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

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

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

Health-related quality-of-life trajectories over time in older men and women with advanced chronic kidney disease

Background and objectives The effect of sex on longitudinal health-related quality of life remains unknown in CKD. Here we assess differences in the sex-specific evolution of health-related quality of life in older men and women with advanced CKD.Design, setting, participants, & measurements The European Quality Study on Treatment in Advanced Chronic Kidney Disease is a European observational prospective cohort study in referred patients with CKD and an incident eGFR = 65 years of age not on dialysis. Health-related quality of life was measured using the 36-Item Short Form Survey at 3- to 6-month intervals between April 2012 and September 2020, providing Physical Component Summary and Mental Component Summary scores. Trajectories were modeled by sex using linear mixed models, and sex differences in health-related quality-of-life slope were explored. Results We included 5345 health-related quality-of-life measurements in 1421 participants. At baseline, women had considerably lower mean Physical Component Summary (42) and Mental Component Summary (60) compared with men (Physical Component Summary: 55; Mental Component Summary: 69; P < 0.001). However, during follow-up, Physical Component Summary and Mental Component Summary scores declined approximately twice as fast in men (Physical Component Summary: 2.5 per year; 95% confidence interval, 1.8 to 3.1; Mental Component Summary: 2.7 per year; 95% confidence interval, 2.0 to 3.4) compared with in women (Physical Component Summary: 1.1 per year; 95% confidence interval, 0.1 to 2.0; Mental Component Summary: 1.6 per year; 95% confidence interval, 0.7 to 2.6). This difference was partly attenuated after adjusting for important covariates, notably eGFR decline. Higher serum phosphate, lower hemoglobin, and the presence of preexisting diabetes were associated with lower Physical Component Summary and Mental Component Summary scores in men but to a lesser extent in women. Conclusions Among older men and women with advanced CKD, women had lower health-related quality of life at baseline, but men experienced a more rapid decline in health-related quality of life over time.Clinical epidemiolog

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

Association between CKD-MBD and mortality in older patients with advanced CKD: results from the EQUAL study

Background Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. Methods We used data from the European Quality study, which includes patients aged & GE;65 years with estimated glomerular filtration rate & LE;20 mL/min/1.73 m(2) from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. Results In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. Conclusions CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.Clinical epidemiolog

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

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Serum potassium and risk of death or kidney replacement therapy in older people with CKD stages 4-5: eight-year follow-up

Rationale & Objective: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5.Study Design: Prospective observational cohort study.Setting & Participants: We followed 1,714 patients (>= 65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR) 3.5-4.0-4.5-5.0-5.5-6.0 mmol/L.Outcome: The combined outcome death before KRT or start of KRT.Analytical Approach: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA).Results: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76 +/- 7 (SD) years, mean eGFR was 17 +/- 5 (SD) mL/min/1.73 m(2), and mean SGA was 6.0 +/- 1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9 mmol/L.Limitations: Shorter intervals between potassium measurements would have allowed for more precise estimations.Conclusions: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4- 5, with a nadir risk at a potassium level of 4.9 mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5.Clinical epidemiolog