores and sexual behaviors of society in ways that are antithetical to Catholic values. The consequences of contraception have directly led to an acceptance of a broad number of behaviors and attitudes that society insists must be tolerated. This challenges the commitments of Catholic physicians both personally and professionally.

Oxidative and nitrosative stress responses during macrophage-Candida albicans biofilm interaction.

Candida albicans is an important source of device-associated infection because of its capacity for biofilm formation. This yeast has the ability to form biofilms which favors the persistence of the infection. Furthermore, the innate immune response has a critical role in the control of these infections and macrophages (Mø) are vital to this process. An important fungicidal mechanism employed by Mø involves the generation of toxic reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI). The interaction between biofilms and these immune cells, and the contribution of oxidative and nitrosative stress, that is determinant to the course of the infection, remains elusive. The aim of this study was to investigate this interaction. To this purpose, two models of Mø-biofilms contact, early (model 1) and mature (model 2) biofilms, were used; and the production of ROS, RNI and the oxidative stress response (OSR) were evaluated. We found that the presence of Mø decreased the biofilm formation at an early stage and increased the production of ROS and RNI, with activation of ORS (enzymatic and nonenzymatic). On the other hand, the interaction between mature biofilms and Mø resulted in an increasing biofilm formation, with low levels of RNI and ROS production and decrease of OSR. Dynamic interactions between Mø and fungal biofilms were also clearly evident from images obtained by confocal scanning laser microscopy. The prooxidant-antioxidant balance was different depending of C. albicans biofilms stages and likely acts as a signal over their formation in presence of Mø. These results may contribute to a better understanding of the immune-pathogenesis of C. albicans biofilm infections.

The Team Based Biopsychosocial Model: Having a Clinical Ethicist as a Facilitator and a Bridge Between Teams.

The biopsychosocial model is characterized by the systematic consideration of biological, psychological, and social factors and their complex interactions in understanding health, illness, and health care delivery. This model opposes the biomedical model, which is the foundation of most current clinical practice. In the biomedical model, quest for evidence based medicine, the patient is reduced to molecules, genes, organelles, systems, diseases, etc. This reduction has brought great advances in medicine, but it lacks a holistic view of the person. To solve the problem, we propose an early team based approach where the primary care physician leads a group of people that can help her/him address the psychosocial issues while she/he attends to the biomedical issues. This article addresses one case where the clinical ethicist facilitating a team based biopsychosocial model for the care of a patient worked as a bridge between the primary team, the critical care team, and the psychosocial team to advance the argument that good communication among the groups can lead to a true biopsychosocial model where the collaboration of the social worker, psychologist, chaplain, ethicist and the different medical teams can improve the overall patient experience.

Curcumin-Loaded Liquid Crystalline Systems for Controlled Drug Release and Improved Treatment of Vulvovaginal Candidiasis.

Vulvovaginal candidiasis (VVC) is the most common infection caused by Candida albicans and greatly reduces the quality of life of women affected by it. Due to the ineffectiveness of conventional treatments, there is growing interest in research involving compounds of natural origin. One such compound is curcumin (CUR), which has been proven to be effective against this microorganism. However, some of CUR's physicochemical properties, especially its low aqueous solubility, make the therapeutic application of this compound difficult. Thus, the incorporation of CUR in mucoadhesive liquid crystalline systems (MLCSs) for vaginal administration may be an efficient strategy for the treatment of VVC. MLCSs are capable of potentiating the compound's action, releasing it in a controlled manner, and can enable longer exposure at the site of infection. In this study, MLCSs consisting of oleic acid and ergosterol 5:1 (w/w) as the oily phase, PPG-5-CETETH-20 as the surfactant, and a polymer dispersion of 1% chitosan as the aqueous phase, were developed for the application of CUR (MLCS-CUR) in VVC treatment. The formulations were characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), oscillatory rheometry, continuous shear rheometry, texture profile analysis, and in vitro mucoadhesion. In addition, the antimicrobial activity was evaluated in vitro, and the effects on local fungal burden and cytokine profiles were investigated in a murine model of VVC. PLM and SAXS showed that the developed formulations presented a characteristic of a microemulsion. However, after the addition of artificial vaginal mucus (AVM), PLM showed that the formulations had structures similar to the "Maltese cross" characteristic of lamellar MLCS. Mucoadhesive test results showed an increase in the mucoadhesive strength of these formulations. Rheology analyses suggested long-lasting action of the formulation at the infected site. The in vitro antimicrobial activity assays suggested that CUR possesses antifungal activity against Candida albicans, determined after its incorporation into the MLCS. Further, MLCS-CUR was also more effective in vivo in the control of vaginal infection than treatment with fluconazole. Immunological assays showed that the ratio of pro-inflammatory (IL-1ß) to anti-inflammatory (TGF-ß) cytokines has decreased and that there is a reduction in the number of polymorphonuclear neutrophils recruited to the vaginal lumen, showing that treatment with MLCS-CUR was effective in modulating the inflammatory reaction associated with the infection. The results suggest that MLCSs could potentially be used in the treatment of VVC with CUR.

Abrogation of spontaneous liver tolerance during immune response to Candida albicans: contribution of NKT and hepatic mononuclear cells.

Hepatic mononuclear cells (HMC) are a heterogeneous population with innate immune properties involved in the response to several pathogens. Herein, during the primary infection with Candida albicans, we observed dynamic changes in CD3+, NK+ and NKT+ intrahepatic lymphoid subsets and a significant increase in the absolute number of antigen-presenting cells (APC). The liver tolerogenic microenvironment sustained by higher levels of IL-10, transforming growth factor-ß and IL-4 was severely modified upon the robust IFN-γ production after the fungal colonization. NKT cells purified from infected animals released significant amounts of IFN-γ and the production of this cytokine was exacerbated after a second contact with the fungus. Interestingly, C. albicans per se was unable to activate tolerogenic NKT cells from naive animals. In vitro experiments performed with HMC cells depleted of the CD11b/c+ population revealed that in the absence of APC, NKT cells are unable to produce IFN-γ in response to C. albicans. Our findings constitute the first evidence that this innate lymphocyte population is involved in the pathogenesis of C. albicans infection.

Evaluation of Syngonanthus nitens (Bong.) Ruhl. extract as antifungal and in treatment of vulvovaginal candidiasis.

The purpose of this study was to evaluate the in vitro anticandidal activity of a methanolic extract of Syngonanthus nitens scapes against different Candida species and clinical isolates from patients with vulvovaginal candidiasis (VVC), and its effect in vivo in the treatment of vaginal infection. Chemical characterization of the extract was performed by HPLC-UV analyses and showed the presence of flavones derivatives. The extract was effective against several Candida strains from our collection and species recovered from VVC patients, and was able to inhibit the yeast-hyphal transition. No cytotoxic activity against human female reproductive tract epithelial cells and no hemolytic activity against human red blood cells were observed. In the in vivo model of VVC, we evaluated the efficacy of the intravaginal treatment with a cream containing the extract at doses of 0.5, 1.0 and 2.0%. The treatment eradicated the vaginal fungal burden in infected rats after 8 days of treatment. S. nitens extract could be considered as an effective and non-toxic natural antifungal agent in the treatment of vulvovaginal candidiasis.

Antifungal stewardship: the Latin American experience.

Antifungal stewardship is a critical component of healthcare management that focuses on optimizing the use of antifungal medications to improve patient outcomes, minimize resistance, and reduce healthcare costs.  In resource-limited settings, the prevalence of fungal infections remains a significant health concern, often exacerbated by factors such as compromised immune systems, inadequate diagnostic capabilities, and limited access to antifungal agents. This paper reviews the current state of antifungal stewardship practices in developing countries, addressing the unique socioeconomic and healthcare landscape.

Different cytokine and chemokine profiles in hospitalized patients with COVID-19 during the first and second outbreaks from Argentina show no association with clinical comorbidities.

Background: COVID-19 severity has been linked to an increased production of inflammatory mediators called "cytokine storm". Available data is mainly restricted to the first international outbreak and reports highly variable results. This study compares demographic and clinical features of patients with COVID-19 from Córdoba, Argentina, during the first two waves of the pandemic and analyzes association between comorbidities and disease outcome with the "cytokine storm", offering added value to the field. Methods: We investigated serum concentration of thirteen soluble mediators, including cytokines and chemokines, in hospitalized patients with moderate and severe COVID-19, without previous rheumatic and autoimmune diseases, from the central region of Argentina during the first and second infection waves. Samples from healthy controls were also assayed. Clinical and biochemical parameters were collected. Results: Comparison between the two first COVID-19 waves in Argentina highlighted that patients recruited during the second wave were younger and showed less concurrent comorbidities than those from the first outbreak. We also recognized particularities in the signatures of systemic cytokines and chemokines in patients from both infection waves. We determined that concurrent pre-existing comorbidities did not have contribution to serum concentration of systemic cytokines and chemokines in COVID-19 patients. We also identified immunological and biochemical parameters associated to inflammation which can be used as prognostic markers. Thus, IL-6 concentration, C reactive protein level and platelet count allowed to discriminate between death and discharge in patients hospitalized with severe COVID-19 only during the first but not the second wave. Conclusions: Our data provide information that deepens our understanding of COVID-19 pathogenesis linking demographic features of a COVID-19 cohort with cytokines and chemokines systemic concentration, presence of comorbidities and different disease outcomes. Altogether, our findings provide information not only at local level by delineating inflammatory/anti-inflammatory response of patients but also at international level addressing the impact of comorbidities and the infection wave in the variability of cytokine and chemokine production upon SARS-CoV-2 infection.

COVID-19 patients display changes in lymphocyte subsets with a higher frequency of dysfunctional CD8lo T cells associated with disease severity.

This work examines cellular immunity against SARS-CoV-2 in patients from Córdoba, Argentina, during two major waves characterized by different circulating viral variants and different social behavior. Using flow cytometry, we evaluated the main lymphocyte populations of peripheral blood from hospitalized patients with moderate and severe COVID-19 disease. Our results show disturbances in the cellular immune compartment, as previously reported in different cohorts worldwide. We observed an increased frequency of B cells and a significant decrease in the frequency of CD3+ T cells in COVID-19 patients compared to healthy donors (HD). We also found a reduction in Tregs, which was more pronounced in severe patients. During the first wave, the frequency of GZMB, CD107a, CD39, and PD-1-expressing conventional CD4+ T (T conv) cells was significantly higher in moderate and severe patients than in HD. During the second wave, only the GZMB+ T conv cells of moderate and severe patients increased significantly. In addition, these patients showed a decreased frequency in IL-2-producing T conv cells. Interestingly, we identified two subsets of circulating CD8+ T cells with low and high CD8 surface expression in both HD and COVID-19 patients. While the percentages of CD8hi and CD8lo T cells within the CD8+ population in HD are similar, a significant increase was observed in CD8lo T cell frequency in COVID-19 patients. CD8lo T cell populations from HD as well as from SARS-CoV-2 infected patients exhibited lower frequencies of the effector cytokine-producing cells, TNF, IL-2, and IFN-γ, than CD8hi T cells. Interestingly, the frequency of CD8lo T cells increased with disease severity, suggesting that this parameter could be a potential marker for disease progression. Indeed, the CD8hi/CD8lo index helped to significantly improve the patient's clinical stratification and disease outcome prediction. Our data support the addition of, at least, a CD8hi/CD8lo index into the panel of biomarkers commonly used in clinical labs, since its determination may be a useful tool with impact on the therapeutic management of the patients.

Correlation among antioxidant, antimicrobial, hemolytic, and antiproliferative properties of Leiothrix spiralis leaves extract.

The biological activities of a plant extract depend on a complex sum of individual properties including the antioxidant activity. Several biological activities protect against the harmful action of reactive oxygen species (ROS), and here we focused our attention on the relationship between the biological activities tested and the antioxidant properties. In this study, the total flavonoid content as well as the antioxidant, antimicrobial, hemolytic and cytotoxicity activities of the methanolic extract of Leitothrix spiralis leaves were evaluated. The extract showed a total flavonoid content of 19.26% and the chemical characterization by HPLC-PAD confirmed the presence of flavonoids as the major secondary metabolite compounds. Significant antioxidant activity (IC(50) = 1.743 µg/mL ± 0.063) was demonstrated and was effective against Gram-negative organisms and all Candida strains tested, and showed an ability to inhibit hyphal formation. Non-hemolytic and antiproliferative activity could be demonstrated.

Invasive Candidiasis: Update and Current Challenges in the Management of This Mycosis in South America.

Invasive candidiasis encompassing Candida bloodstream infections and deep-seated candidiasis can become a persistent health problem. These infections are caused by Candida species and have high morbidity and mortality rates. Species distribution, access to diagnosis, treatment and mortality are different around the world. The mortality rate is high in South America (30-70%), and Candida albicans is the most prevalent species in this region. However, a global epidemiological shift to non-albicans species has been observed. In this group, C. parapsilosis is the species most frequently detected, followed by C. tropicalis, and at a slower rate, C. glabrata, which has also increased, in addition to the emerging C. auris, resistance to several drugs. This article summarizes relevant aspects of candidemia pathogenesis, such as the mechanisms of fungal invasion, immune response, and the impact of genetic defects that increase host susceptibility to developing the infection. We also discuss relevant aspects of treatment and future challenges in South America.

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels.

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level.

Exploring values among three cultures from a global bioethics perspective.

The United Nations Educational, Scientific and Cultural Organisation's (UNESCO) Declaration on Bioethics and Human Rights refers to the importance of cultural diversity and pluralism in ethical discourse and care of humanity. The aim of this meta-narrative review is to identify indigenous ethical values pertaining to the Ojibway (Canada), Xhosa (South Africa), and Mayan (Mexico and Central American) cultures from peer-reviewed sources and cultural review, and to ascertain if there are shared commonalities. Three main themes were identified, namely illness, healing, and health care choices. Illness was described with a more complex and dynamic picture than from the western view, as illness is not considered to be one dimensional. Healing needs to take place on various levels in order to restore a state of equilibrium between the different spheres. Health care choices were also considered from a multi-level perspective. In all three of the indigenous cultures explored, good decision-making is seen to have occurred when choices are informed by commitments to one's moral and ethical responsibilities towards the community, nature, and the spirit world.

Candida albicans Modulates Murine and Human Beta Defensin-1 during Vaginitis.

Vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC) are two forms of a disease caused by Candida spp. ß-defensin (BD) is one of the most important families of antimicrobial peptides in the female genital tract and includes molecules that exert essential local functions as antimicrobial and PMN chemoattractant peptides. However, the information on their role during murine and human VVC and RVVC is limited. Thus, we analyzed the behavior and contribution of BD1 to the local response in a VVC mice model and the local cytokine profile and human BD1 and BD3 expression in cervicovaginal lavage from patients with VVC and RVVC. We demonstrated that, in patients with RVVC BD1, mRNA and protein expression were severely diminished and that the aspartate proteinase and lipase secreted by C. albicans are involved in that decrease. This study provides novel information about the pathogenesis of VVC and describes a highly efficient C. albicans escape strategy for perpetuating the infection; these results may contribute to the development of new or combined treatment approaches.

Immune-metabolic balance in stressed rats during Candida albicans infection.

We evaluated the host metabolic response to chronic varied stress during infection with the fungus Candida albicans. We used four groups of female Wistar rats: normal uninfected and unstressed, stressed, C. albicans infected and infected, and stressed. Infected rats reacted with rapid metabolic adjustments, evident as anorexia and body weight loss, partly mediated by glucocorticoids and TNF-alpha. Higher circulating levels of IL-6 and glucose (p < 0.05) revealed the progress and catabolic effect of the inflammatory response. Infected and stressed rats instead showed anorexia associated with infection and weight loss as the result of reduced food intake. This group exhibited a prompt reduction in circulating leptin on day 3 (p < 0.05), reduction in glucose levels and depletion of hepatic glycogen depots. We also evaluated the contribution of TNF-alpha, glucocorticoids, and food deprivation to liver damage. Lipid peroxidation in liver detected in the infected and infected-stressed groups was exacerbated by the glucocorticoid receptor antagonist RU 486, suggesting the modulatory activity of glucocorticoids, while hepatic fat accumulation and glycogen depletion decreased with anti-TNF-alpha treatment. Food deprivation exacerbated liver injury while the response to stress contributed to greater fungal colonization. Our findings emphasize the impact of metabolic alterations on tissue damage when the host immune activity is modulated by stress mediators.