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Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in  CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated h CARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.

Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous CARD11 mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine. Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11 , which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor–induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.

Emergency airway management requires matching the appropriate intubation tools to anticipated obstacles. Video laryngoscopy and flexible endoscopy are often used for difficult airways. Here we describe a case where neither method alone was anticipated to be sufficient. A 53-year-old female with an obstructing lung mass required intubation for a mixed type 1 and 2 respiratory failure. Chest x-ray revealed a tortuous subglottic obstruction. The patient could not be temporized on maximized non-invasive airway support. These factors made tandem intubation, sequentially using video laryngoscopy and flexible endoscopic intubation, an appropriate intubation strategy. In this case report we describe the rationale and technique for a rapid sequence tandem intubation.

Introduction: The increase in the incidence of pathologies in which fungi appear as emerging pathogens is mainly associated with opportunistic fungi as well as susceptibility in patients with a certain degree of immunodeficiency because they present some risk factors such as neutropenia, diabetes, surgeries, abuse of antibiotic treatment, nosocomial diseases and transplant patients among others. To date, antifungal therapy is far from being ideal because in addition to resistance to antifungals, there is a limitation of their availability as a consequence of their toxicity, as well as the decrease in the effectiveness of the drug in free form, minimal restricted penetration. to tissues, decreased bioavailability, poor pharmacokinetics, lack of selectivity, severe side effects and low water solubility: Due to this situation, it is necessary to have new therapeutic measures that are efficient to combat mainly invasive mycoses, hence the objective of this review work to know the state of the art of the various antifungal delivery systems. Development of the topic: This bibliographic review addresses the following aspects related to: a) Types and structure of nanomaterials, b) Antifungal activity of nanoparticles and c) In vivo evaluation and cytotoxicity of nanoparticles. Conclusion: The development of new technologies and synthesis of nanomaterials emerges as a possible alternative for the treatment of fungal infections. In this work, the main advances related to nanomaterials designed as a possible delivery system for antifungals are presented. Introducción: El aumento en la incidencia de patologías en las que los hongos aparecen como patógenos emergentes, se asocia principalmente con hongos oportunistas así como con la susceptibilidad en pacientes con cierto grado de inmunodeficiencia debido a que presentan algunos factores de riesgo como son la neutropenia, diabetes, cirugías, abuso de tratamiento con antibióticos, enfermedades nosocomiales y pacientes transplantados entre otros. A la fecha la terapia antifúngica está muy lejos de ser ideal porque además de la resistencia a los antifúngicos, existe una limitación de su disponibilidad como consecuencia de su toxicidad, así como a la disminución de la efectividad del fármaco en forma libre, mínima penetración restringida a tejidos, disminución de la biodisponibilidad, pobre farmacocinética, falta de selectividad, efectos colaterales severos y baja solubilidad en agua: Por esta situación, se obliga a contar con nuevas medidas terapéuticas que sean eficientes para combatir principalmente a las micosis invasivas, de ahí el objetivo del presente trabajo de revisión para conocer el estado del arte de los diversos sistemas de entrega de antifúngicos. Desarrollo del tema: La presente revisión bibliográfica aborda los siguientes aspectos relacionados con: a) Tipos y estructura de los nanomateriales, b) Actividad antifúngica de nanopartículas y c) Evaluación in vivo y citotoxicidad de nanopartículas. Conclusión: El desarrollo de nuevas tecnologías y síntesis de nanomateriales surge como una posible alternativa para el tratamiento de las infecciones por hongos. En este este trabajo se presentan los principales avances relacionados con nanomateriales diseñados como un posible sistema de entrega de antifúngicos. Introdução: O aumento da incidência de patologias em que os fungos aparecem como patógenos emergentes está principalmente associado a fungos oportunistas bem como à suscetibilidade em pacientes com certo grau de imunodeficiência por apresentarem alguns fatores de risco como neutropenia, diabetes, cirurgias, abuso de tratamento com antibióticos, doenças nosocomiais e pacientes transplantados, entre outros. Até à data, a terapia antifúngica está longe de ser ideal porque além da resistência aos antifúngicos, existe uma limitação da sua disponibilidade em consequência da sua toxicidade, bem como a diminuição da eficácia do medicamento Nanopartículas: Un sistema de entrega de antifúngicos 539 na forma livre, penetração mínima restrita aos tecidos, diminuição da biodisponibilidade, má farmacocinética, falta de seletividade, efeitos colaterais graves e baixa solubilidade em água: Devido a esta situação, é necessário ter novas medidas terapêuticas que sejam eficientes para combater principalmente micoses invasivas, daí o objetivo deste revisar trabalhos para conhecer o estado da arte dos diversos sistemas de entrega de antifúngicos. Desenvolvimento do tema: Esta revisão bibliográfica aborda os seguintes aspectos relacionados a: a) Tipos e estrutura de nanomateriais, b) Atividade antifúngica de nanopartículas e c) Avaliação in vivo e citotoxicidade de nanopartículas. Conclusão: O desenvolvimento de novas tecnologias e síntese de nanomateriais surge como uma possível alternativa para o tratamento de infecções fúngicas. Neste trabalho são apresentados os principais avanços relacionados aos nanomateriais concebidos como um possível sistema de entrega de antifúngicos.

BackgroundInborn Errors of Immunity (IEI) comprise several genetic anomalies that affect different components of the innate and adaptive responses, predisposing to infectious diseases, autoimmunity and malignancy. Different studies, mostly in adults, have reported a higher prevalence of cancer in IEI patients. However, in part due to the rarity of most of these IEI subtypes (classified in ten categories by the Primary Immunodeficiency Committee of the International Union of Immunological Societies), it is difficult to assess the risk in a large number of patients, especially during childhood.ObjectiveTo document the cancer prevalence in a pediatric cohort from a single referral institution, assessing their risk, together with the type of neoplasia within each IEI subgroup.MethodAn extensive review of clinical records from 1989 to 2022 of IEI patients who at some point developed cancer before the age of sixteen.ResultsOf a total of 1642 patients with IEI diagnosis, 34 developed cancer before 16 years of age, showing a prevalence (2.1%) significantly higher than that of the general age matched population (0.22). Hematologic neoplasms (mostly lymphomas) were the most frequent malignancies.ConclusionThis study represents one of the few reports focused exclusively in pediatric IEI cases, describing not only the increased risk of developing malignancy compared with the age matched general population (a fact that must be taken into account by immunologists during follow-up) but also the association of the different neoplasms with particular IEI subtypes, thus disclosing the possible mechanisms involved.

Background  Didactic education in emergency medicine (EM) residencies has been impacted both by the advent of asynchronous learning and by the shift toward virtual, web-based conference education due to coronavirus disease 2019 (COVID-19). Studies have demonstrated the efficacy of asynchronous education, but few have explored resident opinions about how asynchronous and virtual modifications on conference impact their educational experience.  Objective This study aimed to evaluate resident perceptions of both asynchronous and virtual modifications to a historically in-person didactic curriculum. Methods This was a cross-sectional study of residents of a three-year EM program at a large academic center where a 20% asynchronous curriculum was implemented in January 2020. A questionnaire was administered online with questions assessing how residents perceived their didactic curriculum with regard to convenience, retention of information, work/life balance, enjoyability, and overall preference. Questions compared resident opinions of in-person vs. virtual learning, as well as how the substitution of one hour of asynchronous learning impacted residents' perception of their didactics. Responses were reported on a five-point Likert-type scale.  Results A total of 32 out of 48 residents (67%) completed the questionnaire. When virtual conference was compared to in-person conference, residents favored virtual conference with regard to convenience (78.1%), work-life balance (78.1%), and overall preference (68.8%). They favored in-person conference (40.6%) or felt that the modalities were equivalent (40.6%) with regard to retention of information and favored in-person conference with regard to enjoyability (53.1%). Residents felt that the addition of asynchronous learning to their curriculum increased subjective convenience, work-life balance, enjoyability, retention of information, and overall preference, regardless of whether synchronous conference was virtual or in-person. All 32 responding residents were interested in seeing the asynchronous curriculum continue. Conclusion EM residents value the addition of asynchronous learning to both in-person and virtual didactic curricula. Additionally, virtual conference was favored over in-person conference with regard to work/life balance, convenience, and overall preference. As social distancing restrictions continue to ease post-COVID-19 pandemic, EM residencies may consider adding or maintaining asynchronous or virtual components to their synchronous conference schedule as a means to support resident wellness.

Purpose X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in  XIAP  including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of  XIAP  was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. Methods Targeted next-generation sequencing (NGS) of the entire locus of  XIAP  was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. Results NGS of  XIAP  identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of  XIAP  and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. Conclusions These results identify a key promoter sequence contained in the first non-coding exon of  XIAP . Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

This work deals with the dynamics of an ordinary differential equation system describing a Leslie-Gower predator-prey model with a generalist predator and a non-differentiable functional response proposed by M. L. Rosenzweig, given by h(x) = qxα with 0 < α < 1. Two aspects have a significant impact on the model: (1) the predator’s carrying capacity depends on both the favorite prey population and an alternative food source, and (2) consumers have access to an alternative food source. Among the main results, a separatrix curve Σ arises dividing the phase plane into regions with different dynamic behaviors. Trajectories above the separatrix curve Σ reach the vertical axis in finite time, while those below Σ may converge to positive equilibrium points, limit cycles, or homoclinic connections. Furthermore, the system is non-Lipschitz, implying non-uniqueness of solutions at points of the vertical axis. Several bifurcations, including saddle-node, homoclinic, Hopf, generalized Hopf, and Bogdanov-Takens bifurcations, are identified through the use of computational techniques. The dynamics of the system are visualized by presenting a bifurcation diagram in a convenient parameter space.

In the ecological literature, mutual interference (self-interference) or competition among predators (CAP) to effect the harvesting of their prey has been modeled through different mathematical formulations. In this work, the dynamical properties of a Leslie-Gower type predation model is analyzed, incorporating one of these forms, which is described by the function $g\\left(y\\right) =y^{\\beta }$, with $0<\\beta <1$. This function $g$ is not differentiable for $y=0$, and neither the Jacobian matrix of the system is not defined in the equilibrium points over the horizontal axis ($x-axis$). To determine the nature of these points, we had to use a non-standard methodology. Previously, we have shown the fundamental properties of the Leslie-Gower type model with generalist predators, to carry out an adequate comparative analysis with the model where the competition among predators (CAP) is incorporated. The main obtained outcomes in both systems are: (i) The unique positive equilibrium point, when exists, is globally asymptotically stable (g.a.s), which is proven using a suitable Lyapunov function. (ii) There not exist periodic orbits, which was proved constructing an adequate Dulac function.