Publications by authors named "M J Smith"

21,997 Publications

Anti-microbial antibody response is associated with future onset of Crohn's disease independent of biomarkers of altered gut barrier function, subclinical inflammation, and genetic risk.

Gastroenterology 2021 Jul 19. Epub 2021 Jul 19.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: /Aim: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDR) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to six microbial antigens at enrollment (Prometheus ELISA test: ASCA IgA/IgG, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the CCC-GEM Project. Those who later developed CD (n=77) were matched 1:4 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted OR 6.5, 95% CI 3.4-12.7; p<0.001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early pre-disease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

Bridging neuronal correlations and dimensionality reduction.

Neuron 2021 Jul 16. Epub 2021 Jul 16.

Carnegie Mellon Neuroscience Institute, Pittsburgh, PA 15213, USA; Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Electronic address:

Two commonly used approaches to study interactions among neurons are spike count correlation, which describes pairs of neurons, and dimensionality reduction, applied to a population of neurons. Although both approaches have been used to study trial-to-trial neuronal variability correlated among neurons, they are often used in isolation and have not been directly related. We first established concrete mathematical and empirical relationships between pairwise correlation and metrics of population-wide covariability based on dimensionality reduction. Applying these insights to macaque V4 population recordings, we found that the previously reported decrease in mean pairwise correlation associated with attention stemmed from three distinct changes in population-wide covariability. Overall, our work builds the intuition and formalism to bridge between pairwise correlation and population-wide covariability and presents a cautionary tale about the inferences one can make about population activity by using a single statistic, whether it be mean pairwise correlation or dimensionality.
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http://dx.doi.org/10.1016/j.neuron.2021.06.028DOI Listing
July 2021

Population-based utility scores for HPV infection and cervical squamous cell carcinoma among Australian Indigenous women.

PLoS One 2021 22;16(7):e0254575. Epub 2021 Jul 22.

Adelaide Dental School, Australian Research Centre for Population Oral Health, The University of Adelaide, Adelaide, Australia.

Objective: Working in partnership with Indigenous communities in South Australia, we aimed to develop, pilot test and estimate utility scores for health states relating to cervical cancer screening, precancer, and invasive cervical cancer and precancer/cancer treatment among Indigenous women.

Methods: Development and pilot testing of hypothetical cervical cancer health states, specifically through the lens of being an Indigenous Australian woman, was done with an Indigenous Reference Group in conjunction with five female Indigenous community members. Six health states were developed. These included: (1) Screened: cytology normal; (2) human papillomaviruses (HPV) positive with cytology normal; (3) low grade cytology (LSIL);(4) high grade cytology (HSIL); (5) early stage cervical cancer and; (6) later stage cervical cancer. Utility scores were calculated using a two-stage standard gamble approach among a large cohort of Indigenous Australian women taking part in a broader study involving oral HPV infection. The mean and standard deviation (SD) of the rank, percentage of respondents with a utility = 1 (perfect health) and utility score of each health state was summarised. Mean (SD) and medians and inter-quartile range (IQR) over 12 months and lifetime duration were calculated. Potential differences by age and residential location were assessed using the Wilcox Sum Rank test.

Results: Data was obtained from 513 Indigenous women aged 19+ years. Mean utility scores were higher for the four non-cancer health states than for invasive cervical cancer states (p-values <0.05). Lower mean utility scores were observed for late stage cervical cancer, with 0.69 at 12 months and 0.70 for lifetime duration (Intra-class correlation coefficients = 0.425). Higher utility scores were observed for the four non-cancer health states among non-metropolitan participants (ranged from 0.93 to 0.98) compared with metropolitan participants (ranged from 0.86 to 0.93) (p-values<0.05).

Conclusion: Among a large cohort of Indigenous Australian women, the reduction in quality of life (which utilities reflect) was perceived to be greater with increasing severity of cervical cancer health states. There were differences observed by geographic location, with positive cervical screening and precursor cancer-related quality of life being much higher among non-metropolitan-dwelling participants. These utility values, from one of the largest such studies ever performed in any population will be uniquely able to inform modelled evaluations of the benefits and costs of cervical cancer prevention interventions in Indigenous women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254575PLOS
July 2021

Isolating the Effect of Off-Road Glance Duration on Driving Performance: An Exemplar Study Comparing HDD and HUD in Different Driving Scenarios.

Hum Factors 2021 Jul 22:187208211031416. Epub 2021 Jul 22.

6123 The University of Nottingham, University Park, UK.

Objective: We controlled participants' glance behavior while using head-down displays (HDDs) and head-up displays (HUDs) to isolate driving behavioral changes due to use of different display types across different driving environments.

Background: Recently, HUD technology has been incorporated into vehicles, allowing drivers to, in theory, gather display information without moving their eyes away from the road. Previous studies comparing the impact of HUDs with traditional displays on human performance show differences in both drivers' visual attention and driving performance. Yet no studies have isolated glance from driving behaviors, which limits our ability to understand the cause of these differences and resulting impact on display design.

Method: We developed a novel method to control visual attention in a driving simulator. Twenty experienced drivers sustained visual attention to in-vehicle HDDs and HUDs while driving in both a simple straight and empty roadway environment and a more realistic driving environment that included traffic and turns.

Results: In the realistic environment, but not the simpler environment, we found evidence of differing driving behaviors between display conditions, even though participants' glance behavior was similar.

Conclusion: Thus, the assumption that visual attention can be evaluated in the same way for different types of vehicle displays may be inaccurate. Differences between driving environments bring the validity of testing HUDs using simplistic driving environments into question.

Application: As we move toward the integration of HUD user interfaces into vehicles, it is important that we develop new, sensitive assessment methods to ensure HUD interfaces are indeed safe for driving.
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http://dx.doi.org/10.1177/00187208211031416DOI Listing
July 2021

Ectopic expression of cDNAs from larkspur (Consolida ajacis) for increased synthesis of gondoic acid (cis-11 eicosenoic acid) and its positional redistribution in seed triacylglycerol of Camelina sativa.

Planta 2021 Jul 21;254(2):32. Epub 2021 Jul 21.

Agriculture and Agri-Food Canada, Saskatoon Research Centre, 107 Science Place, Saskatoon, SK, S7N 0X2, Canada.

Main Conclusion: A β-ketoacyl-ACP-synthase II (KAS2) like enzyme and a lysophosphatidic acid acyltransferase (LPAT2) from Consolida ajacis catalyze gondoic acid biosynthesis and incorporation into the sn-2 position of seed TAG in engineered Camelina sativa. Gondoic acid (cis-11 eicosenoic acid, 20:1∆11) is the predominant very-long-chain fatty acid (VLCFA) in camelina (Camelina sativa) seed oil accounting for 12-15% of total triacylglycerol fatty acids. To explore the feasibility of engineering increased levels of this fatty acid in camelina seed, oils from a range of plant species were analyzed to identify those producing 20-Carbon (C20) fatty acids as the only VLCFAs in their seed oil. Seeds of Consolida and Delphinium species (Ranunculaceae) were found to contain moderate levels (0.2% to 25.5%) of C20 fatty acids without accompanying longer chain fatty acids. The C20 fatty acids were abundant in both sn-2 and sn-1/3 positions of seed TAG in Consolida, but were largely absent from the sn-2 position in Delphinium seed TAG. Through generation of a developing seed transcriptome, sequences were identified and cDNAs amplified from Consolida ajacis encoding a β-ketoacyl-ACP-synthase II like protein (CaKAS2B) that lacked a predicted chloroplast transit peptide, and two homologues of Arabidopsis thaliana lysophosphatidic acid acyltransferase 2 (CaLPAT2a and CaLPAT2b). Expression of CaKAS2B in conventional (WT) camelina and a line previously engineered for high seed oleic acid content (HO) resulted in increased seed VLCFA content. Total VLCFA levels were raised from 24 to 35% and from 7 to 23% in T3 seed from representative transformants in the WT and HO backgrounds, respectively. Gondoic acid was the predominant VLCFA in transformed HO lines with low endogenous cytoplasmic fatty acid elongation activity, suggesting limited capacity of CaKAS2B to elongate beyond C20. Expression in camelina of CaLPAT2b resulted in significantly increased C20-VLCFA esterification at the sn-2 position of seed TAG with VLCFA levels of 33.8% in this position in one transformed line compared to 0.3% at sn-2 in the corresponding control line. Only small changes in total seed VLCFA content were observed in transformed lines implying that increased VLCFA esterification capacity in camelina results in positional redistribution of VLCFAs but does not significantly enhance flux through the fatty acid elongation pathway. The full potential of CaKAS2B and CaLPAT2a for the engineering of high gondoic acid levels in camelina remains to be determined. Seed fatty acid composition of Consolida and Delphinium also provides information that may be of value in the systematics of the Ranunculaceae.
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http://dx.doi.org/10.1007/s00425-021-03682-5DOI Listing
July 2021