Maternal risk factors for posterior urethral valves

Introduction: Posterior urethral valves (PUV) is a congenital disorder causing an obstruction of the lower urinary tract that affects approximately 1 in 4,000 male live births. PUV is considered a multifactorial disorder, meaning that both genetic and environmental factors are involved in its development. We investigated maternal risk factors for PUV. Methods: We included 407 PUV patients and 814 controls matched on year of birth from the AGORA data- and biobank and three participating hospitals. Information on potential risk factors (family history of congenital anomalies of the kidney and urinary tract (CAKUT), season of conception, gravidity, subfertility, and conception using assisted reproductive techniques (ART), plus maternal age, body mass index, diabetes, hypertension, smoking, and use of alcohol and folic acid) was derived from maternal questionnaires. After multiple imputation, adjusted odds ratios (aORs) were estimated using conditional logistic regression corrected for minimally sufficient sets of confounders determined using directed acyclic graphs. Results: A positive family history and low maternal age (&lt;25 years) were associated with PUV development [aORs: 3.3 and 1.7 with 95% confidence intervals (95% CI) 1.4–7.7 and 1.0–2.8, respectively], whereas higher maternal age (&gt;35 years) was associated with a lower risk (aOR: 0.7 95% CI: 0.4–1.0). Maternal preexisting hypertension seemed to increase PUV risk (aOR: 2.1 95% CI: 0.9–5.1), while gestational hypertension seemed to decrease this risk (aOR: 0.6 95% CI: 0.3–1.0). Concerning use of ART, the aORs for the different techniques were all above one, but with very wide 95% CIs including one. None of the other factors studied were associated with PUV development. Conclusion: Our study showed that family history of CAKUT, low maternal age, and potentially preexisting hypertension were associated with PUV development, whereas higher maternal age and gestational hypertension seemed to be associated with a lower risk. Maternal age and hypertension as well as the possible role of ART in the development of PUV require further research.</p

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10 '5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10 '9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10 '5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-I 4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice

Genome-wide association study in patients with posterior urethral valves

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations

Oceanographic processes and products around the Iberian margin: a new multidisciplinary approach

Our understanding of the role of bottom currents and associated oceanographic processes (e.g, overflows, barotropic tidal currents) including intermittent processes (e.g, vertical eddies, deep sea storms, horizontal vortices, internal waves and tsunamis) is rapidly evolving. Many deep-water processes remain poorly understood due to limited direct observations, but may generate significant depositional and erosional features on both short-and long-term time scales. This paper describes these oceanographic processes and examines their potential role in the sedimentary features around the Iberian margin. The paper explores the implications of the processes studied, given their secondary role relative to other factors such as mass-transport and turbiditic processes. An integrated interpretation of these oceanographic processes requires an understanding of contourites, sea-floor features, their spatial and temporal evolution, and the near-bottom flows that form them. Given their complex, three-dimensional and temporally-variable nature, integration of these processes into sedimentary, oceanographic and climatological frameworks will require a multidisciplinary approach that includes Geology, Physical Oceanography, Paleoceanography and Benthic Biology. This approach will synthesize oceanographic data, seafloor morphology, sediments and seismic images to improve our knowledge of permanent and intermittent processes around Iberia, and evaluate their conceptual and regional role in the sedimentary evolution of the margin. © 2015, Instituto Geologico y Minero de Espana. All rights reservedEl conocimiento del papel de las corrientes de fondo y los procesos oceanográficos asociados (overflows, corrientes de marea barotrópicas, etc), incluyendo procesos intermitentes (eddies, tormentas profundas, ondas internas, tsunamis, etc), está evolucionando rápidamente. Muchos de estos procesos son poco conocidos, en parte debido a que las observaciones directas son limitadas, si bien pueden generar importantes rasgos deposicionales y/o erosivos a escalas temporales de corto o largo periodo. Este artículo describe dichos procesos oceanográficos y examina su influencia en la presencia de rasgos sedimentarios alrededor del margen Ibérico. El trabajo discute las implicaciones de dichos procesos y el papel secundario que juegan en relación a otros factores tales como los procesos de transporte gravitacionales en masa y los turbidíticos. Para un mejor conocimiento de la sedimentación marina profunda, y en concreto de los sistemas contorníticos, se requiere de una interpretación de estos procesos oceanográficos, cuál es su evolución espacial y temporal, cómo afectan a las corrientes de fondo y cómo se ven afectados por la topografía submarina. Sin embargo, dada su complejidad y su variable naturaleza tridimensional y temporal, es necesario que estos procesos se integren en un marco sedimentológico, oceanográfico y climatológico con un enfoque multidisciplinar que incluyan la Geología, la Oceanografía Física, la Paleoceanografía y la Biología bentónica. Esta integración requiere de una mayor compilación de datos oceanográficos, de un mejor conocimiento de la morfología del fondo marino, y de una mejor caracterización de los sedimentos en ambientes profundos. Todo ello permitirá mejorar nuestro conocimiento de los procesos permanentes e intermitentes alrededor de Iberia y evaluar su verdadero efecto en la evolución sedimentaria delos márgenes continentales que le rodeanPostprint0,000

CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke

Introduction: We investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging. Methods: We analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non-contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R2 was assessed to determine the additional value of CTA and CTP. Results: At follow-up, 612 patients (67.5 %) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8–69.6). Regarding infarct presence, the AUC of 0.82 (95 % confidence interval (CI) 0.79–0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95 % CI 0.82–0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R2 = 0.58) was superior to patient characteristics and non-contrast CT alone (R2 = 0.44) and to addition of CTA alone (R2 = 0.55) or CTP alone (R2 = 0.54; all p < 0.001). Conclusion: In the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment

Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: The Dutch acute stroke trial (DUST) study protocol

Background: Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated.Methods/design: The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0-2 represents good outcome, and a score of 3-6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests.Discussion: This study will provide insight in the added prognosti

Oceanographic processes and morphosedimentary products along the Iberian margins: A new multidisciplinary approach

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No relation between body temperature and arterial recanalization at three days in patients with acute ischaemic stroke

Background: Recanalization of an occluded intracranial artery is influenced by temperature-dependent enzymes, including alteplase. We assessed the relation between body temperature on admission and recanalization. Methods: We included 278 patients with acute ischaemic stroke within nine hours after symptom onset, who had an intracranial arterial occlusion on admission CT angiography, in 13 participating centres. We calculated the relation per every 0.1°Celsius increase in admission body temperature and recanalization at three days. Results: Recanalization occurred in 80% of occluded arteries. There was no relation between body temperature and recanalization at three days after adjustments for age, NIHSS score on admission and treatment with alteplase (adjusted odds ratio per 0.1°Celsius, 0.99; 95% confidence interval, 0.94-1.05; p = 0.70). Results for patients treated or not treated with alteplase were essentially the same. Conclusions: Our findings suggest that in patients with acute ischaemic stroke there is no relation between body temperature on admission and recanalization of an occluded intracranial artery three days later, irrespective of treatment with alteplase