Consensus Expert Recommendations for the Diagnosis and Management of Autosomal Recessive Polycystic Kidney Disease: Report of an International Conference

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a severe, typically early onset form of cystic disease that primarily involves the kidneys and biliary tract. Phenotypic expression and age at presentation can be quite variable1. The incidence of ARPKD is 1 in 20,000 live births2, and its pleotropic manifestations are potentially life-threatening. Optimal care requires proper surveillance to limit morbidity and mortality, knowledgeable approaches to diagnosis and treatment, and informed strategies to optimize quality of life. Clinical management therefore is ideally directed by multidisciplinary care teams consisting of perinatologists, neonatologists, nephrologists, hepatologists, geneticists, and behavioral specialists to coordinate patient care from the perinatal period to adulthood. In May 2013, an international team of 25 multidisciplinary specialists from the US, Canada, Germany, and the United Kingdom convened in Washington, DC, to review the literature published from 1990 to 2013 and to develop recommendations for diagnosis, surveillance, and clinical management. Identification of the gene PKHD1, and the significant advances in perinatal care, imaging, medical management, and behavioral therapies over the past decade, provide the foundational elements to define diagnostic criteria and establish clinical management guidelines as the first steps towards standardizing the clinical care for ARPKD patients. The key issues discussed included recommendations regarding perinatal interventions, diagnostic criteria, genetic testing, management of renal and biliary-associated morbidities, and behavioral assessment. The meeting was funded by the National Institutes of Health and an educational grant from the Polycystic Kidney Disease Foundation. Here we summarize the discussions and provide an updated set of diagnostic, surveillance, and management recommendations for optimizing the pediatric care of patients with ARPKD. Specialist care of ARPKD-related complications including dialysis, transplantation, and management of severe portal hypertension will be addressed in a subsequent report. Given the paucity of information regarding targeted therapies in ARPKD, this topic was not addressed in this conference.

Cross-scale analysis of social-ecological systems:Policy options appraisal for delivering NetZero and other environmental objectives in Scotland

Public policy confronts complex, contested, wicked problems such as climate and biodiversity crises with challenges of how issues are framed, analysed, codified, and interpreted. Social-ecological systems provide an analytical framework that couples the biosphere and technosphere, recognising biophysical limits and emphasising the importance of critical reflection within policy decision-making. Conducting policy-options appraisals is increasingly seen as a transdisciplinary research-policy endeavour with researchers engaging policy actors in an extended peer community (post-normal science). This paper presents a case study of analysis undertaken with researchers, policy analysts, policy makers and other stakeholders to support decisions on how to implement future agriculture support in Scotland, so that the policy programme better delivers across social, economic and environmental objectives. The key change being considered in the future agricultural support programme is Enhanced Conditionality (EC) where the level of financial support provided to farm-businesses will depend on their undertaking agri-environmental measures that deliver against the key priorities of reducing greenhouse gas emissions and reversing biodiversity losses. The paper outlines the policy context within which the EC options appraisal takes place – highlighting how EC is a crucial component in making the wider suite of policy measures work. The transdisciplinary approach, Quantitative Story Telling (QST) is presented, emerging from decision support, participatory research, and post-normal science for policy domains. The stages of QST highlight the importance of analysis that underpins any quantification (decision on how issues are framed and what it included in the analysis) and the expectation that research outputs with be deliberated on with, and interpreted from, stakeholder perspectives. The project specific analyses are outlined, combining top-down options appraisal of how macro-policy decisions could constrain EC and bottom-up analysis of potential uptake and effectiveness of EC measures, undertaken in inter-disciplinary workshops with domain experts from biodiversity, soils and waters. The paper highlights challenges for implementation and evaluation at meso-scale with interactions between farm-businesses and catchment, landscape and regional objectives. The conclusions of the analysis, in policy terms, are that EC presents an opportunity to significantly realign how agricultural land management is conducted in Scotland, so that it is more effective in delivering climate change and biodiversity objectives, but there are formidable challenges in resolving the policy “sudoku”. Meso-scale issues are likely to mean the need to integrate alternative modelling paradigms such as spatial, empirical agent-based modelling (ABM) into policy option appraisals. By taking multi-scale, social-ecological systems perspectives on EC it has been possible to identify key policy decisions at a range of scales on which the success of EC will depend, to have a realistic understanding of how effective the EC measures might be in heterogenous Scottish environments and what are the likely barriers to uptake. The analysis also highlighted where outcomes of the policy change are likely to be challenging to monitor-evaluate; and where there are dependencies between farm-businesses that mean EC measures need to be supplemented with mechanisms that (1) promote cooperation between land managers and (2) identify and respond to agreed local priorities. The value of the participatory QST process was in making sure the analyses being undertaken were salient and the outputs seen as credible – but the challenges of interpreting necessarily complex outputs remain. The greatest value of QST may be that it provides a structured way to navigate complexity with policy makers rather than seeking to control or eliminate it.</p

Cross-scale analysis of social-ecological systems:Policy options appraisal for delivering NetZero and other environmental objectives in Scotland

Public policy confronts complex, contested, wicked problems such as climate and biodiversity crises with challenges of how issues are framed, analysed, codified, and interpreted. Social-ecological systems provide an analytical framework that couples the biosphere and technosphere, recognising biophysical limits and emphasising the importance of critical reflection within policy decision-making. Conducting policy-options appraisals is increasingly seen as a transdisciplinary research-policy endeavour with researchers engaging policy actors in an extended peer community (post-normal science). This paper presents a case study of analysis undertaken with researchers, policy analysts, policy makers and other stakeholders to support decisions on how to implement future agriculture support in Scotland, so that the policy programme better delivers across social, economic and environmental objectives. The key change being considered in the future agricultural support programme is Enhanced Conditionality (EC) where the level of financial support provided to farm-businesses will depend on their undertaking agri-environmental measures that deliver against the key priorities of reducing greenhouse gas emissions and reversing biodiversity losses. The paper outlines the policy context within which the EC options appraisal takes place – highlighting how EC is a crucial component in making the wider suite of policy measures work. The transdisciplinary approach, Quantitative Story Telling (QST) is presented, emerging from decision support, participatory research, and post-normal science for policy domains. The stages of QST highlight the importance of analysis that underpins any quantification (decision on how issues are framed and what it included in the analysis) and the expectation that research outputs with be deliberated on with, and interpreted from, stakeholder perspectives. The project specific analyses are outlined, combining top-down options appraisal of how macro-policy decisions could constrain EC and bottom-up analysis of potential uptake and effectiveness of EC measures, undertaken in inter-disciplinary workshops with domain experts from biodiversity, soils and waters. The paper highlights challenges for implementation and evaluation at meso-scale with interactions between farm-businesses and catchment, landscape and regional objectives. The conclusions of the analysis, in policy terms, are that EC presents an opportunity to significantly realign how agricultural land management is conducted in Scotland, so that it is more effective in delivering climate change and biodiversity objectives, but there are formidable challenges in resolving the policy “sudoku”. Meso-scale issues are likely to mean the need to integrate alternative modelling paradigms such as spatial, empirical agent-based modelling (ABM) into policy option appraisals. By taking multi-scale, social-ecological systems perspectives on EC it has been possible to identify key policy decisions at a range of scales on which the success of EC will depend, to have a realistic understanding of how effective the EC measures might be in heterogenous Scottish environments and what are the likely barriers to uptake. The analysis also highlighted where outcomes of the policy change are likely to be challenging to monitor-evaluate; and where there are dependencies between farm-businesses that mean EC measures need to be supplemented with mechanisms that (1) promote cooperation between land managers and (2) identify and respond to agreed local priorities. The value of the participatory QST process was in making sure the analyses being undertaken were salient and the outputs seen as credible – but the challenges of interpreting necessarily complex outputs remain. The greatest value of QST may be that it provides a structured way to navigate complexity with policy makers rather than seeking to control or eliminate it.</p

Ligand influences on homoleptic Group 12 m-terphenyl complexes

Three m-terphenyl ligands 2,6-Ar2C6H3 – [Ar = 2,6-Me2C6H3 (2,6-Xyl); 3,5-Me2C6H3 (3,5-Xyl); 2,3,4,5,6-Me5C6 (Pmp)] have been used to stabilise three series of two-coordinate Group 12 diaryl complexes; (2,6-Ar2C6H3)2M [M = Zn, Cd, Hg; Ar = 2,6-Xyl 1-3; 3,5-Xyl 4-6; Pmp 7-9], where differing steric demands on the metal centres are imparted. These are the first homoleptic d-block complexes featuring any of these ligands. Complexes 1-9 have been characterised in solution and the solid state; the analysis of structural changes produced by differences in ligand properties is reported. In particular, complexes 4-6 show smaller C–M–C bond angles and contain secondary ligand interactions that are not seen in the analogous complexes 1-3 and 7-9

Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis

Background: Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality. Methods: Clinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models. Results: Of 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p < 0.001), anti-MPO positive vs anti-MPO negative (38.5% vs 13.6%, p = 0.006) and anti-PR3 positive vs anti-PR3 negative patients (44.4% vs 13.4%, p < 0.001). A higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%, p < 0.001) and the anti-PR3 positive groups (50.0% vs 23.4%, p = 0.009). In multivariable analysis, ANCA-positive status remained associated with ILD after adjusting for anti-Scl-70 antibodies. Pulmonary embolism (PE) was more common in ANCA-positive patients (8.6% vs 3.0%, p = 0.002) and anti-PR3-positive patients (16.7% vs 3.3%, p = 0.022). ANCA-positive status remained associated with PE in a multivariable analysis adjusting for anti-phospholipid antibodies. Kaplan-Meier analysis revealed increased mortality in ANCA-positive patients (p = 0.006). In Cox regression analysis, ANCA was associated with increased mortality, after adjusting for age and sex. Conclusions: ANCA is associated with increased prevalence of ILD and PE in SSc. ANCA should be tested in SSc, as it identifies individuals with worse prognosis who require close monitoring for adverse outcomes.Jayne Moxey, Molla Huq, Susanna Proudman, Joanne Sahhar, Gene-Siew Ngian, Jenny Walker, Gemma Strickland, Michelle Wilson, Laura Ross, Gabor Major, Janet Roddy, Wendy Stevens, and Mandana Nikpou

Research activity and the association with mortality.

INTRODUCTION: The aims of this study were to describe the key features of acute NHS Trusts with different levels of research activity and to investigate associations between research activity and clinical outcomes. METHODS: National Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN) funding and number of patients recruited to NIHR Clinical Research Network (CRN) portfolio studies for each NHS Trusts were used as markers of research activity. Patient-level data for adult non-elective admissions were extracted from the English Hospital Episode Statistics (2005-10). Risk-adjusted mortality associations between Trust structures, research activity and, clinical outcomes were investigated. RESULTS: Low mortality Trusts received greater levels of funding and recruited more patients adjusted for size of Trust (n = 35, 2,349 £/bed [95% CI 1,855-2,843], 5.9 patients/bed [2.7-9.0]) than Trusts with expected (n = 63, 1,110 £/bed, [864-1,357] p<0.0001, 2.6 patients/bed [1.7-3.5] p<0.0169) or, high (n = 42, 930 £/bed [683-1,177] p = 0.0001, 1.8 patients/bed [1.4-2.1] p<0.0005) mortality rates. The most research active Trusts were those with more doctors, nurses, critical care beds, operating theatres and, made greater use of radiology. Multifactorial analysis demonstrated better survival in the top funding and patient recruitment tertiles (lowest vs. highest (odds ratio & 95% CI: funding 1.050 [1.033-1.068] p<0.0001, recruitment 1.069 [1.052-1.086] p<0.0001), middle vs. highest (funding 1.040 [1.024-1.055] p<0.0001, recruitment 1.085 [1.070-1.100] p<0.0001). CONCLUSIONS: Research active Trusts appear to have key differences in composition than less research active Trusts. Research active Trusts had lower risk-adjusted mortality for acute admissions, which persisted after adjustment for staffing and other structural factors

Connectivity-change moving mesh methods for high-order meshes: Toward closed advancing-layer high-order boundary layer mesh generation

International audienceCurved mesh generation starting from a P1 mesh and closed advancing-layer boundary layer mesh generation both rely on mesh deformation and mesh optimization techniques. The approach presented in this work is to generalize connectivity-change moving mesh methods to high-order meshes. This approach is based on a high-order linear elasticity solver for the mesh deformation and on high-order mesh optimization operators such as mesh smoothing and generalized swapping. Thanks to this method, Pk meshes are generated from P1 meshes and closed advancing-layer boundary layer mesh generation will soon be possible

Health-Related Quality of Life of Children With Mild to Moderate Chronic Kidney Disease

To compare the health related quality of life (HRQOL) of children with chronic kidney disease (CKD) to healthy children; to evaluate the association between CKD severity and HRQOL; to identity demographic, socioeconomic and health-status variables associated with impairment in HRQOL in children with mild to moderate CKD