Blood Lead Secular Trend in a Cohort of Children in Mexico City (1987–2002)

We determined the secular trend in blood lead levels in a cohort of 321 children born in Mexico City between 1987 and 1992. Blood lead level was measured every 6 months during a 10-year period. We modeled the effect of yearly air lead concentration nested within the calendar year in which the child was born, family use of lead-glazed pottery, socioeconomic status, year in which the child was born, age of the child at the time of blood lead measurement, place of residence, and an indicator variable for subjects with complete or incomplete blood lead values. The yearly mean of air lead of the Valley of Mexico decreased from its highest level of 2.80 μg/m(3) in 1987 to 0.07 μg/m(3) in 2002. The contribution of air lead to blood lead according to year of birth was strongest for subjects born in 1987 and fell to nearly zero for children born in 1992. The geometric mean of the entire cohort rose from 8.4 μg/dL in the first year of life to 10.1 μg/dL in the second and decreased thereafter until it reached 6.4 μg/dL at 10 years of age. Children of families who used lead-glazed ceramics had blood lead levels 18.5% higher than did children of nonusing families. Children who belonged to the lowest socioeconomic levels had blood lead levels 32.2% higher than did those of highest socioeconomic levels. Children who lived in the northeast part of the city had blood lead levels 10.9% higher compared with those who lived in the southwest

Prediction and Topological Models in Neuroscience

In the last two decades, philosophy of neuroscience has predominantly focused on explanation. Indeed, it has been argued that mechanistic models are the standards of explanatory success in neuroscience over, among other things, topological models. However, explanatory power is only one virtue of a scientific model. Another is its predictive power. Unfortunately, the notion of prediction has received comparatively little attention in the philosophy of neuroscience, in part because predictions seem disconnected from interventions. In contrast, we argue that topological predictions can and do guide interventions in science, both inside and outside of neuroscience. Topological models allow researchers to predict many phenomena, including diseases, treatment outcomes, aging, and cognition, among others. Moreover, we argue that these predictions also offer strategies for useful interventions. Topology-based predictions play this role regardless of whether they do or can receive a mechanistic interpretation. We conclude by making a case for philosophers to focus on prediction in neuroscience in addition to explanation alone

Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Id3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the alphabeta and gammadelta T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCRalphabeta+ T lymphocytes. More recently, Id3(-/-) mice on a C57BL/6 background were shown to have a dramatic expansion of gammadelta T cells.Here we report that mice lacking Id3 have reduced thymocyte numbers but increased production of gammadelta T cells that express a Vgamma1.1+Vdelta6.3+ receptor with restricted junctional diversity. These Vgamma1.1+Vdelta6.3+ T cells have multiple characteristics associated with "innate" lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other "innate" lymphocyte populations, development of Id3(-/-) Vgamma1.1+Vdelta6.3+ T cells requires the signaling adapter protein SAP.Our data provide novel insight into the requirements for development of Vgamma1.1+Vdelta6.3+ T cells and indicate a role for Id3 in repressing the response of "innate" gammadelta T cells to SAP-mediated expansion or survival

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication of the 5q22 locus (meta-analysis p = 1.9×10−16), we identified association at 2p23 (encoding CAPN14, p = 2.5×10−10). CAPN14 was specifically expressed in the esophagus, dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13, and located in an epigenetic hotspot modified by IL-13. There was enriched esophageal expression for the genes neighboring the top 208 EoE sequence variants. Multiple allergic sensitization loci were associated with EoE susceptibility (4.8×10−2 < p < 5.1×10−11). We propose a model that elucidates the tissue specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS)

BACKGROUND End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis

Paradox Research in Management Science: Looking Back to Move Forward

Paradox studies offer vital and timely insights into an array of organizational tensions. Yet this field stands at a critical juncture. Over the past 25 years, management scholars have drawn foundational insights from philosophy and psychology to apply a paradox lens to organizational phenomena. Yet extant studies selectively leverage ancient wisdom, adopting some key insights while abandoning others. Using a structured content analysis to review the burgeoning management literature, we surface six key themes, which represent the building blocks of a meta-theory of paradox. These six themes received varying attention in extant studies: paradox scholars emphasize types of paradoxes, collective approaches, and outcomes, but pay less attention to relationships within paradoxes, individual approaches, and dynamics. As this analysis suggests, management scholars have increasingly simplified the intricate, often messy phenomena of paradox. Greater simplicity renders phenomena understandable and testable, however, oversimplifying complex realities can foster reductionist and incomplete theories. We therefore propose a future research agenda targeted at enriching a meta-theory of paradox by reengaging these less developed themes. Doing so can sharpen the focus of this field, while revisiting its rich conceptual roots to capture the intricacies of paradox. This future research agenda leverages the potential of paradox across diverse streams of management science

Absolute uniqueness of phase retrieval with random illumination

Random illumination is proposed to enforce absolute uniqueness and resolve all types of ambiguity, trivial or nontrivial, from phase retrieval. Almost sure irreducibility is proved for any complex-valued object of a full rank support. While the new irreducibility result can be viewed as a probabilistic version of the classical result by Bruck, Sodin and Hayes, it provides a novel perspective and an effective method for phase retrieval. In particular, almost sure uniqueness, up to a global phase, is proved for complex-valued objects under general two-point conditions. Under a tight sector constraint absolute uniqueness is proved to hold with probability exponentially close to unity as the object sparsity increases. Under a magnitude constraint with random amplitude illumination, uniqueness modulo global phase is proved to hold with probability exponentially close to unity as object sparsity increases. For general complex-valued objects without any constraint, almost sure uniqueness up to global phase is established with two sets of Fourier magnitude data under two independent illuminations. Numerical experiments suggest that random illumination essentially alleviates most, if not all, numerical problems commonly associated with the standard phasing algorithms.Comment: 21 pages, 7 figure