A Modified Bicanalicular Crawford Placement Method for Congenital Nasolacrimal Duct Obstruction: Reducing Need for Operative Room Removal.

PURPOSE: This study introduces a method for Crawford bicanalicular stent placement for congenital nasolacrimal duct obstruction by looping the ends to themselves which are tied together with dissolvable sutures to ease in-office removal. METHODS: This is a single institution, retrospective study that evaluates outcomes of patients aged 5 years and under who underwent bicanalicular stenting for congenital nasolacrimal duct obstruction by a single surgeon (G.S.E.) between 2004 and 2020. Only primary surgeries were included in the analysis. Stenting could be accompanied by balloon dilatation and/or turbinate infracture. Age, sex, follow-up time, complications, type of intervention, extrusion, recurrence, and operative room removal were recorded. RESULTS: This study included 56 eyes from 54 patients with a mean age of 19.0 ± 9.5 months (range, 8-50 months). There was a 30.3% extrusion rate, a 5.4% rate of recurrence of disease, and a 3.6% rate of operative room removal. The average follow-up time was 25.1 ± 39.8 months (range, 1-132 months). For patients with or without extrusion, there were no significant differences between age, sex, laterality, type of intervention, follow-up time, or rate of recurrence. Each eye that had recurrence (3 total) or needed operative room removal (2 total) underwent only bicanalicular stenting without accompanying procedures, although the difference in rates between procedures was also not statistically significant. CONCLUSIONS: This method had a low recurrence and operative room removal rate, with similar extrusion and complication rates to other bicanalicular stent and intubation methods for the treatment of congenital nasolacrimal duct obstruction.

Efficient, Formal, Material, and Final Causes in Biology and Technology.

This paper considers how a classification of causal effects as comprising efficient, formal, material, and final causation can provide a useful understanding of how emergence takes place in biology and technology, with formal, material, and final causation all including cases of downward causation; they each occur in both synchronic and diachronic forms. Taken together, they underlie why all emergent levels in the hierarchy of emergence have causal powers (which is Noble's principle of biological relativity) and so why causal closure only occurs when the upwards and downwards interactions between all emergent levels are taken into account, contra to claims that some underlying physics level is by itself causality complete. A key feature is that stochasticity at the molecular level plays an important role in enabling agency to emerge, underlying the possibility of final causation occurring in these contexts.

Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy.

BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

Variability in maximal suggested door-in-door-out time for hospitals transferring patients for primary angioplasty in STEMI.

OBJECTIVES: We derived a formula for maximal suggested door-in-door-out time (DIDO) for hospitals that do not perform primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). BACKGROUND: Efforts to minimize DIDO at non-PCI hospitals can improve door-to-balloon time (D2B). Targeting a maximal suggested DIDO for a transferring hospital can influence reperfusion strategy. METHODS: We examined time to treatment intervals for 193 STEMI patients who underwent primary PCI at our hospital. D2B in transferred patients (D2BT ) was divided into 3 intervals: transferring hospital DIDO, inter-hospital transport time, and interventional time. We defined maximal suggested DIDO as the maximum DIDO that would allow PCI with D2BT ≤ 120 minutes. RESULTS: D2B was higher in transfer compared to on-site patients (147 ± 52 vs. 75 ± 44 minutes, P < 0.0001). In transfer patients, treatment time intervals were: DIDO 80 ± 42 minutes, transport time 37 ± 18 minutes, interventional time 35 ± 16 minutes. The greatest variability in D2BT was related to DIDO. We estimated that maximal suggested DIDO = [120 - (transport time plus interventional time)]. Using a fixed interventional time of 40 minutes, we simplified this as: maximal DIDO = 80 - transport time. Maximal suggested DIDO for 4 transferring hospitals in our network ranged from 1 to 65 minutes. DIDO under the hospital-specific threshold was the strongest predictor of achieving D2BT <120 minutes. CONCLUSIONS: Transferring hospitals' maximal suggested DIDO is variable, and can be calculated from inter-hospital transport time. Instead of a universal target DIDO (e.g., <30 minutes), maximal suggested DIDO can be calculated individually for each non-PCI hospital within a STEMI network.

Revenge and forgiveness in the New South Africa.

Insofar as South Africa underwent a rapid transformation from apartheid to democracy, it may provide a unique laboratory for investigating aspects of revenge and forgiveness. Here we suggest that observations and data from South Africa are partially consistent with the hypotheses generated by MCullough and colleagues. At the same time, the rich range of revenge and forgiveness phenomena in real-life settings is likely to require explanatory concepts other than specialized modules and their computational outputs.

Biological relativity revisited: the pre-eminent role of values.

Multilevel interpretations of development and evolution take to heart the contextual nature of both those processes, and so necessarily assume top-down causation occurs, right down to the physics level. In this article we revisit the Principle of Biological Relativity proposed by Noble in 2012, where all emergent levels of organisation are equally causally valid. While this is true in general for physical interactions between levels, we argue that in the case of conscious organisms making rational choices, there is indeed a preferred causal origin - namely the overall embracing influence of meaning and values. This is the opposite of what is suggested by a reductionist viewpoint, where it is the bottom-most physical level that is stated to be causally preferred (by some physicists), or the genetic level (by some evolutionary theorists). Charles Darwin was therefore correct to distinguish between Artificial (conscious) Selection, where values enter, and Natural Selection. The Modern Synthesis was wrong to exclude Darwin's distinction.

Path: a tool to facilitate pathway-based genetic association analysis.

SUMMARY: Traditional methods of genetic study design and analysis work well under the scenario that a handful of single nucleotide polymorphisms (SNPs) independently contribute to the risk of disease. For complex diseases, susceptibility may be determined not by a single SNP, but rather a complex interplay between SNPs. For large studies involving hundreds of thousands of SNPs, a brute force search of all possible combinations of SNPs associated with disease is not only inefficient, but also results in a multiple testing paradigm, whereby larger and larger sample sizes are needed to maintain statistical power. Pathway-based methods are an example of one of the many approaches in identifying a subset of SNPs to test for interaction. To help determine which SNP-SNP interactions to test, we developed Path, a software application designed to help researchers interface their data with biological information from several bioinformatics resources. To this end, our application brings together currently available information from nine online bioinformatics resources including the National Center for Biotechnology Information (NCBI), Online Mendelian Inheritance in Man (OMIM), Kyoto Encyclopedia of Genes and Genomes (KEGG), UCSC Genome Browser, Seattle SNPs, PharmGKB, Genetic Association Database, the Single Nucleotide Polymorphism database (dbSNP) and the Innate Immune Database (IIDB). AVAILABILITY: The software, example datasets and tutorials are freely available from http://genapha.icapture.ubc.ca/PathTutorial.

The Causal Closure of Physics in Real World Contexts.

The causal closure of physics is usually discussed in a context free way. Here I discuss it in the context of engineering systems and biology, where strong emergence takes place due to a combination of upwards emergence and downwards causation (Ellis, Emergence in Solid State Physics and Biology, 2020, arXiv:2004.13591). Firstly, I show that causal closure is strictly limited in terms of spatial interactions because these are cases that are of necessity strongly interacting with the environment. Effective Spatial Closure holds ceteris parabus, and can be violated by Black Swan Events. Secondly, I show that causal closure in the hierarchy of emergence is a strictly interlevel affair, and in the cases of engineering and biology encompasses all levels from the social level to the particle physics level. However Effective Causal Closure can usefully be defined for a restricted set of levels, and one can experimentally determine Effective Theories that hold at each level. This does not however imply those effective theories are causally complete by themselves. In particular, the particle physics level is not causally complete by itself in the contexts of solid state physics (because of interlevel wave-particle duality), digital computers (where algorithms determine outcomes), or biology (because of time dependent constraints). Furthermore Inextricably Intertwined Levels occur in all these contexts.

Top-down effects in the brain.

The purpose of this investigation is to demonstrate that one is unable to understand the operation of the brain without taking top-down effects into account. This is demonstrated by looking in turn at evolutionary and developmental aspects, then at functional aspects related to sensory systems, learning processes, and motor processes that lead to action on the world. It is also clear in terms of the effects of a society on brains located in that society. The possibility of top down affects exists both because of multiple realisability of higher level processes at lower levels, and because lower level elements are adapted to perform their higher level functions. These top-down processes validate a non-reductionist approach to how the brain works.

The Dynamical Emergence of Biology From Physics: Branching Causation via Biomolecules.

Biology differs fundamentally from the physics that underlies it. This paper proposes that the essential difference is that while physics at its fundamental level is Hamiltonian, in biology, once life has come into existence, causation of a contextual branching nature occurs at every level of the hierarchy of emergence at each time. The key feature allowing this to happen is the way biomolecules such as voltage-gated ion channels can act to enable branching logic to arise from the underlying physics, despite that physics per se being of a deterministic nature. Much randomness occurs at the molecular level, which enables higher level functions to select lower level outcomes according to higher level needs. Intelligent causation occurs when organisms engage in deduction, enabling prediction and planning. This is possible because ion channels enable action potentials to propagate in axons. The further key feature is that such branching biological behavior acts down to cause the underlying physical interactions to also exhibit a contextual branching behavior.