Beyond Domain-Led Conceptualisations of Urban Zero-Carbon Transitions

Rapid, systemic change is needed to achieve zero emissions, but there is uncertainty about how or where to intervene in urban systems. Drawing on the work of Donella Meadows, we apply a Leverage Points Perspective to identify and characterize points of system-level intervention that emerge from a study of climate action in Calgary, Canada, which was unique in applying a mixed set of academic approaches. Reflecting on Meadows’ and other frameworks for conceptualizing complex systems change, we discuss the challenge of conceptualizing change, a task of unique urgency in the context of the climate emergency. Too frequently, we argue, approaches focus attention on specific modes or forms of action seen to have the greatest opportunity for affecting change in place of the complex chains of actors, objects, and processes that collectively are the key to a deep and sustaining transition. We conclude by exploring how the insights of the Leverage Points Perspective and other approaches can be brought together to inform practical action, and by examining how related theoretical work on provisioning systems and applied work on urban Climate Commissions may be drawn on to advance understanding of how to deliver urban systems change

Class-Switch Recombination (CSR)/Hyper-IgM (HIGM) Syndromes and Phosphoinositide 3-Kinase (PI3K) Defects

Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological phenotypes can result in dysregulation of the immune system humoral compartment, including class-switch recombination (CSR) defects associated with hyper-IgM (HIGM) syndromes. The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE isotypes. Recently described autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 cause combined immunodeficiencies that can also present as CSR/HIGM defects. These defects, their pathophysiology and derived clinical manifestations are described in depth. Previously reported forms of CSR/HIGM syndromes are briefly reviewed and compared to the phosphoinositide 3-kinase (PI3K) pathway defects. Diseases involving the PI3K pathway represent a distinctive subset of CSR/HIGM syndromes, presenting with their own characteristic clinical and laboratory attributes as well as individual therapeutic approaches

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

IMPORTANCE: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. OBJECTIVE: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. EVIDENCE REVIEW: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. FINDINGS: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. CONCLUSIONS AND RELEVANCE: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO\u27s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes

A Statistical Activity Cost Analysis of the Relationship Between Physical and Financial Aspects of Fixed Assets

In this paper, Statistical Activity Cost Analysis (SACA) is used to identify the interaction of mutually dependent physical and financial aspects of a fixed asset-like system configuration. The novelty of the approach is, having established a rational description of the uncertainty inherent in both domains, the analysis of their interaction. Little research to date has investigated the duality of engineering and accounting aspects, in a statistical setting. Our approach is conceptual rather than empirical. We use an illustrative 4-component model, a) to explain the concept of SACA by means of a software demonstration tool, b) to relate financial issues of cost to engineering asset capacity to perform specified tasks, and c) to demonstrate how to produce quantified measures of return and risk, both of which are relevant in areas of life-cycle analysis, budgeting and planning decision-making

Symbiotic effectiveness in nodulated red clover IV Influence of host factors

RESP-382