RESUMEN
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/terapia , COVID-19/virología , Evolución Molecular , Mutagénesis/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Anciano , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Enfermedad Crónica , Genoma Viral/efectos de los fármacos , Genoma Viral/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Evasión Inmune/efectos de los fármacos , Evasión Inmune/genética , Evasión Inmune/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Inmunización Pasiva , Terapia de Inmunosupresión , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/inmunología , Mutación , Filogenia , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Factores de Tiempo , Carga Viral/efectos de los fármacos , Esparcimiento de Virus , Sueroterapia para COVID-19RESUMEN
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
Asunto(s)
Enfermedades de Inmunodeficiencia Primaria/genética , Secuenciación Completa del Genoma , Complejo 2-3 Proteico Relacionado con la Actina/genética , Teorema de Bayes , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteínas de Unión al ARN/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Factores de Transcripción/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS.
Asunto(s)
Antineoplásicos , Fosfatidilinositol 3-Quinasas , Humanos , Administración por Inhalación , Inhibidores de Proteínas Quinasas , Fosfatidilinositol 3-QuinasaRESUMEN
PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.
Asunto(s)
Síndromes de Inmunodeficiencia , Adolescente , Adulto , Niño , Humanos , Inmunoglobulina G/uso terapéutico , Inmunoglobulinas Intravenosas , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Infusiones SubcutáneasRESUMEN
Many factors influence the health and well-being of children and the adults they will become. Yet there are significant gaps in how trajectories of healthy development are measured, how the potential for leading a healthy life is evaluated, and how that information can guide upstream policies and investments. The Gross Developmental Potential (GDP2) is proposed as a new capabilities-based framework for assessing threats to thriving and understanding progress in achieving lifelong health and wellbeing. Moving beyond the Gross Domestic Product's (GDP) focus on economic productivity as a measure of progress, the GDP2 focuses on seven essential developmental capabilities for lifelong health and wellbeing. The GDP2 capability domains include Health -living a healthy life; Needs-satisfying basic human requirements; Communication-expressing and understanding thoughts and feelings; Learning-lifelong learning; Adaption -adapting to change; Connections -connecting with others; and Community -engaging in the community. The project team utilized literature reviews and meetings with the subject and technical experts to develop the framework. The framework was then vetted in focus groups of community leaders from three diverse settings. The community leaders' input refined the domains and their applications. This prototype GDP2 framework will next be used to develop specific measures and indices and guide the development of community-level GDP2 dashboards for local sense-making, learning, and application.
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Estado de Salud , Aprendizaje , Adulto , Niño , Emociones , HumanosRESUMEN
OBJECTIVES: The public health sector has long recognized the role of the social determinants of health in health disparities and the importance of achieving health equity. We now appear to be at an inflection point, as we hear increasing demands to dismantle structures that have perpetuated inequalities. Assessing prevailing mindsets about what causes health inequalities and the value of health equity is critical to addressing larger issues of inequity, including racial inequity and other dimensions. Using data from a nationally representative sample of adults in the United States, we examined the factors that Americans think drive health outcomes and their beliefs about the importance of health equity. METHODS: Using data from the 2018 National Survey of Health Attitudes, we conducted factor analyses of 21 survey items and identified three factors from items relating to health drivers-traditional health influencers (THI), social determinants of health (SDoH), and sense of community health (SoC). Health equity beliefs were measured with three questions about opportunities to be healthy. Latent class analysis identified four groups with similar patterns of response. Factor mixture modeling combined factor structure and latent class analysis into one model. We conducted three logistic regressions using latent classes and demographics as predictors and the three equity beliefs as dependent variables. RESULTS: Nearly 90% of respondents comprised one class that was characterized by high endorsement (i.e., rating the driver as having strong effect on health) of THI, but lower endorsement of SDoH and SoC. Logistic regressions showed that respondents endorsing (i.e., rated it as a top priority) all three health equity beliefs tended to be female, older, Black or Hispanic, more educated, and have lower incomes. The class of respondents that endorsed SDoH the most was more likely to endorse all three equity beliefs. CONCLUSIONS: Results suggested that people historically impacted by inequity, e.g., people of color and people with low incomes, had the most comprehensive understanding of the drivers of health and the value of equity. However, dominant beliefs about SDoH and health equity are still generally not aligned with scientific consensus and the prevailing narrative in the public health community.
Asunto(s)
Equidad en Salud , Adulto , Negro o Afroamericano , Actitud Frente a la Salud , Femenino , Humanos , Salud Pública , Determinantes Sociales de la Salud , Estados UnidosRESUMEN
CONTEXT: The COVID-19 pandemic has had a disparate effect on African Americans and Latinos. But it is unknown how aware the public is of these differences and how the pandemic has changed perceptions of equity and access to health care. METHODS: We use panel data from nationally representative surveys fielded to the same respondents in 2018 and 2020 to assess views and changes in views over time. FINDINGS: We found that awareness of inequity is highest among Non-Hispanic Black respondents and higher-income and higher-educated groups, and there have been only small changes in perceptions of inequity over time. However, there have been significant changes in views of the government's obligation to ensure access to health care. CONCLUSIONS: Even in the face of a deadly pandemic, one that has killed disproportionately more African Americans and Latinos, many in the United States continue not to recognize that there are inequities in access to health care and the impact of COVID-19 on certain groups. But policies to address inequity may be shifting. We will continue to follow these respondents to see whether changes in attitudes endure over time or dissipate.
Asunto(s)
COVID-19 , Pandemias , Negro o Afroamericano , Hispánicos o Latinos , Humanos , Grupos Raciales , SARS-CoV-2 , Estados UnidosRESUMEN
BACKGROUND: Civic engagement, including voting, volunteering, and participating in civic organizations, is associated with better psychological, physical and behavioral health and well-being. In addition, civic engagement is increasingly viewed (e.g., in Robert Wood Johnson Foundation's Culture of Health action framework) as a potentially important driver for raising awareness of and addressing unhealthy conditions in communities. As such, it is important to understand the factors that may promote civic engagement, with a particular focus on the less-understood, health civic engagement, or civic engagement in health-related and health-specific activities. Using data from a nationally representative sample of adults in the United States (U.S.), we examined whether the extent to which individuals feel they belong in their community (i.e., perceived sense of community) and the value they placed on investing in community health were associated with individuals' health civic engagement. METHODS: Using data collected on 7187 nationally representative respondents from the 2018 National Survey of Health Attitudes, we examined associations between sense of community, valued investment in community health, and perceived barriers to taking action to invest in community health, with health civic engagement. We constructed continuous scales for each of these constructs and employed multiple linear regressions adjusting for multiple covariates including U.S. region and city size of residence, educational attainment, family income, race/ethnicity, household size, employment status, and years living in the community. RESULTS: Participants who endorsed (i.e., responded with mostly or completely) all 16 sense of community scale items endorsed an average of 22.8% (95%CI: 19.8-25.7%) more of the health civic engagement scale items compared with respondents who did not endorse any of the sense of community items. Those who endorsed (responded that it was an important or top priority) all items capturing valued investment in community health endorsed 14.0% (95%CI: 11.2-16.8%) more of the health civic engagement items than those who did not endorse any valued investment in community health items. CONCLUSIONS: Health civic engagement, including voting and volunteering to ultimately guide government decisions about health issues, may help improve conditions that influence health and well-being for all. Focusing on individuals' sense of community and highlighting investments in community health may concurrently be associated with increased health civic engagement and improved community and population health.
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Actitud Frente a la Salud , Participación de la Comunidad/estadística & datos numéricos , Conducta de Ayuda , Responsabilidad Social , Voluntarios/estadística & datos numéricos , Actividades Cotidianas , Adulto , Organizaciones de Beneficencia/estadística & datos numéricos , Etnicidad/estadística & datos numéricos , Femenino , Humanos , Renta , Estudios Longitudinales , Masculino , Política , Encuestas y Cuestionarios , Estados Unidos , Voluntarios/psicologíaRESUMEN
BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.
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Linfocitos B/inmunología , Inmunodeficiencia Variable Común/genética , Subunidad p50 de NF-kappa B/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , Fenotipo , Linfocitos T/inmunología , Adulto JovenRESUMEN
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Síndromes de Inmunodeficiencia/genética , Trastornos Linfoproliferativos/genética , Mutación/genética , Infecciones del Sistema Respiratorio/genética , Adolescente , Adulto , Animales , Profilaxis Antibiótica , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Estudios de Cohortes , Inhibidores Enzimáticos/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/mortalidad , Infecciones por Herpesviridae/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/mortalidad , Síndromes de Inmunodeficiencia/terapia , Lactante , Cooperación Internacional , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/terapia , Masculino , Ratones , Persona de Mediana Edad , Recurrencia , Infecciones del Sistema Respiratorio/mortalidad , Infecciones del Sistema Respiratorio/terapia , Encuestas y Cuestionarios , Análisis de Supervivencia , Adulto JovenRESUMEN
Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 × 10-9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10-18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is correlated (P = 3.1 × 10-7) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.
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Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción Ikaros/metabolismo , Lupus Eritematoso Sistémico/inmunología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/fisiología , Adolescente , Adulto , Anciano , Autoinmunidad , Células Cultivadas , Niño , Desmetilación , Represión Epigenética , Femenino , Factores de Transcripción Forkhead/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Factor de Transcripción Ikaros/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Linfocitos B/inmunología , Linfocitos B/patología , ADN-Topoisomerasas de Tipo II/genética , Hematopoyesis , Síndromes de Inmunodeficiencia/patología , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Linfocitos B/metabolismo , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Masculino , Linaje , Fenotipo , PronósticoRESUMEN
In order to catalyse the splicing of messenger RNA, multiple proteins and RNA components associate and dissociate in a dynamic highly choreographed process. The Prp19 complex is a conserved essential part of the splicing machinery thought to facilitate the conformational changes the spliceosome undergoes during catalysis. Dynamic protein interactions often involve highly disordered regions that are difficult to study by structural methods. Using amine crosslinking and hydrogen-deuterium exchange coupled to mass spectrometry, we describe the architecture of the Prp19 sub-complex that contains CTNNBL1. Deficiency in CTNNBL1 leads to delayed initiation of cell division and embryonic lethality. Here we show that in vitro CTNNBL1 enhances the association of CWC15 and CDC5L, both core Prp19 complex proteins and identify an overlap in the region of CDC5L that binds either CTNNBL1 or CWC15 suggesting the two proteins might exchange places in the complex. Furthermore, in vivo, CTNNBL1 is required to maintain normal levels of the Prp19 complex and to facilitate the interaction of CWC15 with CDC5L. Our results identify a chaperone function for CTNNBL1 within the essential Prp19 complex, a function required to maintain the integrity of the complex and to support efficient splicing.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Asociadas a Matriz Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Células HEK293 , Humanos , Ratones , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/fisiología , Factores de Empalme de ARN , Proteínas de Unión al ARN/química , Empalmosomas/metabolismoRESUMEN
BACKGROUND: Cowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only. METHODS AND RESULTS: Two patients with Cowden's syndrome and an increased frequency of infections were investigated for possible underlying immunodeficiency. In one patient, hypogammaglobulinaemia with a functional antibody deficiency was identified, while the other patient had a persisting CD4+ T cell lymphopenia (with normal antibody production). CONCLUSIONS: Our data indicate that Cowden's syndrome may be associated with both T cell and B cell immune dysfunction. We recommend that patients with Cowden's syndrome and an increased frequency of infections are investigated for associated immunodeficiency.
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Síndrome de Hamartoma Múltiple/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Niño , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Masculino , Mutación , Fosfohidrolasa PTEN/genéticaRESUMEN
OBJECTIVE: Postoperative delirium, occurring days after surgery, is associated with both short- and long-term adverse events. Postanesthesia care unit (PACU) delirium, immediately after recovery from anesthesia, is associated with continued delirium in the succeeding days and adverse cognitive outcomes at discharge. Longer-term consequences are unclear. The objective was to evaluate 18-month outcomes of patients with versus without delirium in the PACU after surgery with general anesthesia. METHODS: In a prospective, observational, cohort study, 91 consecutive English-speaking patients, aged at least 70 years and capable of independently providing informed consent before surgery, were followed after admission for a surgical procedure in one teaching hospital. Patients completed cognitive testing before surgery. After recovery from general anesthesia, they were evaluated for a DSM-IV diagnosis of delirium. Participants or proxies were evaluated, at a median of 19 months after surgery (interquartile range: 18-20 months), for survival, cognitive and physical functioning, and healthcare utilization outcomes. RESULTS: All 91 patients or proxies (41 with delirium [45%]) were contacted at follow-up, with 7 deaths (8%) and 3 declining further participation (3%); 81 (96% of survivors) completed follow-up evaluations, demonstrating no significant cognitive or functional decline from baseline, with 75% of the cohort living independently in the community, and no differences in any outcomes between patients with versus without PACU delirium. CONCLUSION: In a small cohort of older patients evaluated 18 months after surgery, we could not detect an association of delirium diagnosed in the PACU with patient survival, cognitive/physical functioning, and healthcare utilization.
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Periodo de Recuperación de la Anestesia , Cognición , Delirio/diagnóstico , Complicaciones Posoperatorias/diagnóstico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Hospitalización/estadística & datos numéricos , Hospitales de Enseñanza , Humanos , Tiempo de Internación , Modelos Lineales , Masculino , Maryland , Alta del Paciente , Estudios Prospectivos , Escalas de Valoración PsiquiátricaRESUMEN
PURPOSE: DIF detection within an IRT framework is highly powerful, often identifying significant DIF that is of little clinical importance. This paper introduces two metrics for IRT DIF evaluation that can discern potentially problematic DIF among items flagged with statistically significant DIF. METHODS: Computation of two DIF metrics-(1) a weighted area between the expected score curves (wABC) and (2) a difference in expected a posteriori scores across item response categories (dEAP)-is described. Their use is demonstrated using data from a 27-item cancer stigma index fielded to four adult samples: (1) Arabic (N = 633) and (2) English speakers (N = 324) residing in Jordan and Egypt, and (3) English (N = 500) and (4) Mandarin speakers (N = 500) residing in China. We used IRTPRO's DIF module to calculate IRT-based Wald chi-square DIF statistics according to language within each region. After standard p value adjustments for multiple comparisons, we further evaluated DIF impact with wABC and dEAP. RESULTS: There were a total of twenty statistically significant DIF comparisons after p value adjustment. The wABCs for these items ranged from 0.13 to 0.90. Upon inspection of curves, DIF comparisons with wABCs >0.3 were deemed potentially problematic and were considered further for removal. The dEAP metric was also informative regarding impact of DIF on expected scores, but less consistently useful for narrowing down potentially problematic items. CONCLUSIONS: The calculations of wABC and dEAP function as DIF effect size indicators. Use of these metrics can substantially augment IRT DIF evaluation by discerning truly problematic DIF items among those with statistically significant DIF.