Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415

Foods for a Mission to Mars: Equivalent System Mass and Development of a Multipurpose Small-Scale Seed Processor

The candidate crops for planetary food systems include: wheat, white and sweet potatoes, soybean, peanut, strawberry, dry bean including le ntil and pinto, radish, rice, lettuce, carrot, green onion, tomato, p eppers, spinach, and cabbage. Crops such as wheat, potatoes, soybean, peanut, dry bean, and rice can only be utilized after processing, while others are classified as ready-to-eat. To process foods in space, the food processing subsystem must be capable of producing a variety of nutritious, acceptable, and safe edible ingredients and food produ cts from pre-packaged and resupply foods as well as salad crops grown on the transit vehicle or other crops grown on planetary surfaces. D esigning, building, developing, and maintaining such a subsystem is b ound to many constraints and restrictions. The limited power supply, storage locations, variety of crops, crew time, need to minimize waste , and other equivalent system mass (ESM) parameters must be considere d in the selection of processing equipment and techniques

A robust sequential hypothesis testing method for brake squeal localisation

This contribution deals with the in situ detection and localisation of brake squeal in an automobile. As brake squeal is emitted from regions known a priori, i.e., near the wheels, the localisation is treated as a hypothesis testing problem. Distributed microphone arrays, situated under the automobile, are used to capture the directional properties of the sound field generated by a squealing brake. The spatial characteristics of the sampled sound field is then used to formulate the hypothesis tests. However, in contrast to standard hypothesis testing approaches of this kind, the propagation environment is complex and time-varying. Coupled with inaccuracies in the knowledge of the sensor and source positions as well as sensor gain mismatches, modelling the sound field is difficult and standard approaches fail in this case. A previously proposed approach implicitly tried to account for such incomplete system knowledge and was based on ad hoc likelihood formulations. The current paper builds upon this approach and proposes a second approach, based on more solid theoretical foundations, that can systematically account for the model uncertainties. Results from tests in a real setting show that the proposed approach is more consistent than the prior state-of-the-art. In both approaches, the tasks of detection and localisation are decoupled for complexity reasons. The localisation (hypothesis testing) is subject to a prior detection of brake squeal and identification of the squeal frequencies. The approaches used for the detection and identification of squeal frequencies are also presented. The paper, further, briefly addresses some practical issues related to array design and placement. (C) 2019 Author(s)

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcome

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Social work and the penal state

The Criminal Justice System (CJS) has historically been a key site of social work intervention. Wacquant (2008, 2009a and 2009b) argues that the growth of social insecurity and the expansion of the penal state are endogenous features of the neo-liberal political project. The key premises of neo-liberalism have been accepted by parties of both the left and the right. Wacquant identifies that the “doxa” of the penal state such as “prison works” “zero tolerance” and “broken windows” have been widely accepted in an uncritical fashion. This shift alongside an increase in inequality had led to increasing social anxiety and mistrust. One manifestation of these trends is the “decline of the rehabilitative ideal” (Garland, 2001). Offenders, who were once generally viewed as marginalised individuals in need of social and welfare support are now regarded as sites of risk. The USA has led a penal arms race, in which, the use of imprisonment has grown significantly. In Europe, England and Wales has followed this trend most closely. Whilst acknowledging that penal policy is the result of a complex inter-relationship between social, cultural and historical factors, there are lessons to be learnt from the US experience. These include the impact of race and class inequalities as manifest in the CJS. The act of imprisonment is arguably an act of state violence and alongside the impact on individuals, communities and families, it has huge symbolic significance and value. The expansion of the penal state: the increasing numbers, poor conditions and the over-representation of minority groups mean that it should be a core social work concern. The paper outlines the ways, in which, risk and managerialism have sidelined core social work values in the CJS. It concludes that developments in the USA, particularly the decision in Brown v. Plata highlight a way out of the current impasse. Penal policy and conditions can only be reformed if the inherent dignity of offenders is rediscovered and placed at its centre

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65–0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67–1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45–1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69–1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cell

Youth perceptions of prevention norms and peer violence perpetration and victimization: A prospective analysis

The purpose of the current study is to prospectively examine the extent to which social norms perceptions regarding commitment to ending sexual violence are associated with subsequent peer victimization and perpetration experiences. Two types of social norms perceptions were examined: 1) peer norms (perceptions of norms among other students in their city), and 2) adult norms (perceptions of norms among adults in their city). Participants were 1259 middle and high school youth from a single school district (three high schools and five middle schools) who completed online surveys at two‐time points, 6 months apart. Adolescents for whom perceptions of peer norms were one standard deviation or more above and below the mean of actual norms were “over‐perceivers” and “under‐perceivers,” respectively. Overperceivers overestimated their peers’ commitment to ending sexual violence, whereas underperceivers underestimated their peers’ commitment to ending sexual violence. Other adolescents were “accurate perceivers”; these adolescents were accurate in their estimation of their peers’ commitment to ending sexual violence. In general, underperceivers (22.2% of the sample) were more likely than accurate perceivers (77.8% of the sample) to subsequently experience peer‐to‐peer perpetration and victimization. Adolescents who perceived adults to have a higher commitment to ending sexual violence were less likely to report subsequent perpetration and victimization for some forms of peer-to‐peer violence. These findings highlight the potential promise of the social norms approaches to prevent peer‐to‐peer violence among youth which aligns with increasing calls in the field to integrate these approaches into comprehensive sexual violence prevention

Biogenic Volatiles Emitted from Four Cold-Hardy Grape Cultivars During Ripening

In this research dataset, we summarize for the first time volatile organic compounds (VOCs) emitted in vivo from ripening wine grapes. We studied four cold-hardy cultivars grown in the Midwestern U.S.: St. Croix, Frontenac, Marquette, and La Crescent. These cultivars have gained popularity among local growers and winemakers, but still very little is known about their performance compared with long-established V. vinifera grapes. Volatiles were collected using two novel approaches: biogenic emissions from grape clusters on a vine and single grape berries. A third approach was headspace collection of volatiles from crushed grapes. Solid-phase microextraction (SPME) was used to collect volatiles. Vacuum-assisted SPME was used in the case of single grape berry. Collected VOCs were analyzed using separation and identification on a gas chromatograph mass spectrometer (GC-MS). More than 120 VOCs were identified using mass spectral libraries. The dataset provides evidence that detecting biogenic emissions from growing grapes is feasible. The dataset provides a record of temporal and spatial variability of VOCs, many of which could potentially impart aroma and flavor in the wine. The number of VOCs detected followed the order from single berry (the least) to crushed berry (the most). Thus, more information for potential use in harvesting in order to obtain the desired flavor is found in data from crushed grapes