Faculty Bibliography

Background/Purpose: Given phenotypic similarities between rheumatoid arthritis-associated interstitial lung disease (RAILD) and idiopathic pulmonary fibrosis (IPF), we hypothesized that the strongest risk factor for the development of IPF, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD in patients with RA.
Method(s): Using a discovery population and multi-ethnic validation case series, we tested the association of the MUC5B promoter variant in RA-ILD(N=620), RA without ILD (N=614), and unaffected controls (N=5448).
Result(s): The discovery population revealed an association of the MUC5B promoter variant minor allele with RA-ILD when compared to unaffected controls (ORadj=3.8 95%CI [2.8-5.2]; P=9.7x10^-17). Similar to the discovery population, the MUC5B promoter variant was significantly over-represented among the RA-ILD cases in the multi-ethnic study case series when compared to unaffected controls (ORadj=5.595%CI[4.2-7.2]; P=4.7x10^-35), and when the discovery population and the multi-ethnic case series were combined (ORcombined=4.795%CI[3.9-5.8]; P=1.3x10^-49). Additionally, the MUC5B promoter variant was found to increase the risk of ILD among patients with RA (ORcombined=3.195%CI[1.8-5.4]; P=7.4x10^-5), however, no statistical association with the MUC5B promoter variant was observed for RA alone. The association of the MUC5B promoter variant with RA-ILD increased significantly when restricted to usual interstitial pneumonia(UIP) pattern by high-resolution computed tomography (ORcombined=6.1 95%CI[2.9-13.1]; P=2.5x10^-6). Given our results, we decided to explore 12 other common variants previously reported to be associated with IPF (LLRC34rs6793295, FAM13A rs2609255, TERT rs2736100, EHMT2 rs7887, DSP rs2076295, rs4727443, OBFC1 rs11191865, TOLLIP rs5743890 and rs111521887, ATP11A rs1278769, IVDrs2034650 and DPP9 rs12610495). In this exploratory analyze, we found that 2 other IPF risk variants, TOLLIPrs5743890 and IVD rs2034650, were also preliminarily associated with RA-ILD (ORcombined=2.1 95%CI [1.1-4.1]; P=0.02 and ORcombined=0.5995%CI[0.4-0.9]; P=0.01, respectively). These findings should be replicated to further conclude to their role in the RA-ILD genetic background.
Conclusion(s): Our findings demonstrate that the MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of the UIP pattern. Furthermore, other IPF related common variants may also participate in RA-ILD genetic susceptibility (Figure Presented)

Individuals can vary substantially in size, but the proportions of their body plans are often maintained. We generated smaller zebrafish by removing 30% of their cells at the blastula stages and found that these embryos developed into normally patterned individuals. Strikingly, the proportions of all germ layers adjusted to the new embryo size within 2 hours after cell removal. As Nodal-Lefty signalling controls germ-layer patterning, we performed a computational screen for scale-invariant models of this activator-inhibitor system. This analysis predicted that the concentration of the highly diffusive inhibitor Lefty increases in smaller embryos, leading to a decreased Nodal activity range and contracted germ-layer dimensions. In vivo studies confirmed that Lefty concentration increased in smaller embryos, and embryos with reduced Lefty levels or with diffusion-hindered Lefty failed to scale their tissue proportions. These results reveal that size-dependent inhibition of Nodal signalling allows scale-invariant patterning.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared to those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus, raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions. Donor aortae from western diet-fed Ldlr

Introduction: We will discuss recent progress in developing a single molecule nanotechnology to detect and characterize genomic translocations of diagnostic and prognostic significance in hematologic malignancies. In the clinical lab, fluorescent in situ hybridization (FISH) and PCR remain the mainstays; unfortunately, they fail in a meaningful fraction of cases, due either to insufficient resolution (FISH) or the fact that the vast majority of structural variant breakpoints are scattered widely and thus cannot be localized a priori for amplification by PCR. While microarrays can improve the detection of copy number variations, they are not a replacement for FISH, for example, because they cannot detect un-localized balanced translocations. Methods: In our approach, structural variations (indels and translocations) are identified by 'molecular barcoding', using targeted CRISPR-Cas9 DNA binding proteins as 'nanoparticles', identifiable with high-speed Atomic Force Microscopy (HSAFM). The resulting pattern and spacing of the markers allows precise identification of the genomic loci involved. Results: Using this novel technique, we mapped a known BCL2-IGH translocation present in the follicular lymphoma cell line DOHH-2, obtained commercially, and detected similar translocations in lymph node tissue samples from follicular lymphoma patients. We also present preliminary results showing detection and quantitation of a variety diagnostic targets including IGH-MYC translocations, and FLT3-ITD length polymorphisms. Conclusions: This approach has the potential to resolve diagnostic uncertainty in cases where fluorescent in situ hybridization (FISH) and PCR prove insufficient

Biological macromolecules encode information: some of it to endow the molecule with structural flexibility, some of it to enable molecular actions as a catalyst or a substrate, but a residual part can be used to communicate with other macromolecules. Thus, macromolecules do not need to possess information only to survive in an environment, but also to strategically interact with others by sending signals to a receiving macromolecule that can properly interpret the signal and act suitably. These sender-receiver signalling games are sustained by the information asymmetry that exists among the macromolecules. In both biochemistry and molecular evolution, the important role of information asymmetry remains largely unaddressed. Here, we provide a new unifying perspective on the impact of information symmetry between macromolecules on molecular evolutionary processes, while focusing on molecular deception. Biomolecular games arise from the ability of biological macromolecules to exert precise recognition, and their role as units of selection, meaning that they are subject to competition and cooperation with other macromolecules. Thus, signalling game theory can be used to better understand fundamental features of living systems such as molecular recognition, molecular mimicry, selfish elements and 'junk' DNA. We show how deceptive behaviour at the molecular level indicates a conflict of interest, and so provides evidence of genetic conflict. This model proposes that molecular deception is diagnostic of selfish behaviour, helping to explain the evasive behaviour of transposable elements in 'junk' DNA, for example. Additionally, in this broad review, a range of major evolutionary transitions are shown to be associated with the establishment of signalling conventions, many of which are susceptible to molecular deception. These perspectives allow us to assign rudimentary behaviour to macromolecules, and show how participation in signalling games differentiates biochemistry from abiotic chemistry.

PURPOSE/OBJECTIVE:The purpose of this report is to describe the development of an evidence-based care pathway that can be implemented globally. METHODS:The Global Spine Care Initiative (GSCI) care pathway development team extracted interventions recommended for the management of spinal disorders from six GSCI articles that synthesized the available evidence from guidelines and relevant literature. Sixty-eight international and interprofessional clinicians and scientists with expertise in spine-related conditions were invited to participate. An iterative consensus process was used. RESULTS:After three rounds of review, 46 experts from 16 countries reached consensus for the care pathway that includes five decision steps: awareness, initial triage, provider assessment, interventions (e.g., non-invasive treatment; invasive treatment; psychological and social intervention; prevention and public health; specialty care and interprofessional management), and outcomes. The care pathway can be used to guide the management of patients with any spine-related concern (e.g., back and neck pain, deformity, spinal injury, neurological conditions, pathology, spinal diseases). The pathway is simple and can be incorporated into educational tools, decision-making trees, and electronic medical records. CONCLUSION/CONCLUSIONS:A care pathway for the management of individuals presenting with spine-related concerns includes evidence-based recommendations to guide health care providers in the management of common spinal disorders. The proposed pathway is person-centered and evidence-based. The acceptability and utility of this care pathway will need to be evaluated in various communities, especially in low- and middle-income countries, with different cultural background and resources. These slides can be retrieved under Electronic Supplementary Material.

PURPOSE/OBJECTIVE:Spinal disorders, including back and neck pain, are major causes of disability, economic hardship, and morbidity, especially in underserved communities and low- and middle-income countries. Currently, there is no model of care to address this issue. This paper provides an overview of the papers from the Global Spine Care Initiative (GSCI), which was convened to develop an evidence-based, practical, and sustainable, spinal healthcare model for communities around the world with various levels of resources. METHODS:Leading spine clinicians and scientists around the world were invited to participate. The interprofessional, international team consisted of 68 members from 24 countries, representing most disciplines that study or care for patients with spinal symptoms, including family physicians, spine surgeons, rheumatologists, chiropractors, physical therapists, epidemiologists, research methodologists, and other stakeholders. RESULTS:Literature reviews on the burden of spinal disorders and six categories of evidence-based interventions for spinal disorders (assessment, public health, psychosocial, noninvasive, invasive, and the management of osteoporosis) were completed. In addition, participants developed a stratification system for surgical intervention, a classification system for spinal disorders, an evidence-based care pathway, and lists of resources and recommendations to implement the GSCI model of care. CONCLUSION/CONCLUSIONS:The GSCI proposes an evidence-based model that is consistent with recent calls for action to reduce the global burden of spinal disorders. The model requires testing to determine feasibility. If it proves to be implementable, this model holds great promise to reduce the tremendous global burden of spinal disorders. These slides can be retrieved under Electronic Supplementary Material.

PURPOSE/OBJECTIVE:The purpose of this report is to describe the Global Spine Care Initiative (GSCI) contributors, disclosures, and methods for reporting transparency on the development of the recommendations. METHODS:World Spine Care convened the GSCI to develop an evidence-based, practical, and sustainable healthcare model for spinal care. The initiative aims to improve the management, prevention, and public health for spine-related disorders worldwide; thus, global representation was essential. A series of meetings established the initiative's mission and goals. Electronic surveys collected contributorship and demographic information, and experiences with spinal conditions to better understand perceptions and potential biases that were contributing to the model of care. RESULTS:Sixty-eight clinicians and scientists participated in the deliberations and are authors of one or more of the GSCI articles. Of these experts, 57 reported providing spine care in 34 countries, (i.e., low-, middle-, and high-income countries, as well as underserved communities in high-income countries.) The majority reported personally experiencing or having a close family member with one or more spinal concerns including: spine-related trauma or injury, spinal problems that required emergency or surgical intervention, spinal pain referred from non-spine sources, spinal deformity, spinal pathology or disease, neurological problems, and/or mild, moderate, or severe back or neck pain. There were no substantial reported conflicts of interest. CONCLUSION/CONCLUSIONS:The GSCI participants have broad professional experience and wide international distribution with no discipline dominating the deliberations. The GSCI believes this set of papers has the potential to inform and improve spine care globally. These slides can be retrieved under Electronic Supplementary Material.

PURPOSE/OBJECTIVE:Spine-related disorders are a leading cause of global disability and are a burden on society and to public health. Currently, there is no comprehensive, evidence-based model of care for spine-related disorders, which includes back and neck pain, deformity, spine injury, neurological conditions, spinal diseases, and pathology, that could be applied in global health care settings. The purposes of this paper are to propose: (1) principles to transform the delivery of spine care; (2) an evidence-based model that could be applied globally; and (3) implementation suggestions. METHODS:The Global Spine Care Initiative (GSCI) meetings and literature reviews were synthesized into a seed document and distributed to spine care experts. After three rounds of a modified Delphi process, all participants reached consensus on the final model of care and implementation steps. RESULTS:Sixty-six experts representing 24 countries participated. The GSCI model of care has eight core principles: person-centered, people-centered, biopsychosocial, proactive, evidence-based, integrative, collaborative, and self-sustaining. The model of care includes a classification system and care pathway, levels of care, and a focus on the patient's journey. The six steps for implementation are initiation and preparation; assessment of the current situation; planning and designing solutions; implementation; assessment and evaluation of program; and sustain program and scale up. CONCLUSION/CONCLUSIONS:The GSCI proposes an evidence-based, practical, sustainable, and scalable model of care representing eight core principles with a six-step implementation plan. The aim of this model is to help transform spine care globally, especially in low- and middle-income countries and underserved communities. These slides can be retrieved under Electronic Supplementary Material.