Dialysis and pediatric acute kidney injury: choice of renal support modality

Dialytic intervention for infants and children with acute kidney injury (AKI) can take many forms. Whether patients are treated by intermittent hemodialysis, peritoneal dialysis or continuous renal replacement therapy depends on specific patient characteristics. Modality choice is also determined by a variety of factors, including provider preference, available institutional resources, dialytic goals and the specific advantages or disadvantages of each modality. Our approach to AKI has benefited from the derivation and generally accepted defining criteria put forth by the Acute Dialysis Quality Initiative (ADQI) group. These are known as the risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria. A modified pediatrics RIFLE (pRIFLE) criteria has recently been validated. Common defining criteria will allow comparative investigation into therapeutic benefits of different dialytic interventions. While this is an extremely important development in our approach to AKI, several fundamental questions remain. Of these, arguably, the most important are “When and what type of dialytic modality should be used in the treatment of pediatric AKI?” This review will provide an overview of the limited data with the aim of providing objective guidelines regarding modality choice for pediatric AKI. Comparisons in terms of cost, availability, safety and target group will be reviewed

Management of toxic ingestions with the use of renal replacement therapy

Although rare, renal replacement therapy (RRT) for the treatment of the metabolic, respiratory and hemodynamic complications of intoxications may be required. Understanding the natural clearance of the medications along with their volume of distribution, protein binding and molecular weight will help in understanding the benefit of commencing RRT. This information will aid in choosing the optimal forms of RRT in an urgent setting. Overdose of common pediatric medications are discussed with suggestions on the type of RRT within this educational review

Effects of early feeding on growth velocity and overweight/obesity in a cohort of HIV unexposed South African infants and children

BACKGROUND: South Africa has the highest prevalence of overweight/obesity in Sub-Saharan Africa. Assessing the effect of modifiable factors such as early infant feeding on growth velocity and overweight/obesity is therefore important. This paper aimed to assess the effect of infant feeding in the transitional period (12 weeks) on 12–24 week growth velocity amongst HIV unexposed children using WHO growth velocity standards and on the age and sex adjusted body mass index (BMI) Z-score distribution at 2 years. METHODS: Data were from 3 sites in South Africa participating in the PROMISE-EBF trial. We calculated growth velocity Z-scores using the WHO growth standards and assessed feeding practices using 24-hour and 7-day recall data. We used quantile regression to study the associations between 12 week infant feeding and 12–24 week weight velocity (WVZ) with BMI-for-age Z-score at 2 years. We included the internal sample quantiles (70th and 90th centiles) that approximated the reference cut-offs of +2 (corresponding to overweight) and +3 (corresponding to obesity) of the 2 year BMI-for-age Z-scores. RESULTS: At the 2-year visit, 641 children were analysed (median age 22 months, IQR: 17–26 months). Thirty percent were overweight while 8.7% were obese. Children not breastfed at 12 weeks had higher 12–24 week mean WVZ and were more overweight and obese at 2 years. In the quantile regression, children not breastfed at 12 weeks had a 0.37 (95% CI 0.07, 0.66) increment in BMI-for-age Z-score at the 50th sample quantile compared to breast-fed children. This difference in BMI-for-age Z-score increased to 0.46 (95% CI 0.18, 0.74) at the 70th quantile and 0.68 (95% CI 0.41, 0.94) at the 90th quantile . The 12–24 week WVZ had a uniform independent effect across the same quantiles. CONCLUSIONS: This study demonstrates that the first 6 months of life is a critical period in the development of childhood overweight and obesity. Interventions targeted at modifiable factors such as early infant feeding practices may reduce the risks of rapid weight gain and subsequent childhood overweight/obesity.Scopu

Membrane anchoring stabilizes and favors secretion of New Delhi metallo-β-lactamase

Carbapenems, 'last-resort' β-lactam antibiotics, are inactivated by zinc-dependent metallo-β-lactamases (MBLs). The host innate immune response withholds nutrient metal ions from microbial pathogens by releasing metal-chelating proteins such as calprotectin. We show that metal sequestration is detrimental for the accumulation of MBLs in the bacterial periplasm, because those enzymes are readily degraded in their nonmetallated form. However, the New Delhi metallo-β-lactamase (NDM-1) can persist under conditions of metal depletion. NDM-1 is a lipidated protein that anchors to the outer membrane of Gram-negative bacteria. Membrane anchoring contributes to the unusual stability of NDM-1 and favors secretion of this enzyme in outer-membrane vesicles (OMVs). OMVs containing NDM-1 can protect nearby populations of bacteria from otherwise lethal antibiotic levels, and OMVs from clinical pathogens expressing NDM-1 can carry this MBL and the bla[subscript NDM] gene. We show that protein export into OMVs can be targeted, providing possibilities of new antibacterial therapeutic strategies.Kinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

Why we need easy access to all data from all clinical trials and how to accomplish it

International calls for registering all trials involving humans and for sharing the results, and sometimes also the raw data and the trial protocols, have increased in recent years. Such calls have come, for example, from the Organization for Economic Cooperation and Development (OECD), the World Health Organization (WHO), the US National Institutes of Heath, the US Congress, the European Commission, the European ombudsman, journal editors, The Cochrane Collaboration, and several funders, for example the UK Medical Research Council, the Wellcome Trust, the Bill and Melinda Gates Foundation and the Hewlett Foundation

Hox10 Genes Function in Kidney Development in the Differentiation and Integration of the Cortical Stroma

Organogenesis requires the differentiation and integration of distinct populations of cells to form a functional organ. In the kidney, reciprocal interactions between the ureter and the nephrogenic mesenchyme are required for organ formation. Additionally, the differentiation and integration of stromal cells are also necessary for the proper development of this organ. Much remains to be understood regarding the origin of cortical stromal cells and the pathways involved in their formation and function. By generating triple mutants in the Hox10 paralogous group genes, we demonstrate that Hox10 genes play a critical role in the developing kidney. Careful examination of control kidneys show that Foxd1-expressing stromal precursor cells are first observed in a cap-like pattern anterior to the metanephric mesenchyme and these cells subsequently integrate posteriorly into the kidney periphery as development proceeds. While the initial cap-like pattern of Foxd1-expressing cortical stromal cells is unaffected in Hox10 mutants, these cells fail to become properly integrated into the kidney, and do not differentiate to form the kidney capsule. Consistent with loss of cortical stromal cell function, Hox10 mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that Hox11 genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique Hox codes, and that differential Hox function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis

Local Modelling Techniques for Assessing Micro-Level Impacts of Risk Factors in Complex Data: Understanding Health and Socioeconomic Inequalities in Childhood Educational Attainments

Although inequalities in health and socioeconomic status have an important influence on childhood educational performance, the interactions between these multiple factors relating to variation in educational outcomes at micro-level is unknown, and how to evaluate the many possible interactions of these factors is not well established. This paper aims to examine multi-dimensional deprivation factors and their impact on childhood educational outcomes at micro-level, focusing on geographic areas having widely different disparity patterns, in which each area is characterised by six deprivation domains (Income, Health, Geographical Access to Services, Housing, Physical Environment, and Community Safety). Traditional health statistical studies tend to use one global model to describe the whole population for macro-analysis. In this paper, we combine linked educational and deprivation data across small areas (median population of 1500), then use a local modelling technique, the Takagi-Sugeno fuzzy system, to predict area educational outcomes at ages 7 and 11. We define two new metrics, “Micro-impact of Domain” and “Contribution of Domain”, to quantify the variations of local impacts of multidimensional factors on educational outcomes across small areas. The two metrics highlight differing priorities. Our study reveals complex multi-way interactions between the deprivation domains, which could not be provided by traditional health statistical methods based on single global model. We demonstrate that although Income has an expected central role, all domains contribute, and in some areas Health, Environment, Access to Services, Housing and Community Safety each could be the dominant factor. Thus the relative importance of health and socioeconomic factors varies considerably for different areas, depending on the levels of each of the other factors, and therefore each component of deprivation must be considered as part of a wider system. Childhood educational achievement could benefit from policies and intervention strategies that are tailored to the local geographic areas' profiles

Principles of genetic circuit design

Cells navigate environments, communicate and build complex patterns by initiating gene expression in response to specific signals. Engineers seek to harness this capability to program cells to perform tasks or create chemicals and materials that match the complexity seen in nature. This Review describes new tools that aid the construction of genetic circuits. Circuit dynamics can be influenced by the choice of regulators and changed with expression 'tuning knobs'. We collate the failure modes encountered when assembling circuits, quantify their impact on performance and review mitigation efforts. Finally, we discuss the constraints that arise from circuits having to operate within a living cell. Collectively, better tools, well-characterized parts and a comprehensive understanding of how to compose circuits are leading to a breakthrough in the ability to program living cells for advanced applications, from living therapeutics to the atomic manufacturing of functional materials.National Institute of General Medical Sciences (U.S.) (Grant P50 GM098792)National Institute of General Medical Sciences (U.S.) (Grant R01 GM095765)National Science Foundation (U.S.). Synthetic Biology Engineering Research Center (EEC0540879)Life Technologies, Inc. (A114510)National Science Foundation (U.S.). Graduate Research FellowshipUnited States. Office of Naval Research. Multidisciplinary University Research Initiative (Grant 4500000552