Aminoglycoside-induced nephrotoxicity in children

Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multi-ligand receptor megalin. Recent epidemiological studies, using more widely accepted definitions of acute kidney injury (AKI), have suggested that AKI may occur in between 20 and 33 % of children exposed to aminoglycosides. A consensus set of phenotypic criteria for aminoglycoside-induced nephrotoxicity have recently been published. These are specifically designed to provide robust phenotyping for pharmacogenomic studies, but they can pave the way for standardisation for all clinical studies. Novel renal biomarkers, in particular kidney injury molecule-1, identify aminoglycoside-induced proximal tubular injury earlier than traditional markers and have shown promise in observational studies. Further studies need to demonstrate a clear association with clinically relevant outcomes to inform translation into clinical practice. Extended interval dosing of aminoglycosides results in a reduction in nephrotoxicity, but its use needs to become more widespread. Inhibition of megalin-mediated endocytosis by statins represents a novel approach to the prevention of aminoglycoside-induced nephrotoxicity which is currently being evaluated in a clinical trial. Recommendations for future directions are provided

Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies

How does denial, minimization, justifying, and blaming operate in intimate partner abuse committed by men: a systematic review of the literature

Intimate partner abuse (IPA) is widespread, and denial, minimization, justifying, and blaming (DMJB) are common among people who have committed IPA. Views on the function of DMJB in IPA are mixed, often based on the theoretical standpoint of the authors. This systematic review brings together the knowledge of how distorted accounts operate in IPA committed by men. A systematic review of primary research related to DMJB in heterosexual men who have committed to IPA was conducted. In all, 31 papers were found to meet the inclusion criteria (adult, male-to-female abuse, in western culture, peer reviewed and published in English) and were quality appraised. Data were extracted and analyzed using narrative synthesis. The findings indicate the way DMJB operates in this group is complex. It can represent facilitators of abusive behavior, a way to protect the individual’s identity and self-esteem, and a tool men use instrumentally to achieve goals. Themes were present within and between studies highlighting the complex function of DMJB. A model representing the hypothesized intertwined function of DMJB for IPA is proposed. The limitations of the review are discussed and implications and recommendations for policy, practice, and future research are proposed

Australia's coastal fisheries and farmed seafood: An ecological basis for determining sustainability

In response to consumer concerns about the sustainability of Australian-sourced seafood we derive a set of criteria within an explicit decision-process that can be used to determine whether locally farmed and wild-caught Australian seafood products meet standards of ecological sustainability and Ecologically Sustainable Development. These criteria substantially address the ecological deficiencies we identified in other systems commonly used for assessing seafood sustainability. The criteria address the issues that are relevant to local seafood production, and are populated with indicators (metrics) and benchmarks relevant to the Australian context. The indicators establish performance thresholds drawn from public domain data about the products, including observed empirical data and proxies, and include default decisions to be applied in the absence of adequate information. This decision structure is set within a peer-reviewed expert jury decision-making process. The criteria, decision process and decision outcomes from assessment of a number of pilot products were tested in a real seafood market (Melbourne), where we found a high level of producer, reseller and consumer acceptance of the judgements and ratings. The use of ecologically-derived standards results in several outcomes that differ from those of other seafood assessment systems, especially those assessments more focused on production standards, such as government, industry and NGO-supported programs, popularly used in Australia and worldwide. We conclude that despite high levels of uncertainty surrounding many of the population parameters, ecological patterns and processes, empirical cost-effective proxies can be used to reasonably estimate a form of sustainability that matches consumer interests/expectations for production of fresh local seafood. Despite the plethora of industry and government programs, there remains a significant but presently unmet consumer demand for ecologically-based, technically robust, independently derived, and readily available information about the local sustainability attributes of Australian wild-caught and farmed fresh seafood

Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children

Aim: The aim of this study was to establish reference intervals in healthy children for two novel urinary biomarkers of acute kidney injury, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Materials & Methods: Urinary biomarkers were determined in samples from children in the UK (n = 120) and the USA (n = 171) using both Meso Scale Discovery (MSD) and Luminex-based analytical approaches. Results: 95% reference intervals for each biomarker in each cohort are presented and stratified by sex or ethnicity where necessary, and age-related variability is explored using quantile regression. We identified consistently higher NGAL concentrations in females than males (p < 0.0001), and lower KIM-1 concentrations in African–Americans than Caucasians (p = 0.02). KIM-1 demonstrated diurnal variation, with higher concentrations in the morning (p < 0.001). Conclusion: This is the first report of reference intervals for KIM-1 and NGAL using two analytical methods in a healthy pediatric population in both UK and US-based populations

Exogenous Transforming Growth Factor-β1 and Its Helminth-Derived Mimic Attenuate the Heart\u27s Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size

\ua9 2024 American Society for Investigative Pathology. Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-β1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1β and chemokine (C-C motif) ligand 2 (&gt;50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-β1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-β signaling in the vascular endothelium

Investigating the utility of combining Phi 29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArray (TM) genotyping

Background: Sustainable DNA resources and reliable high-throughput genotyping methods are required for large-scale, long-term genetic association studies. In the genetic dissection of common disease it is now recognised that thousands of samples and hundreds of thousands of markers, mostly single nucleotide polymorphisms (SNPs), will have to be analysed. In order to achieve these aims, both an ability to boost quantities of archived DNA and to genotype at low costs are highly desirable. We have investigated Phi29 polymerase Multiple Displacement Amplification (MDA)-generated DNA product (MDA product), in combination with highly multiplexed BeadArray(TM) genotyping technology. As part of a large-scale BeadArray genotyping experiment we made a direct comparison of genotyping data generated from MDA product with that from genomic DNA (gDNA) templates. Results: Eighty-six MDA product and the corresponding 86 gDNA samples were genotyped at 345 SNPs and a concordance rate of 98.8% was achieved. The BeadArray sample exclusion rate, blind to sample type, was 10.5% for MDA product compared to 5.8% for gDNA. Conclusions: We conclude that the BeadArray technology successfully produces high quality genotyping data from MDA product. The combination of these technologies improves the feasibility and efficiency of mapping common disease susceptibility genes despite limited stocks of gDNA samples

Secure Multiparty Computation from SGX

International audienceIsolated Execution Environments (IEE) offered by novel commodity hardware such as Intel's SGX deployed in Skylake processors permit executing software in a protected environment that shields it from a malicious operating system; it also permits a remote user to obtain strong interactive attestation guarantees on both the code running in an IEE and its input/output behaviour. In this paper we show how IEEs provide a new path to constructing general secure multiparty computation (MPC) protocols. Our protocol is intuitive and elegant: it uses code within an IEE to play the role of a trusted third party (TTP), and the attestation guarantees of SGX to bootstrap secure communications between participants and the TTP. In our protocol the load of communications and computations on participants only depends on the size of each party's inputs and outputs and is thus small and independent from the intricacy of the functionality to be computed. The remaining computational load-essentially that of computing the functionality-is moved to an untrusted party running an IEE-enabled machine, an appealing feature for Cloud-based scenarios. However, as often the case even with the simplest cryptographic protocols, we found that there is a large gap between this intuitively appealing solution and a protocol with rigorous security guarantees. We bridge this gap through a comprehensive set of results that include: i. a detailed construction of a protocol for secure computation for arbitrary functionalities; ii. formal security definitions for the security of the overall protocol and that of its components; and iii. a modular security analysis of our protocol that relies on a novel notion of labeled attested computation. We implemented and extensively evaluated our solution on SGX-enabled hardware, providing detailed measurements of our protocol as well as comparisons with software-only MPC solutions. Furthermore, we show the cost induced by using constant-time, i.e., timing side channel resilient, code in our implementation

Semantics for first-order affine inductive data types via slice categories

Affine type systems are substructural type systems where copying of information is restricted, but discarding of information is permissible at all types. Such type systems are well-suited for describing quantum programming languages, because copying of quantum information violates the laws of quantum mechanics. In this paper, we consider a first-order affine type system with inductive data types and present a novel categorical semantics for it. The most challenging aspect of this interpretation comes from the requirement to construct appropriate discarding maps for our data types which might be defined by mutual/nested recursion. We show how to achieve this for all types by taking models of a first-order linear type system whose atomic types are discardable and then presenting an additional affine interpretation of types within the slice category of the model with the tensor unit. We present some concrete categorical models for the language ranging from classical to quantum. Finally, we discuss potential ways of dualising and extending our methods and using them for interpreting coalgebraic and lazy data types

Standardisation of Bull's mental skills questionnaire in South Africa and the United Kingdom

The contemporary science of sport and exercise psychology requires the standardisation of mental skills questionnaires to facilitate accurate assessment of and intervention for individuals and groups in various health and sport related contexts. The study presents international research findings regarding the standardisation of a Mental Skills Scale with a sample of university students (N=420) from South Africa (n=211) and the United Kingdom (n=209) respectively. Although further international and national standardisation in both English and other languages is recommended, factor and reliability analyses indicated satisfactory validity and reliability of the current English version of the scale.The University of Zululand and the South African National Research Foundation (NRF).http://www.ajol.info/index.php/sajrshttp://academic.sun.ac.za/sajrsper/am201