Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Genetic Analysis of SARS-CoV-2 Variants in Mexico during the First Year of the COVID-19 Pandemic

During the first year of the SARS-CoV-2 pandemic in Mexico, more than two million people were infected. In this study, we analyzed full genome sequences from 27 February 2020 to 28 February 2021 to characterize the geographical and temporal distribution of SARS-CoV-2 lineages and identify the most common circulating lineages during this period. We defined six different geographical regions with particular dynamics of lineage circulation. The Northeast and Northwest regions were the ones that exhibited the highest lineage diversity, while the Central south and South/Southeast regions presented less diversity with predominance of a certain lineage. Additionally, by late February 2021, lineage B.1.1.519 represented more than 89% of all circulating lineages in the country

Dominance of Three Sublineages of the SARS-CoV-2 Delta Variant in Mexico

In this study, we analyzed the sequences of SARS-CoV-2 isolates of the Delta variant in Mexico, which has completely replaced other previously circulating variants in the country due to its transmission advantage. Among all the Delta sublineages that were detected, 81.5 % were classified as AY.20, AY.26, and AY.100. According to publicly available data, these only reached a world prevalence of less than 1%, suggesting a possible Mexican origin. The signature mutations of these sublineages are described herein, and phylogenetic analyses and haplotype networks are used to track their spread across the country. Other frequently detected sublineages include AY.3, AY.62, AY.103, and AY.113. Over time, the main sublineages showed different geographical distributions, with AY.20 predominant in Central Mexico, AY.26 in the North, and AY.100 in the Northwest and South/Southeast. This work describes the circulation, from May to November 2021, of the primary sublineages of the Delta variant associated with the third wave of the COVID-19 pandemic in Mexico and highlights the importance of SARS-CoV-2 genomic surveillance for the timely identification of emerging variants that may impact public health

Clinical and Virological Features of Patients Hospitalized with Different Types of COVID-19 Vaccination in Mexico City

Coronavirus disease 2019 (COVID-19) vaccines effectively protect against severe disease and death. However, the impact of the vaccine used, viral variants, and host factors on disease severity remain poorly understood. This work aimed to compare COVID-19 clinical presentations and outcomes in vaccinated and unvaccinated patients in Mexico City. From March to September 2021, clinical, demographic characteristics, and viral variants were obtained from 1014 individuals with a documented SARS-CoV-2 infection. We compared unvaccinated, partially vaccinated, and fully vaccinated patients, stratifying by age groups. We also fitted multivariate statistical models to evaluate the impact of vaccination status, SARS-CoV-2 lineages, vaccine types, and clinical parameters. Most hospitalized patients were unvaccinated. In patients over 61 years old, mortality was significantly higher in unvaccinated compared to fully vaccinated individuals. In patients aged 31 to 60 years, vaccinated patients were more likely to be outpatients (46%) than unvaccinated individuals (6.1%). We found immune disease and age above 61 years old to be risk factors, while full vaccination was found to be the most protective factor against in-hospital death. This study suggests that vaccination is essential to reduce mortality in a comorbid population such as that of Mexico

Resultados de la estadificación clínica ganglionar mediastínica del cáncer pulmonar quirúrgico: datos de la cohorte prospectiva nacional del Grupo Español de Cirugía Torácica Videoasistida

Introducción: El objetivo del estudio es valorar el rendimiento diagnóstico de la tomografía computarizada (TC) y la tomografía por emisión de positrones (PET) en la estadificación clínica mediastínica del cáncer pulmonar quirúrgico según los datos de la cohorte prospectiva del Grupo Español de Cirugía Torácica Videoasistida (GEVATS). Métodos: Se han analizado 2.782 pacientes intervenidos por carcinoma pulmonar primario. Se ha estudiado el acierto diagnóstico en la estadificación mediastínica (cN2). Se ha realizado un análisis bivariante y multivariante de los factores que influyen en el acierto. Se ha estudiado el riesgo de pN2 inesperado en los factores con los que se recomienda una prueba invasiva de estadificación: cN1, tumor central o tamaño mayor de 3cm. Resultados: El acierto global de la TC y PET en conjunto es del 82,9% con VPP y VPN de 0,21 y 0,93. En tumores mayores de 3cm y a mayor SUVmax del mediastino, el acierto es menor, OR de 0,59 (0,44 - 0,79) y 0,71 (0,66 - 0,75), respectivamente. En el abordaje VATS el acierto es mayor, OR de 2,04 (1,52 - 2,73). El riesgo de pN2 inesperado aumenta con el número de los factores cN1, tumor central o tamaño mayor de 3cm: entre el 4,5% (0 factores) y 18,8% (3 factores), pero no hay diferencias significativas con la realización de prueba invasiva. Conclusiones: La TC y PET en conjunto tienen un elevado valor predictivo negativo. Su acierto global es menor en tumores mayores de 3cm y SUVmax del mediastino elevado, y mayor en el abordaje VATS. El riesgo de pN2 inesperado es mayor si cN1, tumor central o mayor de 3cm y no varía significativamente con prueba invasiva

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease