RESUMEN
Importance: There are limited comparative data on the durability of neutralizing antibody (nAb) responses elicited by messenger RNA (mRNA) vaccines against the SARS-CoV-2 variants of concern (VOCs) in immunocompromised patients and healthy controls. Objective: To assess the humoral responses after vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines. Design, Setting, and Participants: In this prospective, longitudinal monocentric comparative effectiveness study conducted at the Lausanne University Hospital, binding IgG anti-spike antibody and nAb levels were measured at 1 week, 1 month, 3 months, and 6 months after vaccination with mRNA-1273 (24.6% of participants) or BNT162b2 (75.3% of participants). Interventions: All participants received 2 doses of either mRNA-1273 or BNT162b2 vaccines 4 to 6 weeks apart. Main Outcomes and Measures: The primary outcome of the study was the persistence of nAb responses against the original, nonvariant SARS-CoV-2 (2019-nCoV) and different VOCs at 6 months after vaccination. Key secondary outcomes were associations of the type of mRNA vaccine, the underlying disease, and the treatment with the response to vaccination. Results: Among the 841 participants enrolled between January 14 and August 8, 2021, the patient population comprised 637 participants (mean [SD] age, 61.8 [13.7] years; 386 [60.6%] female), and the healthy control population comprised 204 participants (mean [SD] age, 45.9 [12.0] years; 144 [70.6%] female). There were 399 patients with solid cancers, 101 with hematologic cancers, 38 with solid organ transplants, 99 with autoimmune diseases, and 204 healthy controls. More than 15 000 nAb determinations were performed against the original, nonvariant 2019-nCoV and the Alpha, Beta, Gamma, and Delta variants. The proportions of nAbs and their titers decreased in all study groups at 6 months after vaccination, with the greatest decreases for the Beta and Delta variants. For Beta, the proportion decreased to a median (SE) of 39.2% (5.5%) in those with hematologic cancers, 44.8% (2.7%) in those with solid cancers, 23.1% (8.3%) in those with solid organ transplants, and 22.7% (4.8%) in those with autoimmune diseases compared with 52.1% (4.2%) in healthy controls. For Delta, the proportions decreased to 41.8% (5.6%) in participants with hematologic cancer, 51.9% (2.7%) in those with solid cancers, 26.9% (8.7%) in those with solid organ transplants, and 30.7% (5.3%) in those with autoimmune diseases compared with 56.9% (4.1%) healthy controls. Neutralizing antibody titers decreased 3.5- to 5-fold between month 1 and month 6, and the estimated duration of response was greater and more durable among those participants vaccinated with mRNA-1273. In participants with solid cancers, the estimated duration of nAbs against the Beta variant was 221 days with mRNA-1273 and 146 days with BNT162b2, and against the Delta variant, it was 226 days with mRNA-1273 and 161 with BNT162b2. The estimated duration of nAbs in participants with hematologic cancers was 113 and 127 days against Beta and Delta variants, respectively. Conclusions and Relevance: This comparative effectiveness study suggests that approximately half of patients with hematologic cancers and solid cancers, about 70% of patients with solid organ transplants or autoimmune diseases, and 40% of healthy controls have lost nAbs against the circulating VOCs at 6 months after vaccination. These findings may be helpful for developing the best boosting vaccination schedule especially in immunocompromised patients.
Asunto(s)
Enfermedades Autoinmunes , COVID-19 , Neoplasias Hematológicas , Neoplasias , Anciano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Femenino , Humanos , Huésped Inmunocomprometido , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2 , Vacunación , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy. Here we have investigated whether variants in NODAL are present in patients with heterotaxy and/or isolated cardiovascular malformations (CVM) thought to be caused by abnormal heart tube looping. Analysis of a large cohort of cases (n = 269) affected with either classic heterotaxy or looping CVM revealed four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%). Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (P = 0.001) compared with cases without a detectable NODAL mutation. Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects.
Asunto(s)
Anomalías Cardiovasculares/genética , Proteína Nodal/genética , Proteína Nodal/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Tipificación del Cuerpo , Anomalías Cardiovasculares/metabolismo , Niño , Estudios de Cohortes , Femenino , Variación Genética , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Proteína Nodal/química , Alineación de Secuencia , Transducción de Señal , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismoRESUMEN
Inflammatory allergic and nonallergic respiratory disorders are spreading worldwide and often coexist. The root cause is not clear. This review demonstrates that, from a biochemical point of view, it is ascribable to protons (H+) released into cells by exogenous and endogenous acids. The hypothesis of acids as the common cause stems from two considerations: (a) it has long been known that exogenous acids present in air pollutants can induce the irritation of epithelial surfaces, particularly the airways, inflammation, and bronchospasm; (b) according to recent articles, endogenous acids, generated in cells by phospholipases, play a key role in the biochemical mechanisms of initiation and progression of allergic-type reactions. Therefore, the intracellular acidification and consequent Ca2+ increase, induced by protons generated by either acid pollutants or endogenous phospholipases, may constitute the basic mechanism of the multimorbidity of these disorders, and environmental acidity may contribute to their spread.
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Contaminantes Atmosféricos , Hipersensibilidad , Exposición por Inhalación/análisis , Enfermedades Respiratorias , Contaminantes Ambientales , Humanos , Exposición por Inhalación/estadística & datos numéricosRESUMEN
Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States-sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population.
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Alelos , Frecuencia de los Genes , Variación Genética , Lenguaje , Análisis por Conglomerados , Elementos Transponibles de ADN/genética , Europa (Continente) , Asia Oriental , Eliminación de Gen , Humanos , India/etnología , Repeticiones de Microsatélite/genética , Medio Oriente , Polimorfismo Genético , Programas InformáticosRESUMEN
BACKGROUND: CHARGE syndrome is a complex of birth defects including coloboma, choanal atresia, ear malformations and deafness, cardiac defects, and growth delay. We have previously hypothesized that CHARGE syndrome could be caused by unidentified genomic microdeletion, but no such deletion was detected using short tandem repeat (STR) markers spaced an average of 5 cM apart. Recently, microdeletion at 8q12 locus was reported in two patients with CHARGE, although point mutation in CHD7 on chromosome 8 was the underlying etiology in most of the affected patients. METHODS: We have extended our previous study by employing a much higher density of SNP markers (3258) with an average spacing of approximately 800 kb. These SNP markers are diallelic and, therefore, have much different properties for detection of deletions than STRs. RESULTS: A global error rate estimate was produced based on Mendelian inconsistency. One marker, rs431722 exceeded the expected frequency of inconsistencies, but no deletion could be demonstrated after retesting the 4 inconsistent pedigrees with local flanking markers or by FISH with the corresponding BAC clone. Expected deletion detection (EDD) was used to assess the coverage of specific intervals over the genome by deriving the probability of detecting a common loss of heterozygosity event over each genomic interval. This analysis estimated the fraction of unobserved deletions, taking into account the allele frequencies at the SNPs, the known marker spacing and sample size. CONCLUSIONS: The results of our genotyping indicate that more than 35% of the genome is included in regions with very low probability of a deletion of at least 2 Mb.
Asunto(s)
Anomalías Múltiples/genética , Atresia de las Coanas/genética , Deleción Cromosómica , Coloboma/genética , Sordera/genética , Pruebas Genéticas/métodos , Cardiopatías Congénitas/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico/métodos , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Femenino , Marcadores Genéticos/genética , Genotipo , Humanos , MasculinoRESUMEN
BACKGROUND: Aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) are obstructive malformations of the left ventricular outflow tract that account for a significant proportion of infant mortality. Two previous small case-control studies suggested methylenetetrahydrofolate reductase (MTHFR) polymorphisms may be associated with this group of malformations. METHODS: We used a family-based association design with inclusion criteria of nonsyndromic diagnosis of AVS, CoA, and HLHS, powered to detect an odds ratio for the heterozygote of <1.5. A total of 207 affected offspring-parent trios were genotyped by restriction fragment length polymorphisms at the two common polymorphic loci C677T and A1298C. RESULTS: Error rate estimation based on replicate samples was 0.76%. Mendelian inconsistency at either polymorphism was noted in 10 trios, for a calculated undetected error rate of 1.95%. A total of 197 trios were analyzed using the transmission disequilibrium test. Significant association was not found between both the C677T or A1298C polymorphisms and presence of a heart defect, whether analyzed as a group, or by sex, ethnicity, or specific diagnosis. A log-linear analysis did not find increased relative risk based on the maternal genotype. CONCLUSIONS: We were unable to replicate previous association studies and concluded that neither the affected nor the maternal MTHFR genotype, by itself, is a major risk factor for congenital left ventricular outflow tract malformations.
Asunto(s)
Familia , Cardiopatías Congénitas/enzimología , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Cardiopatías Congénitas/genética , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype.