Publications by authors named "Bernard Ng"

78 Publications

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

Cell 2021 Apr 13. Epub 2021 Apr 13.

Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.
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http://dx.doi.org/10.1016/j.cell.2021.03.050DOI Listing
April 2021

The U.S. Veterans Health Administration national giant cell arteritis (GCA) database cohort: incident ophthalmic complications in biopsy-negative GCA patients.

Clin Rheumatol 2021 Jan 8. Epub 2021 Jan 8.

Division of Rheumatology, University of Washington, Seattle, WA, USA.

Introduction/objectives: This study aimed to identify the incidence of ophthalmic complications of giant cell arteritis (GCA) among subjects with negative temporal artery biopsy (TAB) and to determine if duration of prednisone exposure relative to GCA diagnosis was associated with ophthalmic complications in TAB-negative subjects.

Method: The U.S. Veterans Health Administration (VHA) national database was queried for subjects between 1999 and 2017 with ICD-9/-10 diagnosis code for GCA, procedure code for TAB, and ICD-9/-10 diagnosis code for blindness, anterior or posterior ischemic optic neuropathy, or branch or central retinal artery occlusion. Pharmacy data regarding prednisone dispensation were collected. A Cox proportional hazard model was performed using ophthalmic complication by 1 year as the outcome variable in TAB-negative subjects, adjusting for age, TAB length, TAB laterality, and prednisone dose relative to GCA diagnosis date.

Results: Incident ophthalmic complication occurred by 1 year in 9.6% with positive TAB and in 6.2% with negative TAB. The majority of complications occurred within the first month for both groups. Compared to a reference group of prednisone initiation 0-14 days prior to GCA diagnosis, ophthalmic complications in TAB-negative subjects were significantly higher when prednisone initiation was delayed 14-28 days after GCA diagnosis.

Conclusions: A substantial number of TAB-negative subjects accrued an incident ICD-9/-10 code for ophthalmologic complication within a year after diagnosis, most occurring within the first month. Delaying prednisone initiation 14-28 days after GCA diagnosis in TAB-negative subjects led to a 3.5-fold higher rate of ophthalmic events occurring by 1 year. Key Points • This study provides an incidence rate of ophthalmic complication by one year in biopsy-negative subjects suspected of having GCA. • Delaying prednisone initiation 14-28 days after GCA diagnosis in TAB-negative GCA subjects led to a 3.5-fold higher rate of ophthalmic events occurring by 1 year.
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http://dx.doi.org/10.1007/s10067-020-05543-0DOI Listing
January 2021

"Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation".

Front Immunol 2020 16;11:571884. Epub 2020 Oct 16.

Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

It is established that pediatric hematopoietic stem cell transplant (HSCT) recipients have a lower rate of chronic graft-versus-host disease (cGvHD) compared to adults. Our group has previously published immune profiles changes associated with cGvHD of clinically well-defined adult and pediatric HSCT cohorts. Since all analyses were performed by the same research group and analyzed using identical methodology, we first compared our previous immune profile analyses between adults and children. We then performed additional analyses comparing the T cell populations across age groups, and a sub-analysis of the impact of the estimated pubertal status at time of HSCT in our pediatric cohort. In all analyses, we corrected for clinical covariates including total body irradiation and time of onset of cGvHD. Three consistent findings were seen in both children and adults, including elevations of ST2 and naive helper T (Th) cells and depression of NK cells. However, significant differences exist between children and adults in certain cytokines, B cell, and T populations. In children, we saw a broad suppression of newly formed B (NF-B) cells, whereas adults exhibited an increase in T1-CD21 B cells and a decrease in T1-CD24CD38 B cells. Prepubertal children had elevations of aminopeptidase N (sCD13) and ICAM-1. T abnormalities in children appeared to be primarily in memory T cells, whereas in adults the abnormalities were in naïve T cells. In adults, the loss of PD1 expression in naïve T and naïve Th cells was associated with cGvHD. We discuss the possible mechanisms for these age-related differences, and how they might theoretically impact on different therapeutic approaches to cGvHD between children and adults.
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http://dx.doi.org/10.3389/fimmu.2020.571884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641628PMC
October 2020

Positive effect of hydroxychloroquine on lipid profiles of patients with rheumatoid arthritis: A Veterans Affair cohort.

Eur J Rheumatol 2020 Nov 5. Epub 2020 Nov 5.

Section of Rheumatology, VA Puget Sound Healthcare System, Seattle, WA, USA.

Objective: Despite remarkable improvements in rheumatoid arthritis (RA) treatment, there is evidence indicating that the mortality gap between patients with RA and the general population is not closing. The increase in mortality rates in patients with RA is predominantly due to cardiovascular disease (CVD). Literature suggests that important links exist between RA inflammation and atherosclerosis in CVD. Dyslipidemia is a well-known risk factor of atherosclerosis. Previous studies have suggested that antimalarials, chloroquine diphosphate, and hydroxychloroquine (HCQ), used in the treatment of autoimmune diseases, have a beneficial effect on the lipid levels. However, the studies had small sample sizes. We analyzed a Veterans Affair RA cohort of 2,925 patients to characterize the effect of 4 months' use of HCQ on the lipid levels.

Methods: Data for this cohort were obtained from the department of Veterans Affairs administrative database. Individuals (age ≥18 years) with a diagnosis of RA (ICD-9 code) at 2 or more outpatient visits from 1999 to 2009 were identified. Only the patients with at least 1 lipid level measured at 120-180 days before staring HCQ were included. Lipids levels on pre- and poststart dates of HCQ (120-180 days) were compared using student's t-test and adjusted for age, sex, race, C-reactive protein (CRP), and statin use with multivariable regression (analysis of variance/analysis of covariance) for the change in different lipid levels. To give equal weightage to covariables, we conducted an analysis of marginal means for race in each lipid level. All analyses were performed using STATA 11.

Results: After adjusting for sex, age, race, statin use, and post CRP values >10 mg/dL using a linear regression, the factor driving the change in the different lipid levels was race (p values for total cholesterol, 0.006; low-density lipoprotein, 0.09; non-high-density lipoprotein [HDL], 0.03; atherogenic index, 0.08; and HDL, 0.17). When considering race individually using marginal means analysis, the race in the subgroup "others" was more influential.

Conclusion: Our results suggest that sex and race influences the HCQ effect on the lipid profiles in patients with RA. Use of HCQ in males is found to be associated with positive changes in the lipid profiles independent from the use of statins. There is a suggestion that whites and African Americans might be less susceptible to HCQ effect on lipid profiles than other races.
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http://dx.doi.org/10.5152/eurjrheum.2020.20193DOI Listing
November 2020

Management of Rheumatic Diseases During the COVID-19 pandemic: A National Veterans Affairs Survey of Rheumatologists.

Arthritis Care Res (Hoboken) 2020 Oct 15. Epub 2020 Oct 15.

University of Washington, Division of Rheumatology, Seattle, WA, USA.

Objective: To assess the experience, views and opinions of rheumatology providers at Veterans Affairs (VA) facilities about rheumatic disease healthcare issues during the COVID-19 pandemic.

Methods: We performed an anonymized cross-sectional survey, conducted from April 16 to May 18, 2020, of VA rheumatology providers. We assessed provider perspective on COVID-19 issues and resilience.

Results: Of the 153 eligible VA rheumatologists, 103 (67%) completed the survey. A significant proportion of providers reported ≥50% increase related to COVID-19 in visits by: (1) telephone, 53%; (2) video-based VA video connect (VVC), 44%; and (3) clinical video telehealth (CVT) with a facilitator, 29%. A majority of the responders were somewhat or very comfortable with technology for providing healthcare to established patients during COVID-19 pandemic using: (1) telephone, 87%; (2) VA video connect (VVC), 64%; and (3) in-person visits, 54%. A smaller proportion were comfortable with technology providing healthcare to new patients. At least 65% of rheumatologists considered telephone visits appropriate for established patients with gout, osteoporosis, polymyalgia rheumatica, stable rheumatoid arthritis, stable spondyloarthritis, or osteoarthritis; 32% reported a rheumatology medication shortage. Adjusted for age, sex and ethnicity, high provider resilience was associated with significantly higher odds ratio (OR) of comfort with technology for telephone (OR, 3.1 (95% CI, 1.1-9.7)) and VVC visits for new patients (OR, 4.7 (95% CI, 1.4-15.7)).

Conclusions: A better understanding of COVID-19 rheumatic disease healthcare issues using a health-system approach can better inform providers, improve provider satisfaction and have positive effects on the care of Veterans with rheumatic disease.
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http://dx.doi.org/10.1002/acr.24487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675431PMC
October 2020

Deep learning of immune cell differentiation.

Proc Natl Acad Sci U S A 2020 10 25;117(41):25655-25666. Epub 2020 Sep 25.

Department of Statistics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;

Although we know many sequence-specific transcription factors (TFs), how the DNA sequence of cis-regulatory elements is decoded and orchestrated on the genome scale to determine immune cell differentiation is beyond our grasp. Leveraging a granular atlas of chromatin accessibility across 81 immune cell types, we asked if a convolutional neural network (CNN) could learn to infer cell type-specific chromatin accessibility solely from regulatory DNA sequences. With a tailored architecture and an ensemble approach to CNN parameter interpretation, we show that our trained network ("AI-TAC") does so by rediscovering ab initio the binding motifs for known regulators and some unknown ones. Motifs whose importance is learned virtually as functionally important overlap strikingly well with positions determined by chromatin immunoprecipitation for several TFs. AI-TAC establishes a hierarchy of TFs and their interactions that drives lineage specification and also identifies stage-specific interactions, like Pax5/Ebf1 vs. Pax5/Prdm1, or the role of different NF-κB dimers in different cell types. AI-TAC assigns Spi1/Cebp and Pax5/Ebf1 as the drivers necessary for myeloid and B lineage fates, respectively, but no factors seemed as dominantly required for T cell differentiation, which may represent a fall-back pathway. Mouse-trained AI-TAC can parse human DNA, revealing a strikingly similar ranking of influential TFs and providing additional support that AI-TAC is a generalizable regulatory sequence decoder. Thus, deep learning can reveal the regulatory syntax predictive of the full differentiative complexity of the immune system.
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http://dx.doi.org/10.1073/pnas.2011795117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568267PMC
October 2020

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

Hum Mol Genet 2020 Sep;29(16):2788-2802

Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia V5Z 4H4, Canada.

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in HTT. The length of this repeat, however, only explains a proportion of the variability in age of onset in patients. Genome-wide association studies have identified modifiers that contribute toward a proportion of the observed variance. By incorporating tissue-specific transcriptomic information with these results, additional modifiers can be identified. We performed a transcriptome-wide association study assessing heritable differences in genetically determined expression in diverse tissues, with genome-wide data from over 4000 patients. Functional validation of prioritized genes was undertaken in isogenic HD stem cells and patient brains. Enrichment analyses were performed with biologically relevant gene sets to identify the core pathways. HD-associated gene coexpression modules were assessed for associations with neurological phenotypes in an independent cohort and to guide drug repurposing analyses. Transcriptomic analyses identified genes that were associated with age of HD onset and displayed colocalization with gene expression signals in brain tissue (FAN1, GPR161, PMS2, SUMF2), with supporting evidence from functional experiments. This included genes involved in DNA repair, as well as novel-candidate modifier genes that have been associated with other neurological conditions. Further, cortical coexpression modules were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder. Further, these analyses expanded the pathways potentially involved in modifying HD onset and prioritized candidate therapeutics for future study.
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http://dx.doi.org/10.1093/hmg/ddaa184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530525PMC
September 2020

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression.

PLoS Comput Biol 2020 08 17;16(8):e1008120. Epub 2020 Aug 17.

Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer's disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).
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http://dx.doi.org/10.1371/journal.pcbi.1008120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451979PMC
August 2020

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study.

Pediatr Hematol Oncol 2019 Nov 18;36(8):468-481. Epub 2019 Sep 18.

Department of Pediatric Hematology, Oncology & BMT, University of British Columbia, Vancouver, USA.

: Preclinical studies show that TLR9 agonists can eradicate leukemia by induction of immune responses against AML and ALL. These studies demonstrated that TLR9 agonists induce an immediate NK response followed by adaptive T and B cells responses resulting in long term anti-leukemia immunity. : The Therapeutic Advances in Childhood Leukemia and Lymphoma Phase I consortium performed a pilot study on 3 patients with MRD positive acute leukemia after an initial remission on conventional chemotherapy (TACL T2009-008) with the TLR 9 agonist (GNKG168). To guide future trial development, we evaluated the impact of GNKG168 by Nanostring on the expression 608 genes before and 8 days after initiation of GNKG168 therapy. : Twenty-three out of 578 markers on the nanostring panel showed significant difference ( ≤ 0.05). We focused on 8 markers that had the greatest differences with  < 0.01. Two genes were increased, and , and 6 were decreased, and (). Tumor inhibitory pathways were downregulated including the (), important in signaling and NK cell inhibition. TLR9 can induce IL-33, which is known to downregulate ST2 (IL1RL1) a receptor for IL-33. : GNKG168 therapy is associated with immunologic changes in pediatric leukemia patients. Further work with a larger sample size is required to assess the impact of these changes on disease treatment and persistence of leukemia remission.
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http://dx.doi.org/10.1080/08880018.2019.1667461DOI Listing
November 2019

Using Transcriptomic Hidden Variables to Infer Context-Specific Genotype Effects in the Brain.

Am J Hum Genet 2019 09 22;105(3):562-572. Epub 2019 Aug 22.

Department of Statistics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4; Centre for Molecular Medicine and Therapeutics, Vancouver, BC V5Z 4H4, Canada; Canadian Institute for Advanced Research, Child and Brain Development Program, Toronto M5G 1M1, Canada. Electronic address:

Deciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). Applying this approach to two largest brain eQTL datasets (n = 1,100), we show that LVs and GxE eQTLs in one dataset replicate well in the other dataset. Combining the two samples via meta-analysis, 895 GxE eQTLs are identified. On average, GxE effect explains an additional ∼4% variation in expression of each gene that displays a GxE effect. Ten of these 52 genes are associated with cell-type-specific eQTLs, and the remaining genes are multi-functional. Furthermore, after substituting LVs with expression of transcription factors (TF), we found 91 TF-specific eQTLs, which demonstrates an important use of our brain GxE eQTLs.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731371PMC
September 2019

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

Arthritis Rheumatol 2019 10 22;71(10):1599-1613. Epub 2019 Aug 22.

Rocky Mountain Regional VA Medical Center and University of Colorado, Aurora.

Objective: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).

Methods: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel.

Results: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended.

Conclusion: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.
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http://dx.doi.org/10.1002/art.41042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764882PMC
October 2019

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

Arthritis Care Res (Hoboken) 2019 10 21;71(10):1285-1299. Epub 2019 Aug 21.

Rocky Mountain Regional VA Medical Center and University of Colorado, Aurora.

Objective: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).

Methods: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel.

Results: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended.

Conclusion: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.
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http://dx.doi.org/10.1002/acr.24025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764857PMC
October 2019

Corrigendum: Increased Binding of Specificity Protein 1 to the Promoter in B Cells Results in Enhanced B Cell Responses in Rheumatoid Arthritis.

Front Immunol 2019 16;10:1122. Epub 2019 May 16.

Translational Research Program, Benaroya Research Institute, Seattle, WA, United States.

[This corrects the article DOI: 10.3389/fimmu.2018.01978.].
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http://dx.doi.org/10.3389/fimmu.2019.01122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532707PMC
May 2019

Using metro lines for integration of nucleotide metabolic pathways.

Biochem Mol Biol Educ 2019 09 24;47(5):532-537. Epub 2019 May 24.

Information Technology Services Centre, The Chinese University of Hong Kong, Hong Kong, HKSAR.

Students always encounter difficulties in studying biochemical pathways. They are especially weak in understanding the relationships between metabolic pathways and their integration because these pathways are always taught one-by-one in class. In the past, various online resources have been developed to facilitate students' understanding toward energy metabolism. Although these learning materials enable students to understand individual metabolic pathway in a clearer manner, many of them fail to demonstrate the linkages between these pathways. The "AG City" is a self-learning tool which aims to arouse students' interest in exploring nucleotide metabolism. We have designed a metro map as a concept map to allow students to have an overview of different pathways as well as their integration. Major pathways are presented as railway lines in an easy-to-understand and interactive manner using navigation, animations, and narrations. Key molecules involved in the pathways are presented as "railway stations". Students can easily identify common "railway stations" presented in different pathways and link the concepts that they have learnt together. This interactive self-learning tool has been packaged as a courseware using the Articulate Storyline eLearning authoring software. © 2019 International Union of Biochemistry and Molecular Biology, 47(5):532-537, 2019.
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http://dx.doi.org/10.1002/bmb.21256DOI Listing
September 2019

Determinants of Positive Temporal Artery Biopsies in the Veterans Health Administration National Database Cohort.

Arthritis Care Res (Hoboken) 2020 05 8;72(5):699-704. Epub 2020 Apr 8.

University of Washington Medical Center and Veterans Health Administration Puget Sound, Seattle, Washington.

Objective: This study sought to determine the effect of temporal artery biopsy (TAB) postfixation length, laterality, age, and prior prednisone exposure on TAB positivity utilizing the Veterans Health Administration national database.

Methods: Subjects with procedure code for TAB between 1999 and 2017 were queried, and pathology reports were reviewed manually. Demographic, laboratory, and prescription data were extracted. Multivariate analyses and logistic regression were run using Stata, version 13.0.

Results: A total of 3,057 pathology reports were reviewed; 306 biopsies (10%) were designated positive. The likelihood of a positive TAB significantly correlated with TAB postfixation length of >3.0 cm (odds ratio [OR] 1.58 [95% confidence interval (95% CI) 1.06, 2.36], P < 0.05) as well as with bilateral biopsy in 1 sitting (OR 1.83 [95% CI 1.29, 2.59], P < 0.01). Positive TAB also significantly correlated with age >71 years. Prednisone administration up to and beyond 42 days prior to TAB did not influence TAB result.

Conclusion: This retrospective study examined predictors of TAB positivity and utilized national data collected on US veterans over the span of 18 years. The results suggest consideration of pursuing initial bilateral TAB or achieving a TAB postfixation length of at least 3 cm to improve yield. The results also agree with prior studies showing that pre-TAB steroid exposure does not appear to affect yield even up to and beyond 42 days prior to biopsy.
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http://dx.doi.org/10.1002/acr.23897DOI Listing
May 2020

Multimodal Brain Parcellation Based on Functional and Anatomical Connectivity.

Brain Connect 2018 Nov 30. Epub 2018 Nov 30.

University of British Columbia, Electrical and Computer Engineering, Vancouver, British Columbia, Canada ;

Brain parcellation is often a prerequisite for network analysis due to the statistical challenges, computational burdens, and interpretation difficulties arising from the high dimensionality of neuroimaging data. Predominant approaches are largely unimodal with functional magnetic resonance imaging (fMRI) being the primary modality used. These approaches thus neglect other brain attributes that relate to brain organization. In this paper, we propose an approach for integrating fMRI and diffusion MRI (dMRI) data. Our approach introduces a nonlinear mapping between the connectivity values of two modalities, and adaptively balances their weighting based on their voxel-wise test-retest reliability. An efficient region level extension that additionally incorporates structural information on gyri and sulci is further presented. To validate, we compare multimodal parcellations with unimodal parcellations and existing atlases on the Human Connectome Project data. We show that multimodal parcellations achieve higher reproducibility, comparable/higher functional homogeneity, and comparable/higher leftout data likelihood. The boundaries of multimodal parcels are observed to align to those based on cyto-architecture, and subnetworks extracted from multimodal parcels matched well with established brain systems. Our results thus show that multimodal information improves brain parcellation.
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http://dx.doi.org/10.1089/brain.2017.0576DOI Listing
November 2018

Implications of the diagnostic criteria of idiopathic pulmonary fibrosis in clinical practice: Analysis from the Australian Idiopathic Pulmonary Fibrosis Registry.

Respirology 2019 04 17;24(4):361-368. Epub 2018 Oct 17.

Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background And Objective: Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry.

Methods: All patients enrolled in the registry undergo a diagnostic review whereby international IPF guidelines are applied via a registry MDD. We investigated the clinical applicability of these guidelines with regard to: (i) adherence to guidelines, (ii) Natural history of IPF diagnostic categories and (iii) Concordance for diagnostic features.

Results: A total of 417 participants (69% male, 70.6 ± 8.0 years) with a clinical diagnosis of IPF underwent MDD. The 23% of participants who did not meet IPF diagnostic criteria displayed identical disease behaviour to those with confirmed IPF. Honeycombing on radiology was associated with a worse prognosis and this translated into poorer prognosis in the 'definite' IPF group. While there was moderate agreement for IPF diagnostic categories, agreement for specific radiological features, other than honeycombing, was poor.

Conclusion: In clinical practice, physicians do not always follow IPF diagnostic guidelines. We demonstrate a cohort of IPF patients who do not meet IPF diagnostic guideline criteria, based largely on their radiology and lack of lung biopsy, but who have outcomes identical to those with IPF.
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http://dx.doi.org/10.1111/resp.13427DOI Listing
April 2019

Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility.

Nat Genet 2018 11 8;50(11):1584-1592. Epub 2018 Oct 8.

Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Here we use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer's disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicing of 3,006 genes is influenced by genetic variation. We report that altered splicing is the mechanism for the effects of the PICALM, CLU and PTK2B susceptibility alleles. Furthermore, we performed a transcriptome-wide association study and identified 21 genes with significant associations with Alzheimer's disease, many of which are found in known loci, whereas 8 are in novel loci. These results highlight the convergence of old and new genes associated with Alzheimer's disease in autophagy-lysosomal-related pathways. Overall, this study of the transcriptome of the aging brain provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer's disease and is, in some cases, genetically driven.
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http://dx.doi.org/10.1038/s41588-018-0238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354244PMC
November 2018

Increased Binding of Specificity Protein 1 to the Promoter in B Cells Results in Enhanced B Cell Responses in Rheumatoid Arthritis.

Front Immunol 2018 5;9:1978. Epub 2018 Sep 5.

Translational Research Program, Benaroya Research Institute, Seattle, WA, United States.

B cells are implicated in rheumatoid arthritis (RA) based on the presence of autoantibodies and the therapeutic response to B cell depletion. IL-21 has a significant role in B cell development and function. Here we assess B cell responses to IL-21 and the mechanisms responsible for altered IL-21R expression in RA. Flow cytometry of PBMC and cultured B cells was used to quantify protein and mRNA levels of IL-21R, IL-21 signaling through pSTAT3, specificity protein 1 (SP1) and to determine cytokine production (IL-6) and maturation status of B cells in RA and healthy control subjects. SP1 binding to the promoter region in B cells was assessed with ChIP-qPCR. We demonstrate an increase in IL-21R expression in total and memory B cells from RA subjects, which correlated with responsiveness to IL-21 stimulation. Stimulation of naïve RA B cells with IL-21 and CD40L resulted in an increase in differentiation into plasmablasts and an increase in IL-6 production in comparison to healthy controls, which was dose dependent on IL-21 stimulation. IL-21R expression on memory B cells in RA synovial fluid was comparable to peripheral blood making our study pertinent to understanding B cell responses in the joint and site of inflammation. We identified an increase in SP1 protein and mRNA in RA B cells and demonstrate an increase in binding of SP1 to the promoter region, which suggests a mechanism by which IL-21R expression is enhanced on B cells in RA. Taken together, our results indicate a mechanism by which IL-21 enhances B cell development and function in RA through an SP1 mediated increase in IL-21R expression on B cells.
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http://dx.doi.org/10.3389/fimmu.2018.01978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134023PMC
September 2019

Using subcutaneous methotrexate to prolong duration of methotrexate therapy in rheumatoid arthritis.

Eur J Rheumatol 2018 Jul 13;5(2):85-91. Epub 2018 Feb 13.

Department of Rheumatology, University of Washington School of Medicine, Seattle, Washington, USA.

Objective: Our study aims to determine whether the use of subcutaneous methotrexate (SC MTX) is associated with prolonged MTX use and lower incidence of hepatotoxicity in rheumatoid arthritis (RA) patients on MTX monotherapy and multiple drug therapy.

Methods: We conducted a retrospective cohort study using national databases of a large hospital system. Subjects had been diagnosed with RA and treated with MTX between September 30, 1999, and October 1, 2009. Outcomes of interest were the amount of time on MTX monotherapy or multiple disease-modifying anti-rheumatic drug (DMARD) therapy before addition of additional DMARDs or biologic agents, respectively. We conducted Cox regressions and Kaplan-Meier curves for association between SC MTX use and length of time before therapeutic change. We conducted chi-square tests for association between SC MTX use and elevated liver function tests (LFT).

Results: MTX monotherapy: SC MTX was associated with a significantly lower likelihood of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Multiple DMARD therapy: SC MTX was not associated with a lower risk of adding a biologic (HR 1.13, 95% CI 0.97-1.31). Liver enzymes: There was no significant association between use of SC MTX and decreased frequency of abnormal LFTs [p=0.09 for alanine aminotransferase (ALT), p=0.924 for aspartate aminotransferase (AST)].

Conclusion: Use of SC MTX is associated with longer duration of MTX monotherapy before addition of other DMARDs/biologic agents in RA patients. Use of SC MTX is not associated with significantly longer duration of multiple DMARD therapy before addition of biologic agents. Use of oral MTX is not significantly associated with increased frequency of elevated LFTs.
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http://dx.doi.org/10.5152/eurjrheum.2018.17113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072697PMC
July 2018

Using subcutaneous methotrexate to prolong duration of methotrexate therapy in rheumatoid arthritis.

Eur J Rheumatol 2018 Jul 13;5(2):85-91. Epub 2018 Feb 13.

Department of Rheumatology, University of Washington School of Medicine, Seattle, Washington, USA.

Objective: Our study aims to determine whether the use of subcutaneous methotrexate (SC MTX) is associated with prolonged MTX use and lower incidence of hepatotoxicity in rheumatoid arthritis (RA) patients on MTX monotherapy and multiple drug therapy.

Methods: We conducted a retrospective cohort study using national databases of a large hospital system. Subjects had been diagnosed with RA and treated with MTX between September 30, 1999, and October 1, 2009. Outcomes of interest were the amount of time on MTX monotherapy or multiple disease-modifying anti-rheumatic drug (DMARD) therapy before addition of additional DMARDs or biologic agents, respectively. We conducted Cox regressions and Kaplan-Meier curves for association between SC MTX use and length of time before therapeutic change. We conducted chi-square tests for association between SC MTX use and elevated liver function tests (LFT).

Results: MTX monotherapy: SC MTX was associated with a significantly lower likelihood of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Multiple DMARD therapy: SC MTX was not associated with a lower risk of adding a biologic (HR 1.13, 95% CI 0.97-1.31). Liver enzymes: There was no significant association between use of SC MTX and decreased frequency of abnormal LFTs [p=0.09 for alanine aminotransferase (ALT), p=0.924 for aspartate aminotransferase (AST)].

Conclusion: Use of SC MTX is associated with longer duration of MTX monotherapy before addition of other DMARDs/biologic agents in RA patients. Use of SC MTX is not associated with significantly longer duration of multiple DMARD therapy before addition of biologic agents. Use of oral MTX is not significantly associated with increased frequency of elevated LFTs.
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http://dx.doi.org/10.5152/eurjrheum.2018.17113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072697PMC
July 2018

Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study.

JACC Cardiovasc Imaging 2018 02 18;11(2 Pt 2):305-316. Epub 2017 Oct 18.

Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, New South Wales, Australia. Electronic address:

Objectives: The authors sought to evaluate the plaque-modifying effects of low-dose colchicine therapy plus optimal medical therapy (OMT) in patients post-acute coronary syndrome (ACS), as assessed by coronary computed tomography angiography (coronary CTA).

Background: Colchicine therapy has been postulated to have beneficial anti-inflammatory effects in patients with ACS, translating into reduction in future adverse cardiovascular events. However, whether favorable plaque modification underpins this is yet unproven.

Methods: In this prospective nonrandomized observational study of 80 patients with recent ACS (<1 month), patients received either 0.5 mg/day colchicine plus OMT or OMT alone and were followed for 1 year. Our primary outcome was change in low attenuation plaque volume (LAPV), a marker of plaque instability on coronary CTA and robust predictor of adverse cardiovascular events. Secondary outcomes were changes in other coronary CTA measures and in high-sensitivity C-reactive protein (hsCRP).

Results: Mean duration of follow-up was 12.6 months; mean age was 57.4 years. Colchicine therapy significantly reduced LAPV (mean 15.9 mm [-40.9%] vs. 6.6 mm [-17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [-37.3%] vs. 0.38 mg/l [-14.6%]; p < 0.001) versus controls. Reductions in total atheroma volume (mean 42.3 mm vs. 26.4 mm; p = 0.28) and low-density lipoprotein levels (mean 0.44 mmol/l vs. 0.49 mmol/l; p = 0.21) were comparable in both groups. With multivariate linear regression, colchicine therapy remained significantly associated with greater reduction in LAPV (p = 0.039) and hsCRP (p = 0.004). There was also a significant linear association (p < 0.001) and strong positive correlation (r = 0.578) between change in LAPV and hsCRP.

Conclusions: Our findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies.
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http://dx.doi.org/10.1016/j.jcmg.2017.08.013DOI Listing
February 2018

Distinct alterations in Parkinson's medication-state and disease-state connectivity.

Neuroimage Clin 2017 6;16:575-585. Epub 2017 Sep 6.

Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States.

Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily 'normalize' disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and medication-associated changes in brain connectivity relate differently to specific motor manifestations of disease, such as bradykinesia/rigidity and tremor. In this study, we applied a novel covariance projection approach in combination with a bootstrapped permutation test to resting state functional MRI data from 57 Parkinson's disease and 20 healthy control participants to determine the Parkinson's medication-state and disease-state connectivity changes associated with different motor manifestations of disease. First, we identified brain connections that best classified Parkinson's disease ON versus OFF dopamine and Parkinson's disease versus healthy controls, achieving 96.9 ± 5.9% and 72.7 ± 12.4% classification accuracy, respectively. Second, we investigated the connections that significantly contribute to the classifications. We found that the connections greater in Parkinson's disease OFF compared to ON dopamine are primarily between motor (cerebellum and putamen) and posterior cortical regions, such as the posterior cingulate cortex. By contrast, connections that are greater in ON compared to OFF dopamine are between the right and left medial prefrontal cortex. We also identified the connections that are greater in healthy control compared to Parkinson's disease and found the most significant connections are associated with primary motor regions, such as the striatum and the supplementary motor area. Notably, these are different connections than those identified in Parkinson's disease OFF compared to ON. Third, we determined which of the Parkinson's medication-state and disease-state connections are associated with the severity of different motor symptoms. We found two connections correlate with both bradykinesia/rigidity severity and tremor severity, whereas four connections correlate with only bradykinesia/rigidity severity, and five connections correlate with only tremor severity. Connections that correlate with only tremor severity are anchored by the cerebellum and the supplemental motor area, but only those connections that include the supplemental motor area predict dopaminergic improvement in tremor. Our results suggest that dopaminergic medications do not simply 'normalize' abnormal brain connectivity associated with Parkinson's disease, but rather dopamine drives distinct connectivity changes, only some of which are associated with improved motor symptoms. In addition, the dissociation between of connections related to severity of bradykinesia/rigidity versus tremor highlights the distinct abnormalities in brain circuitry underlying these specific motor symptoms.
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http://dx.doi.org/10.1016/j.nicl.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608603PMC
June 2018

CD56 natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft--host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

Haematologica 2017 11 21;102(11):1936-1946. Epub 2017 Sep 21.

Michael Cuccione Childhood Cancer research Program, BC Children's Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

Randomized trials have conclusively shown higher rates of chronic graft--host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft--host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft--host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft--host disease frequency was associated with lower proportions of CD56 natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56 natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft--host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56 natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56 natural killer regulatory cells results in the high rate of chronic graft--host disease seen in filgrastim-stimulated apheresis peripheral blood. .
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http://dx.doi.org/10.3324/haematol.2017.170928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664398PMC
November 2017

Overdominant Effect of a Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control.

J Neurosci 2017 10 6;37(40):9657-9666. Epub 2017 Sep 6.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305.

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total = 1586, behavioral total = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence = 1.33 * 10). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating expression levels. This is the first report of overdominance in the nicotinic system. These findings connect genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities. The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes and is dysregulated in several neuropsychiatric disorders. Despite this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show the impact of a common polymorphism of the high-affinity nicotinic receptor α4β2 that is consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of interindividual differences in cognitive control.
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http://dx.doi.org/10.1523/JNEUROSCI.0991-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596609PMC
October 2017

An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome.

Nat Neurosci 2017 Oct 4;20(10):1418-1426. Epub 2017 Sep 4.

Broad Institute, Cambridge, Massachusetts, USA.

We report a multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adults who have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also reanalyze published genome wide association studies using an xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based expression eQTL resource.
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http://dx.doi.org/10.1038/nn.4632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785926PMC
October 2017

Use of multicriteria decision analysis for assessing the benefit and risk of over-the-counter analgesics.

J Pharm Pharmacol 2017 Oct 13;69(10):1364-1373. Epub 2017 Jul 13.

Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK.

Objectives: To test the ability of a multicriteria decision analysis (MCDA) model to incorporate disparate data sources of varying quality along with clinical judgement in a benefit-risk assessment of six well-known pain-relief drugs.

Methods: Six over-the-counter (OTC) analgesics were evaluated against three favourable effects and eight unfavourable effects by seven experts who specialise in the relief of pain, two in a 2-day facilitated workshop whose input data and judgements were later peer-reviewed by five additional experts.

Key Findings: Ibuprofen salts and solubilised emerged with the best benefit-risk profile, followed by naproxen, ibuprofen acid, diclofenac, paracetamol and aspirin.

Conclusions: Multicriteria decision analysis enabled participants to evaluate the OTC analgesics against a range of favourable and unfavourable effects in a group setting that enabled all issues to be openly aired and debated. The model was easily communicated and understood by the peer reviewers, so the model should be comprehensible to physicians, pharmacists and other health professionals.
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http://dx.doi.org/10.1111/jphp.12770DOI Listing
October 2017

High-quality fuel from food waste - investigation of a stepwise process from the perspective of technology development.

Environ Technol 2017 Jul 8;38(13-14):1735-1741. Epub 2017 Mar 8.

a Residues and Resource Reclamation Centre (R3C), Nanyang Environment and Water Research Institute , Nanyang Technological University , Singapore , Singapore.

A stepwise process (SP) was developed for sustainable energy production from food waste (FW). The process comprised of hydrothermal treatment followed by oil upgrading. Synthetic food waste was primarily used as feedstock in the hydrothermal reactor under subcritical water conditions. The produced hydrochars were analyzed for calorific value (17.0-33.7 MJ/kg) and elemental composition indicating high-quality fuel comparable to coal. Hydrothermal carbonization (e.g. 180°C) would be efficient for oil recovery (>90%) from FW, as compared to hydrothermal liquefaction (320°C) whereby lipid degradation may take place. The recovered oil was upgraded to biodiesel in a catalytic refinery process. Selected biodiesels, that is, B3 and B4 were characterized for density (872.7 and 895.5 kg/m), kinematic viscosity (3.115 and 8.243 cSt), flash and pour point (30°C and >126°C), micro carbon (0.03% and 0.04%), sulfur (both <0.0016%), and calorific value (38,917 and 39,584 J/g), suggesting similar quality to commercial biodiesel. Fatty acid methyl ethers content was further analyzed to assess the influence of hydrothermal treatment in biodiesel quality, indicating the limited impacts. Overall, the SP provides a promising alternative for sustainable energy recovery through high-quality biofuel and hydrochar production.
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http://dx.doi.org/10.1080/09593330.2017.1297851DOI Listing
July 2017

Regional brain hypometabolism is unrelated to regional amyloid plaque burden.

Brain 2015 Dec 29;138(Pt 12):3734-46. Epub 2015 Sep 29.

1 FIND Lab, Department of Neurology and Neurological Sciences, Stanford University, Stanford California, USA

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism.
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http://dx.doi.org/10.1093/brain/awv278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806718PMC
December 2015