Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

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

Palinología del Neógeno de la región de Urumaco, Falcón noroccidental.

El estudio palinoestratigr&aacute;fico de la secuencia neogena depositada en el surco de Urumaco, Falc&oacute;n noroccidental, permite precisar las edades y condiciones paleoambientales de sedimentaci&oacute;n. La Formaci&oacute;n Agua Clara, del Mioceno Temprano, termina con sedimentaci&oacute;n propia de prodelta. La Formaci&oacute;n Cerro Pelado, (Zona de Echitricolporites maristellae-Psiladiporites minimus, Mioceno Temprano) representa un ambiente deltaico. La Formaci&oacute;n Querales, (parte superior de la Zona de Echitricolporites maristellae-Psiladiporites minimus, final del Mioceno Temprano) corresponde a una transgresi&oacute;n marina. La Formaci&oacute;n Socorro (Zona de Crassoretitriletes vanraadshooveni, Mioceno Medio) se sediment&oacute; en un complejo fluvio deltaico. La Formaci&oacute;n Urumaco (Zona de Echitricolporites spinosus,&nbsp;del Mioceno Tard&iacute;o) es de ambiente pr&oacute;ximo costero a fluvial. El Miembro Chiguaje de la Formaci&oacute;n Codore (parte superior de la Zona de Echitricolporites spinosus al final del Mioceno Tard&iacute;o) representa una corta invasi&oacute;n marina sobre una llanura costera baja. El Miembro Cocuiza de la Formaci&oacute;n San Gregorio (Zona de Echitricolporites mcneillyi, Plioceno) se sediment&oacute; relativamente lejos de la costa, en ambiente marino abierto de poca profundidad.&nbsp;ABSTRACT The palynostratigraphic study of the Neogene sequence from the Urumaco Trough, in northwestern Falc&oacute;n, results in a more precise understanding of the age and paleoecological relationships of the sedimentary units. The upper Agua Clara Formation of Early Miocene age was deposited in a prodelta setting. The Cerro Pelado Formation, (Echitricolporites maristellaePsiladiporites minimus Zone, Early Miocene) is of deltaic origin. The Querales Formation, (upper part of the Echitricolporites maristellae-Psiladiporites minimus Zone, end of Early Miocene) represents a marine transgression. The Socorro Formation (Crassoretitriletes vanraadshooveni Zone, Middle Miocene) was deposited in a fluvio-deltaic complex. The Urumaco Formation (Echitricolporites spinosus Zone, Late Miocene) represents a coastal to fluvial environment. The Chiguaje Member of the Codore Formation (upper part of the Echitricolporites spinosus Zone, latest Miocene) corresponds to a short marine invasion over the lower coastal plain. The Cocuiza Member of the San Gregorio Formation (Echitricolporites mcneillyi Zone, Pliocene) was deposited in a shallow marine environment, relatively far from the coast.&nbsp

Notas Geológicas

Historia metam&oacute;rfica de la parte norcentral de la Cordillera de la Costa entre Carayaca y Puerto Cruz y su significado (Resumen).Arcinella (Davnicollia) J. &amp; W. Gibson-Smith subgenus renamed (Resumen).&nbsp;Pedro J. Berm&uacute;dez (1905-1979).&nbsp;Rese&ntilde;a bibliogr&aacute;fica. Verna, Paul 1975. Las Minas del Libertador (Tres siglos y medio de historia venezolana). Ediciones de la Presidencia de la Rep&uacute;blica.Circular: 26&ordm; Congreso Geol&oacute;gico Internacional, Paris 1960.&nbsp