Modelled ocean changes at the Plio-Pleistocene transition driven by Antarctic ice advance

The Earth underwent a major transition from the warm climates of the Pliocene to the Pleistocene ice ages between 3.2 and 2.6 million years ago. The intensification of Northern Hemisphere Glaciation is the most obvious result of the Plio-Pleistocene transition. However, recent data show that the ocean also underwent a significant change, with the convergence of deep water mass properties in the North Pacific and North Atlantic Ocean. Here we show that the lack of coastal ice in the Pacific sector of Antarctica leads to major reductions in Pacific Ocean overturning and the loss of the modern North Pacific Deep Water (NPDW) mass in climate models of the warmest periods of the Pliocene. These results potentially explain the convergence of global deep water mass properties at the Plio-Pleistocene transition, as Circumpolar Deep Water (CDW) became the common source

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Renal outcome in adults with renal insufficiency and irregular asymmetric kidneys

BACKGROUND: The commonest cause of end-stage renal failure (ESRF) in children and young adults is congenital malformation of the kidney and urinary tract. In this retrospective review, we examine whether progression to ESRF can be predicted and whether treatment with angiotensin converting enzyme inhibitors (ACEI) can delay or prevent this. METHODS: We reviewed 78 patients with asymmetric irregular kidneys as a consequence of either primary vesico-ureteric reflux or renal dysplasia (Group 1, n = 44), or abnormal bladder function (Group 2, n = 34). Patients (median age 24 years) had an estimated GFR (eGFR) < 60 ml/min/1.73 m(2 )with at least 5 years of follow up (median 143 months). 48 patients received ACEI. We explored potential prognostic factors that affect the time to ESRF using Cox-regression analyses. RESULTS: At start, mean (SE) creatinine was 189 (8) μmol/l, mean eGFR 41 (1) ml/min 1.73 m(2), mean proteinuria 144 (14) mg/mmol creatinine (1.7 g/24 hrs). Of 78 patients, 36 (46%) developed ESRF, but none of 19 with proteinuria less than 50 mg/mmol and only two of 18 patients with eGFR above 50 ml/min did so. Renal outcome between Groups 1 and 2 appeared similar with no evidence for a difference. A benefit in favour of treatment with ACEI was observed above an eGFR of 40 ml/min (p = 0.024). CONCLUSION: The similar outcome of the two groups supports the nephrological nature of progressive renal failure in young men born with abnormal bladders. There is a watershed GFR of 40–50 ml/min at which ACEI treatment can be successful at improving renal outcome

Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux

Abstract Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions – congenital dysplasia, acquired scarring or both – are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations

Applying the ALARA concept to the evaluation of vesicoureteric reflux

The voiding cystourethrogram (VCUG) is a widely used study to define lower urinary tract anatomy and to diagnose vesicoureteric reflux (VUR) in children. We examine the technical advances in the VCUG and other examinations for reflux that have reduced radiation exposure of children, and we give recommendations for the use of imaging studies in four groups of children: (1) children with urinary tract infection, (2) siblings of patients with VUR, (3) infants with antenatal hydronephrosis (ANH), and (4) children with a solitary functioning kidney. By performing examinations with little to no radiation, carefully selecting only the children who need imaging studies and judiciously timing follow-up examinations, we can reduce the radiation exposure of children being studied for reflux

Prediction of High-Grade Vesicoureteral Reflux after Pediatric Urinary Tract Infection: External Validation Study of Procalcitonin-Based Decision Rule

BACKGROUND: Predicting vesico-ureteral reflux (VUR) 653 at the time of the first urinary tract infection (UTI) would make it possible to restrict cystography to high-risk children. We previously derived the following clinical decision rule for that purpose: cystography should be performed in cases with ureteral dilation and a serum procalcitonin level 650.17 ng/mL, or without ureteral dilatation when the serum procalcitonin level 650.63 ng/mL. The rule yielded a 86% sensitivity with a 46% specificity. We aimed to test its reproducibility. STUDY DESIGN: A secondary analysis of prospective series of children with a first UTI. The rule was applied, and predictive ability was calculated. RESULTS: The study included 413 patients (157 boys, VUR 653 in 11%) from eight centers in five countries. The rule offered a 46% specificity (95% CI, 41-52), not different from the one in the derivation study. However, the sensitivity significantly decreased to 64% (95%CI, 50-76), leading to a difference of 20% (95%CI, 17-36). In all, 16 (34%) patients among the 47 with VUR 653 were misdiagnosed by the rule. This lack of reproducibility might result primarily from a difference between derivation and validation populations regarding inflammatory parameters (CRP, PCT); the validation set samples may have been collected earlier than for the derivation one. CONCLUSIONS: The rule built to predict VUR 653 had a stable specificity (ie. 46%), but a decreased sensitivity (ie. 64%) because of the time variability of PCT measurement. Some refinement may be warranted

Pre-clinical quantitative imaging and mouse-specific dosimetry for In-111-labelled radiotracers

Cancer Research UK and Engineering and Physical Sciences Research Council support to the Cancer Imaging Centre at The Institute of Cancer Research (ICR) and the Royal Marsden Hospital NHS Foundation Trust (RMH) in association with Medical Research Council and Department of Health C1060/A10334, C1060/A16464