IL-18 neutralization ameliorates obstruction-induced epithelial–mesenchymal transition and renal fibrosis

Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, α-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial– mesenchymal transition, without demonstrating alterations in TGF-β1 or TNF-α activity. Similarly, the HK-2 cells exhibited increased α-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-α or TGF-β1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial– mesenchymal transition independent of downstream TGF-β1 or TNF-α production

Structure and Evolution of Nearby Stars with Planets. I. Short-Period Systems

Using the Yale stellar evolution code, we have calculated theoretical models for nearby stars with planetary-mass companions in short-period nearly circular orbits: 51 Pegasi, Tau Bootis, Upsilon Andromedae, Rho Cancri, and Rho Coronae Borealis. We present tables listing key stellar parameters such as mass, radius, age, and size of the convective envelope as a function of the observable parameters (luminosity, effective temperature, and metallicity), as well as the unknown helium fraction. For each star we construct best models based on recently published spectroscopic data and the present understanding of galactic chemical evolution. We discuss our results in the context of planet formation theory, and, in particular, tidal dissipation effects and stellar metallicity enhancements.Comment: 48 pages including 13 tables and 5 figures, to appear in Ap

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy.

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to \u3c16 \u3eyears) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619

Considering methodological options for reviews of theory: illustrated by a review of theories linking income and health

Background: Review of theory is an area of growing methodological advancement. Theoretical reviews are particularly useful where the literature is complex, multi-discipline, or contested. It has been suggested that adopting methods from systematic reviews may help address these challenges. However, the methodological approaches to reviews of theory, including the degree to which systematic review methods can be incorporated, have received little discussion in the literature. We recently employed systematic review methods in a review of theories about the causal relationship between income and health. Methods: This article discusses some of the methodological issues we considered in developing the review and offers lessons learnt from our experiences. It examines the stages of a systematic review in relation to how they could be adapted for a review of theory. The issues arising and the approaches taken in the review of theories in income and health are considered, drawing on the approaches of other reviews of theory. Results: Different approaches to searching were required, including electronic and manual searches, and electronic citation tracking to follow the development of theories. Determining inclusion criteria was an iterative process to ensure that inclusion criteria were specific enough to make the review practical and focused, but not so narrow that key literature was excluded. Involving subject specialists was valuable in the literature searches to ensure principal papers were identified and during the inductive approaches used in synthesis of theories to provide detailed understanding of how theories related to another. Reviews of theory are likely to involve iterations and inductive processes throughout, and some of the concepts and techniques that have been developed for qualitative evidence synthesis can be usefully translated to theoretical reviews of this kind. Conclusions: It may be useful at the outset of a review of theory to consider whether the key aim of the review is to scope out theories relating to a particular issue; to conduct in-depth analysis of key theoretical works with the aim of developing new, overarching theories and interpretations; or to combine both these processes in the review. This can help decide the most appropriate methodological approach to take at particular stages of the review

Public Health and Cost Benefits of Successful Reperfusion After Thrombectomy for Stroke

Background and Purpose- The benefit that endovascular thrombectomy offers to patients with stroke with large vessel occlusions depends strongly on reperfusion grade as defined by the expanded Thrombolysis in Cerebral Infarction (eTICI) scale. Our aim was to determine the lifetime health and cost consequences of the quality of reperfusion for patients, healthcare systems, and society. Methods- A Markov model estimated lifetime quality-adjusted life years (QALY) and lifetime costs of endovascular thrombectomy-treated patients with stroke based on eTICI grades. The analysis was performed over a lifetime horizon in a United States setting, adopting healthcare and societal perspectives. The reference case analysis was conducted for stroke at 65 years of age. National health and cost consequences of improved eTICI 2c/3 reperfusion rates were estimated. Input parameters were based on best available evidence. Results- Lifetime QALYs increased for every grade of improved reperfusion (median QALYs for eTICI 0/1: 2.62; eTICI 2a: 3.46; eTICI 2b: 5.42; eTICI 2c: 5.99; eTICI 3: 6.73). Achieving eTICI 3 over eTICI 2b reperfusion resulted on average in 1.31 incremental QALYs as well as healthcare and societal cost savings of $10 327 and$20 224 per patient. A 10% increase in the eTICI 2c/3 reperfusion rate of all annually endovascular thrombectomy-treated patients with stroke in the United States is estimated to yield additional 3656 QALYs and save $21.0 million and$36.8 million for the healthcare system and society, respectively. Conclusions- Improved reperfusion grants patients with stroke additional QALYs and leads to long-term cost savings. Procedural strategies to achieve complete reperfusion should be assessed for safety and feasibility, even when initial reperfusion seems to be adequate

Falls in young, middle-aged and older community dwelling adults: perceived cause, environmental factors and injury

BACKGROUND: Falls in older people have been characterized extensively in the literature, however little has been reported regarding falls in middle-aged and younger adults. The objective of this paper is to describe the perceived cause, environmental influences and resultant injuries of falls in 1497 young (20–45 years), middle-aged (46–65 years) and older (> 65 years) men and women from the Baltimore Longitudinal Study on Aging. METHODS: A descriptive study where participants completed a fall history questionnaire describing the circumstances surrounding falls in the previous two years. RESULTS: The reporting of falls increased with age from 18% in young, to 21% in middle-aged and 35% in older adults, with higher rates in women than men. Ambulation was cited as the cause of the fall most frequently in all gender and age groups. Our population reported a higher percentage of injuries (70.5%) than previous studies. The young group reported injuries most frequently to wrist/hand, knees and ankles; the middle-aged to their knees and the older group to their head and knees. Women reported a higher percentage of injuries in all age groups. CONCLUSION: This is the first study to compare falls in young, middle and older aged men and women. Significant differences were found between the three age groups with respect to number of falls, activities engaged in prior to falling, perceived causes of the fall and where they fell

Discrepancy between radiological and pathological size of renal masses

<p>Abstract</p> <p>Background</p> <p>Tumor size is a critical variable in staging for renal cell carcinoma. Clinicians rely on radiological estimates of pathological tumor size to guide patient counseling regarding prognosis, choice of treatment strategy and entry into clinical trials. If there is a discrepancy between radiological and pathological measurements of renal tumor size, this could have implications for clinical practice. Our study aimed to compare the radiological size of solid renal tumors on computed tomography (CT) to the pathological size in an Australian population.</p> <p>Methods</p> <p>We identified 157 patients in the Westmead Renal Tumor Database, for whom data was available for both radiological tumor size on CT and pathological tumor size. The paired Student's <it>t</it>-test was used to compare the mean radiological tumor size and the mean pathological tumor size. Statistical significance was defined as <it>P </it>< 0.05. We also identified all cases in which post-operative down-staging or up-staging occurred due to discrepancy between radiological and pathological tumor sizes. Additionally, we examined the relationship between Fuhrman grade and radiological tumor size and pathological T stage.</p> <p>Results</p> <p>Overall, the mean radiological tumor size on CT was 58.3 mm and the mean pathological size was 55.2 mm. On average, CT overestimated pathological size by 3.1 mm (<it>P </it>= 0.012). CT overestimated pathological tumor size in 92 (58.6%) patients, underestimated in 44 (28.0%) patients and equaled pathological size in 21 (31.4%) patients. Among the 122 patients with pT1 or pT2 tumors, there was a discrepancy between clinical and pathological staging in 35 (29%) patients. Of these, 21 (17%) patients were down-staged post-operatively and 14 (11.5%) were up-staged. Fuhrman grade correlated positively with radiological tumor size (<it>P </it>= 0.039) and pathological tumor stage (<it>P </it>= 0.003).</p> <p>Conclusions</p> <p>There was a statistically significant but small difference (3.1 mm) between mean radiological and mean pathological tumor size, but this is of uncertain clinical significance. For some patients, the difference leads to a discrepancy between clinical and pathological staging, which may have implications for pre-operative patient counseling regarding prognosis and management.</p

Automatic segmentation of cerebral infarcts in follow-up computed tomography images with convolutional neural networks

Background and purpose: Infarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice. Objective: To assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke. Materials and methods: We included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentati

Cohort profile : The resilience for eating and activity despite inequality (READI) study

The Resilience for Eating and Activity Despite Inequality (READI) cohort was established to address the following two key aims: to investigate the pathways (personal, social and structural) by which socio-economic disadvantage influences lifestyle choices associated with obesity risk (physical inactivity, poor dietary choices) and to explore mechanisms underlying &lsquo;resilience&rsquo; to obesity risk in socio-economically disadvantaged women and children. A total of 4349 women aged 18&ndash;46 years and 685 children aged 5&ndash;12 years were recruited from 80 socio-economically disadvantaged urban and rural neighbourhoods of Victoria, Australia, and provided baseline (T1: 2007&ndash;08) measures of adiposity, physical activity, sedentary and dietary behaviours; socio-economic and demographic factors; and psychological, social and perceived environmental factors that might impact on obesity risk. Audits of the 80 neighbourhoods were undertaken at baseline to provide objective neighbourhood environmental data. Three-year follow-up data (2010&ndash;11) have recently been collected from 1912 women and 382 children. Investigators welcome enquiries regarding data access and collaboration