Publications by authors named "B Brett Finlay"

737 Publications

Diversity and dynamism of IgA-microbiota interactions.

Nat Rev Immunol 2021 Feb 10. Epub 2021 Feb 10.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.

IgA mediates microbial homeostasis at the intestinal mucosa. Within the gut, IgA acts in a context-dependent manner to both prevent and promote bacterial colonization and to influence bacterial gene expression, thus providing exquisite control of the microbiota. IgA-microbiota interactions are highly diverse across individuals and populations, yet the factors driving this variation remain poorly understood. In this Review, we summarize evidence for the host, bacterial and environmental factors that influence IgA-microbiota interactions. Recent advances have helped to clarify the antigenic specificity and immune selection of intestinal IgA and have highlighted the importance of microbial glycan recognition. Furthermore, emerging evidence suggests that diet and nutrition play an important role in shaping IgA recognition of the microbiota. IgA-microbiota interactions are disrupted during both overnutrition and undernutrition and may be altered dynamically in response to diet, with potential implications for host health. We situate this research in the context of outstanding questions and future directions in order to better understand the fascinating paradigm of IgA-microbiota homeostasis.
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http://dx.doi.org/10.1038/s41577-021-00506-1DOI Listing
February 2021

Accurate identification and quantification of commensal microbiota bound by host immunoglobulins.

Microbiome 2021 01 30;9(1):33. Epub 2021 Jan 30.

Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Background: Identifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins.

Results: Using germ-free and Rag1 mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence-activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data from in vivo disease models.

Conclusions: We provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00992-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847592PMC
January 2021

When a pandemic and an epidemic collide: COVID-19, gut microbiota, and the double burden of malnutrition.

BMC Med 2021 01 28;19(1):31. Epub 2021 Jan 28.

Department of Microbiology and Immunology, University of British Columbia, Vancouver, V6T 1Z3, Canada.

Background: It is estimated that the COVID-19 pandemic will drastically increase all forms of malnutrition. Of particular concern, yet understated, is the potential to increase the double burden of malnutrition (DBM) epidemic. This coexistence of undernutrition together with overweight and obesity, or diet-related non-communicable disease (NCD), within low- to middle-income countries (LMICs) is increasing rapidly. Although multiple factors contribute to the DBM, food insecurity (FI) and gut microbiota dysbiosis play a crucial role. Both under- and overnutrition have been shown to be a consequence of food insecurity. The gut microbiota has also been recently implicated in playing a role in under- and overnutrition, with altered community structure and function common to both. The pandemic has already caused significant shifts in food availability which has immediate effects on the gut microbiome. In this opinion paper, we discuss how COVID-19 may indirectly exacerbate the DBM through food insecurity and the gut microbiome.

Main Text: The World Food Programme (WFP) estimates that 265 million people in LMICs will experience acute hunger in 2020 due to the pandemic, nearly doubling the original projection of 135 million. Global border closures to food trade, loss of food production, and stark decline in household income will exacerbate starvation while simultaneously necessitating that families resort to calorie-dense, nutrient-poor foods, thereby increasing obesity. While food insecurity, which is the persistent lack of consistent access to adequate and nutrient-rich foods, will primarily drive nutrition behavior, the gut microbiome is perhaps a key biological mechanism. Numerous human and animal studies describe low diversity and an increase in inflammatory species as characteristic features of the undernourished and overnourished gut microbiota. Indeed, fecal transplant studies show that microbiota transfer from undernourished and overnourished humans to germ-free mice lacking a microbiome transfers the physical and metabolic phenotype, suggesting a causal role for the microbiota in under- and overnutrition. The observed microbiome dysbiosis within severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coupled with the DBM presents a viscous cycle.

Conclusion: Low- to mid-income countries will likely see an increase in the DBM epidemic. Providing access to nutritious foods and protecting individuals' gut microbiome to "flatten the curve" of the DBM trajectory should be prioritized.
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http://dx.doi.org/10.1186/s12916-021-01910-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840385PMC
January 2021

The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome.

Proc Natl Acad Sci U S A 2021 02;118(6)

Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, ON M5G 1M1, Canada;

The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19-induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome's influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.
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http://dx.doi.org/10.1073/pnas.2010217118DOI Listing
February 2021

Cryo-EM structure of the EspA filament from enteropathogenic Escherichia coli: revealing the mechanism of effector translocation in the T3SS.

Structure 2021 Jan 13. Epub 2021 Jan 13.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; HRMEM facility, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address:

The type III secretion system (T3SS) is a virulence mechanism employed by Gram-negative pathogens. The T3SS forms a proteinaceous channel that projects a needle into the extracellular medium where it interacts with the host cell to deliver virulence factors. Enteropathogenic Escherichia coli (EPEC) is unique in adopting a needle extension to the T3SS-a filament formed by EspA-which is absolutely required for efficient colonization of the gut. Here, we describe the cryoelectron microscopy structure of native EspA filaments from EPEC at 3.6-Å resolution. Within the filament, positively charged residues adjacent to a hydrophobic groove line the lumen of the filament in a spiral manner, suggesting a mechanism of substrate translocation mediated via electrostatics. Using structure-guided mutagenesis, in vivo studies corroborate the role of these residues in secretion and translocation function. The high-resolution structure of the EspA filament could aid in structure-guided drug design of antivirulence therapeutics.
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http://dx.doi.org/10.1016/j.str.2020.12.009DOI Listing
January 2021

Biogeography of the Relationship between the Child Gut Microbiome and Innate Immune System.

mBio 2021 01 12;12(1). Epub 2021 Jan 12.

Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, Canada

The gut microbiome is a well-recognized modulator of host immunity, and its compositions differ between geographically separated human populations. Systemic innate immune responses to microbial derivatives also differ between geographically distinct human populations. However, the potential role of the microbiome in mediating geographically varied immune responses is unexplored. We here applied 16S amplicon sequencing to profile the stool microbiome and, in parallel, measured whole-blood innate immune cytokine responses to several pattern recognition receptor (PRR) agonists among 2-year-old children across biogeographically diverse settings. Microbiomes differed mainly between high- and low-resource environments and were not strongly associated with other demographic factors. We found strong correlations between responses to Toll-like receptor 2 (TLR2) and relative abundances of and populations, shared among Canadian and Ecuadorean children. Additional correlations between responses to TLR2 and bacterial populations were specific to individual geographic cohorts. As a proof of concept, we gavaged germfree mice with human donor stools and found murine splenocyte responses to TLR stimulation were consistent with responses of the corresponding human donor populations. This study identified differences in immune responses correlating to gut microbiomes across biogeographically diverse settings and evaluated biological plausibility using a mouse model. This insight paves the way to guide optimization of population-specific interventions aimed to improve child health outcomes. Both the gut microbiome and innate immunity are known to differ across biogeographically diverse human populations. The gut microbiome has been shown to directly influence systemic immunity in animal models. With this, modulation of the gut microbiome represents an attractive avenue to improve child health outcomes associated with altered immunity using population-specific approaches. However, there are very scarce data available to determine which members of the gut microbiome are associated with specific immune responses and how these differ around the world, creating a substantial barrier to rationally designing such interventions. This study addressed this knowledge gap by identifying relationships between distinct bacterial taxa and cytokine responses to specific microbial agonists across highly diverse settings. Furthermore, we provide evidence that immunomodulatory effects of region-specific stool microbiomes can be partially recapitulated in germfree mice. This is an important contribution toward improving global child health by targeting the gut microbiome.
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http://dx.doi.org/10.1128/mBio.03079-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845628PMC
January 2021

MIND and Mediterranean Diets Associated with Later Onset of Parkinson's Disease.

Mov Disord 2021 Jan 6. Epub 2021 Jan 6.

Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health, UBC, Vancouver, British Columbia, Canada.

Background: The MIND diet has been linked with prevention of Alzheimer's disease and cognitive decline but has not been fully assessed in the context of Parkinson's disease (PD). The objective of the present study was to determine whether MIND diet adherence is associated with the age of Parkinson's disease onset in a manner superior to that of the Mediterranean diet.

Methods: Food Frequency Questionnaires from 167 participants with PD and 119 controls were scored for MIND and 2 versions of Mediterranean diet adherence. Scores were compared between sex and disease subgroups, and PD diet adherence was correlated with age at onset using univariate and multivariate linear models.

Results: The female subgroup adhered more closely to the MIND diet than the male subgroup, and diet scores were not modified by disease status. Later age of onset correlated most strongly with MIND diet adherence in the female subgroup, corresponding to differences of up to 17.4 years (P < 0.001) between low and high dietary tertiles. Greek Mediterranean adherence was also significantly associated with later PD onset across all models (P = 0.05-0.03). Conversely, only Greek Mediterranean diet adherence remained correlated with later onset across all models in men, with differences of up to 8.4 years (P = 0.002).

Conclusions: This cross-sectional study found a strong correlation between age of onset of PD and dietary habits, suggesting that nutritional strategies may be an effective tool to delay PD onset. Further studies may help to elucidate potential nutrition-related sex-specific pathophysiological mechanisms and differential prevalence rates in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28464DOI Listing
January 2021

Reply to: 'Comment on "Microbiota Composition and Metabolism Are Associated With Gut Function in Parkinson's Disease"'.

Mov Disord 2020 09;35(9):1695-1697

Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.1002/mds.28208DOI Listing
September 2020

Changes in IgA-targeted microbiota following fecal transplantation for recurrent infection.

Gut Microbes 2021 Jan-Dec;13(1):1-12

Michael Smith Laboratories and the Department of Microbiology and Immunology, University of British Columbia , Vancouver, British Columbia, Canada.

Secretory immunoglobulin A (IgA) interacts with intestinal microbiota and promotes mucosal homeostasis. IgA-bacteria interactions are altered during inflammatory diseases, but how these interactions are shaped by bacterial, host, and environmental factors remains unclear. In this study, we utilized IgA-SEQ to profile IgA-bound fecal bacteria in 48 recurrent patients before and after successful fecal microbiota transplantation (FMT) to gain further insight. Prior to FMT, was the most highly IgA-targeted taxon; following restoration of the microbiota by FMT, highly IgA-targeted taxa included multiple species. Post-FMT IgA-targeting was unaffected by the route of FMT delivery (colonoscopy versus capsule), suggesting that both methods lead to the establishment of healthy immune-bacterial interactions in the gut. Interestingly, IgA-targeting in FMT recipients closely resembled the IgA-targeting patterns of the donors, and fecal donor identity was significantly associated with IgA-targeting of the recipient microbiota. These data support the concept that intrinsic bacterial properties drive IgA recognition across genetically distinct human hosts. Together, this study suggests that IgA-bacterial interactions are reestablished in human FMT recipients to resemble that of the healthy fecal donor.
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http://dx.doi.org/10.1080/19490976.2020.1862027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781654PMC
December 2020

Response to "Re A Multidisciplinary Approach to Oncological Resections with Vascular Surgeons Improves Patient Outcomes".

Eur J Vasc Endovasc Surg 2020 Nov 28. Epub 2020 Nov 28.

Royal Adelaide Hospital and Discipline of Surgery, University of Adelaide, Adelaide, Australia.

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http://dx.doi.org/10.1016/j.ejvs.2020.10.031DOI Listing
November 2020

The Gut Mycobiome in Parkinson's Disease.

J Parkinsons Dis 2021 ;11(1):153-158

Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health, UBC, Vancouver, British Columbia, Canada.

The gut microbiome has been increasingly implicated in Parkinson's disease (PD); however, most existing studies employ bacterial-specific sequencing, and have not investigated non-bacterial microbiome constituents. Here, we use fungal-specific internal transcribed spacer (ITS)-2 amplicon sequencing in a cross-sectional PD cohort to investigate associations between the fungal gut microbiome and PD. Fungal load among participants was extremely low, and genera identified were almost exclusively of proposed dietary or environmental origin. We observed significantly lower fungal DNA relative to bacterial DNA among PD patients. No fungi differed in abundance between patients and controls, nor were any associated with motor, cognitive, or gastrointestinal features among patients.
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http://dx.doi.org/10.3233/JPD-202237DOI Listing
January 2021

Structural and Cellular Insights into the l,d-Transpeptidase YcbB as a Therapeutic Target in Citrobacter rodentium, Typhimurium, and Typhi Infections.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada

The bacterial cell wall plays a key role in viability and is an important drug target. The cell wall is made of elongated polymers that are cross-linked to one another to form a load-bearing mesh. An alternative cell wall cross-linking mechanism used by the l,d-transpeptidase YcbB has been implicated in the stress-regulated roles of β-lactam resistance, outer membrane defect rescue, and typhoid toxin release. The role for this stress-linked cross-linking in the context of a host infection was unclear. Here, we resolve the crystallographic structures of both Typhi YcbB and YcbB acylated with ertapenem that delineate the conserved structural characteristics of YcbB. In parallel, we show that the general involvement of YcbB in peptidoglycan reinforcement under conditions of bacterial outer envelope stress does not play a significant role in acute infections of mice by and Typhimurium. Cumulatively, in this work we provide a foundation for the development of novel YcbB-specific antibacterial therapeutics to assist in treatment of increasingly drug-resistant Typhi infections.
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http://dx.doi.org/10.1128/AAC.01592-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849009PMC
January 2021

Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition.

mSystems 2020 Sep 8;5(5). Epub 2020 Sep 8.

Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada

Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative / gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition. Nonalcoholic fatty liver disease (NAFLD) remains a global epidemic, but it is often studied in the context of obesity and aging. Nutritional deficits, however, also trigger hepatic steatosis, influencing health trajectories in undernourished pediatric populations. Here, we report that exposure to specific gut microbes impacts fatty liver pathology in mice fed a protein/fat-deficient diet. We utilize a multiomics approach to (i) characterize NAFLD in the context of early undernutrition and (ii) examine the impact of diet and gut microbes in the pathology and reversal of hepatic steatosis. We provide compelling evidence that an early-life, critical development window facilitates undernutrition-induced fatty liver pathology. Moreover, we demonstrate that sustained dietary intervention largely reverses fatty liver features and microbiome shifts observed during early-life malnutrition.
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http://dx.doi.org/10.1128/mSystems.00499-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483509PMC
September 2020

Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study.

Microbiome 2020 07 27;8(1):113. Epub 2020 Jul 27.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.

Background: Child undernutrition is a global health issue that is associated with poor sanitation and an altered intestinal microbiota. Immunoglobulin (Ig) A mediates host-microbial homeostasis in the intestine, and acutely undernourished children have been shown to have altered IgA recognition of the fecal microbiota. We sought to determine whether chronic undernutrition (stunting) or intestinal inflammation were associated with antibody recognition of the microbiota using two geographically distinct populations from the Afribiota project. Fecal bacteria from 200 children between 2 and 5 years old in Antananarivo, Madagascar, and Bangui, Central African Republic (CAR), were sorted into IgA-positive (IgA+) and IgA-negative (IgA-) populations by flow cytometry and subsequently characterized by 16S rRNA gene sequencing to determine IgA-bacterial targeting. We additionally measured IgG+ fecal bacteria by flow cytometry in a subset of 75 children.

Results: Stunted children (height-for-age z-score ≤ -2) had a greater proportion of IgA+ bacteria in the fecal microbiota compared to non-stunted controls. This trend was consistent in both countries, despite the higher overall IgA-targeting of the microbiota in Madagascar, but lost significance in each country individually. Two of the most highly IgA-recognized bacteria regardless of nutritional status were Campylobacter (in CAR) and Haemophilus (in both countries), both of which were previously shown to be more abundant in stunted children; however, there was no association between IgA-targeting of these bacteria and either stunting or inflammatory markers. IgG-bound intestinal bacteria were rare in both stunted and non-stunted children, similar to levels observed in healthy populations.

Conclusions: Undernourished children carry a high load of intestinal pathogens and pathobionts. Our data suggest that stunted children have a greater proportion of IgA-recognized fecal bacteria. We moreover identify two putative pathobionts, Haemophilus and Campylobacter, that are broadly targeted by intestinal IgA. This study furthers our understanding of host-microbiota interactions in undernutrition and identifies immune-recognized microbes for future study.
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http://dx.doi.org/10.1186/s40168-020-00890-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385872PMC
July 2020

Can we harness the microbiota to enhance the efficacy of cancer immunotherapy?

Nat Rev Immunol 2020 09 13;20(9):522-528. Epub 2020 Jul 13.

Faculty of Medicine, Paris-Saclay University, Le Kremlin-Bicêtre, France.

There is currently much interest in defining how the microbiota shapes immune responses in the context of cancer. Various studies in both mice and humans have associated particular commensal species with better (or worse) outcomes in different cancer types and following treatment with cancer immunotherapies. However, the mechanisms involved remain ill-defined and even controversial. In this Viewpoint, Nature Reviews Immunology has invited six eminent scientists in the field to share their thoughts on the key questions and challenges for the field.
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http://dx.doi.org/10.1038/s41577-020-0374-6DOI Listing
September 2020

Breastmilk Feeding Practices Are Associated with the Co-Occurrence of Bacteria in Mothers' Milk and the Infant Gut: the CHILD Cohort Study.

Cell Host Microbe 2020 08 10;28(2):285-297.e4. Epub 2020 Jul 10.

Children's Hospital Research Institute of Manitoba and Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada. Electronic address:

Gut microbiota play a critical role in infant health. It is now accepted that breastmilk contains live bacteria from endogenous and exogenous sources, but it remains unclear whether these bacteria transfer to the infant gut and whether this process is influenced by breastmilk feeding practices. Here, we show that certain bacteria, including Streptococcus spp. and Veillonella dispar, co-occur in mothers' milk and their infants' stool, and co-occurrence is reduced when infants receive pumped breastmilk. The relative abundances of commonly shared species are positively correlated between breastmilk and stool. Overall, gut microbiota composition is strongly associated with breastfeeding exclusivity and duration but not breastmilk feeding mode (nursing versus pumping). Moreover, breastmilk bacteria contributed to overall gut microbiota variation to a similar extent as other modifiers of the infant microbiome, such as birth mode. These results provide evidence that breastmilk may transfer bacteria to the infant gut and influence microbiota development.
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http://dx.doi.org/10.1016/j.chom.2020.06.009DOI Listing
August 2020

Multiple Salmonella-pathogenicity island 2 effectors are required to facilitate bacterial establishment of its intracellular niche and virulence.

PLoS One 2020 25;15(6):e0235020. Epub 2020 Jun 25.

Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.

The pathogenesis of Salmonella Typhimurium depends on the bacterium's ability to survive and replicate within host cells. The formation and maintenance of a unique membrane-bound compartment, termed the Salmonella-containing vacuole (SCV), is essential for S. Typhimurium pathogenesis. SCV-bound S. Typhimurium induces formation of filamentous tubules that radiate outwards from the SCV, termed Salmonella-induced filaments (SIFs). SIF formation is concomitant with the onset of replication within host epithelial cells. SIF biogenesis, formation and maintenance of the SCV, and the intracellular positioning of the SCV within the host cell requires translocation of bacterial proteins (effectors) into the host cell. Effectors secreted by the type III secretion system encoded on Salmonella pathogenicity island 2 (T3SS2) function to interfere with host cellular processes and promote both intracellular survival and replication of S. Typhimurium. Seven T3SS2-secreted effectors, SifA, SopD2, PipB2, SteA, SseJ, SseF, and SseG have previously been implicated to play complementary, redundant, and/or antagonistic roles with respect to SIF biogenesis, intracellular positioning of the SCV, and SCV membrane dynamics modulation during infection. We undertook a systematic study to delineate the contribution of each effector to these processes by (i) deleting all seven of these effectors in a single S. Typhimurium strain; and (ii) deleting combinations of multiple effectors based on putative effector function. Using this deletion mutant library, we show that each of SIF biogenesis, intracellular SCV localization, intramacrophage replication, colonization, and virulence depends on the activities of multiple effectors. Together, our data demonstrates the complex interplay between these seven effectors and highlights the necessity to study T3SS2-secreted effectors as groups, rather than studies of individual effectors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235020PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316343PMC
August 2020

Master Sculptor at Work: Enteropathogenic Escherichia coli Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death.

mSystems 2020 Jun 2;5(3). Epub 2020 Jun 2.

Department of Microbiology & Immunology, University of British Columbia, Vancouver, Canada

Enteropathogenic (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into human intestinal cells. Three effectors travel to mitochondria and modulate apoptosis; however, the mechanisms by which effectors control apoptosis from within mitochondria are unknown. To identify and quantify global changes in mitochondrial proteolysis during infection, we applied the mitochondrial terminal proteomics technique itochondrial table isotope labeling by amino acids in cell culture-erminal mine sotopic abeling of ubstrates (MS-TAILS). MS-TAILS identified 1,695 amino N-terminal peptides from 1,060 unique proteins and 390 N-terminal peptides from 215 mitochondrial proteins at a false discovery rate of 0.01. Infection modified 230 cellular and 40 mitochondrial proteins, generating 27 cleaved mitochondrial neo-N termini, demonstrating altered proteolytic processing within mitochondria. To distinguish proteolytic events specific to EPEC from those of canonical apoptosis, we compared mitochondrial changes during infection with those reported from chemically induced apoptosis. During infection, fewer than half of all mitochondrial cleavages were previously described for canonical apoptosis, and we identified nine mitochondrial proteolytic sites not previously reported, including several in proteins with an annotated role in apoptosis, although none occurred at canonical Asp-Glu-Val-Asp (DEVD) sites associated with caspase cleavage. The identification and quantification of novel neo-N termini evidences the involvement of noncaspase human or EPEC protease(s) resulting from mitochondrial-targeting effectors that modulate cell death upon infection. All proteomics data are available via ProteomeXchange with identifier PXD016994 To our knowledge, this is the first study of the mitochondrial proteome or N-terminome during bacterial infection. Identified cleavage sites that had not been previously reported in the mitochondrial N-terminome and that were not generated in canonical apoptosis revealed a pathogen-specific strategy to control human cell apoptosis. These data inform new mechanisms of virulence factors targeting mitochondria and apoptosis during infection and highlight how enteropathogenic (EPEC) manipulates human cell death pathways during infection, including candidate substrates of an EPEC protease within mitochondria. This understanding informs the development of new antivirulence strategies against the many human pathogens that target mitochondria during infection. Therefore, itochondrial table isotope labeling by amino acids in cell culture-erminal mine sotopic abeling of ubstrates (MS-TAILS) is useful for studying other pathogens targeting human cell compartments.
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http://dx.doi.org/10.1128/mSystems.00283-20DOI Listing
June 2020

A Multidisciplinary Approach to Oncological Resections with Vascular Surgeons Improves Patient Outcomes.

Eur J Vasc Endovasc Surg 2020 Aug 8;60(2):293-299. Epub 2020 May 8.

Trauma & Surgical Oncology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia; Department of Vascular & Endovascular Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia; Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.

Objective: Oncological resections have become more radical in pursuit of disease free margins. Consequently, vascular structures may be injured inadvertently or purposely resected, with or without subsequent reconstruction. Thus, vascular surgeons have an increasing role in oncological surgery. The present authors sought to review their experience and examine the effect of timing of referral to a Vascular Surgeon (VS) on patient and surgical outcomes following tumour resection.

Methods: A retrospective review was conducted of a prospectively maintained database at a public hospital network in Adelaide, Australia. All cases of collaboration between a VS and other surgeons for resection of cancer or non-malignant tumour were included. Medical records and operative, pathological, and transfusion data were reviewed, with particular attention to referring team, timing of VS referral (pre- or intra-operative), and the operative role of the VS.

Results: Seventy-two cases were identified from January 2004 to June 2018. The most common collaborators were General Surgery and Urology. Of the cases, 86% were elective and 71% were referred to the VS pre-operatively. Pre-operative referral was associated with a predominant VS role of dissection and exposure. Pre-operative referral was associated with lower odds of vessel repair and reconstruction compared with intra-operative referral (adjusted OR = 0.20; 95% CI 0.04-0.93; p = .040) and a lower incidence of positive surgical margins (35% vs. 80%, p = .028). The rate of blood product units required was lower among pre-operative referrals relative to intra-operative referrals, but the effect of timing was not significant after adjustment for potential confounders (IRR = 0.80, 95% CI 0.26-2.44; p = .70).

Conclusion: Pre-operative planned involvement of vascular surgery in oncological operations can improve surgical outcomes, with additional expected benefits for surgical training and cross specialty collaboration.
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http://dx.doi.org/10.1016/j.ejvs.2020.04.011DOI Listing
August 2020

Microbiota Composition and Metabolism Are Associated With Gut Function in Parkinson's Disease.

Mov Disord 2020 07 1;35(7):1208-1217. Epub 2020 May 1.

Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health, UBC, Vancouver, British Columbia, Canada.

Background: Parkinson's disease is characterized by a high burden of gastrointestinal comorbidities, especially constipation and reduced colonic transit time, and by gut microbiota alterations. The diverse metabolites produced by the microbiota are broadly relevant to host health. How microbiota composition and metabolism relate to gastrointestinal function in Parkinson's disease is largely unknown. The objectives of the current study were to assesses associations between microbiota composition, stool consistency, constipation, and systemic microbial metabolites in Parkinson's disease to better understand how intestinal microbes contribute to gastrointestinal disturbances commonly observed in patients.

Methods: Three hundred participants (197 Parkinson's patients and 103 controls) were recruited for this cross-sectional cohort study. Participants supplied fecal samples for microbiota sequencing (n = 300) and serum for untargeted metabolomics (n = 125). Data were collected on motor and nonmotor Parkinson's symptoms, medications, diet, and demographics.

Results: Significant microbiota taxonomic differences were observed in Parkinson's patients, even when controlling for gastrointestinal function. Parkinson's microbiota was characterized by reduced carbohydrate fermentation and butyrate synthesis capacity and increased proteolytic fermentation and production of deleterious amino acid metabolites, including p-cresol and phenylacetylglutamine. Taxonomic shifts and elevated proteolytic metabolites were strongly associated with stool consistency (a proxy for colonic transit time) and constipation among patients.

Conclusions: Compositional and metabolic alterations in the Parkinson's microbiota are highly associated with gut function, suggesting plausible mechanistic links between altered bacterial metabolism and reduced gut health in this disease. The systemic detection of elevated deleterious proteolytic microbial metabolites in Parkinson's serum suggests a mechanism whereby microbiota dysbiosis contributes to disease etiology and pathophysiology. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28052DOI Listing
July 2020

Commensal Bacteria Modulate Immunoglobulin A Binding in Response to Host Nutrition.

Cell Host Microbe 2020 06 13;27(6):909-921.e5. Epub 2020 Apr 13.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address:

Immunoglobulin (Ig) A controls host-microbial homeostasis in the gut. IgA recognition of beneficial bacteria is decreased in acutely undernourished children, but the factors driving these changes in IgA targeting are unknown. Child undernutrition is a global health challenge that is exacerbated by poor sanitation and intestinal inflammation. To understand how nutrition impacts immune-microbe interactions, we used a mouse model of undernutrition with or without fecal-oral exposure and assessed IgA-bacterial targeting from weaning to adulthood. In contrast to healthy control mice, undernourished mice fail to develop IgA recognition of intestinal Lactobacillus. Glycan-mediated interactions between Lactobacillus and host antibodies are lost in undernourished mice due to rapid bacterial adaptation. Lactobacillus adaptations occur in direct response to nutritional pressure, independently of host IgA, and are associated with reduced mucosal colonization and with bacterial mutations in carbohydrate processing genes. Together these data indicate that diet-driven bacterial adaptations shape IgA recognition in the gut.
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http://dx.doi.org/10.1016/j.chom.2020.03.012DOI Listing
June 2020

Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies.

Lancet Respir Med 2020 11 24;8(11):1094-1105. Epub 2020 Mar 24.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada. Electronic address:

Background: Childhood asthma incidence is decreasing in some parts of Europe and North America. Antibiotic use in infancy has been associated with increased asthma risk. In the present study, we tested the hypothesis that decreases in asthma incidence are linked to reduced antibiotic prescribing and mediated by changes in the gut bacterial community.

Methods: This study comprised population-based and prospective cohort analyses. At the population level, we used administrative data from British Columbia, Canada (population 4·7 million), on annual rates of antibiotic prescriptions and asthma diagnoses, to assess the association between antibiotic prescribing (at age <1 year) and asthma incidence (at age 1-4 years). At the individual level, 2644 children from the Canadian Healthy Infant Longitudinal Development (CHILD) prospective birth cohort were examined for the association of systemic antibiotic use (at age <1 year) with the diagnosis of asthma (at age 5 years). In the same cohort, we did a mechanistic investigation of 917 children with available 16S rRNA gene sequencing data from faecal samples (at age ≤1 year), to assess how composition of the gut microbiota relates to antibiotic exposure and asthma incidence.

Findings: At the population level between 2000 and 2014, asthma incidence in children (aged 1-4 years) showed an absolute decrease of 7·1 new diagnoses per 1000 children, from 27·3 (26·8-28·3) per 1000 children to 20·2 (19·5-20·8) per 1000 children (a relative decrease of 26·0%). Reduction in incidence over the study period was associated with decreasing antibiotic use in infancy (age <1 year), from 1253·8 prescriptions (95% CI 1219·3-1288·9) per 1000 infants to 489·1 (467·6-511·2) per 1000 infants (Spearman's r=0·81; p<0·0001). Asthma incidence increased by 24% with each 10% increase in antibiotic prescribing (adjusted incidence rate ratio 1·24 [95% CI 1·20-1·28]; p<0·0001). In the CHILD cohort, after excluding children who received antibiotics for respiratory symptoms, asthma diagnosis in childhood was associated with infant antibiotic use (adjusted odds ratio [aOR] 2·15 [95% CI 1·37-3·39]; p=0·0009), with a significant dose-response; 114 (5·2%) of 2182 children unexposed to antibiotics had asthma by age 5 years, compared with 23 (8·1%) of 284 exposed to one course, five (10·2%) of 49 exposed to two courses, and six (17·6%) of 34 exposed to three or more courses (aOR 1·44 [1·16-1·79]; p=0·0008). Increasing α-diversity of the gut microbiota, defined as an IQR increase (25th to 75th percentile) in the Chao1 index, at age 1 year was associated with a 32% reduced risk of asthma at age 5 years (aOR for IQR increase 0·68 [0·46-0·99]; p=0·046). In a structural equation model, we found the gut microbiota at age 1 year, characterised by α-diversity, β-diversity, and amplicon sequence variants modified by antibiotic exposure, to be a significant mediator between outpatient antibiotic exposure in the first year of life and asthma diagnosis at age 5 years (β=0·08; p=0·027).

Interpretation: Our findings suggest that the reduction in the incidence of paediatric asthma observed in recent years might be an unexpected benefit of prudent antibiotic use during infancy, acting via preservation of the gut microbial community.

Funding: British Columbia Ministry of Health, Pharmaceutical Services Branch; Canadian Institutes of Health Research; Allergy, Genes and Environment (AllerGen) Network of Centres of Excellence; Genome Canada; and Genome British Columbia.
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http://dx.doi.org/10.1016/S2213-2600(20)30052-7DOI Listing
November 2020

Mining the infant gut microbiota for therapeutic targets against atopic disease.

Allergy 2020 08 10;75(8):2065-2068. Epub 2020 Mar 10.

University of British Columbia, Vancouver, BC, Canada.

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http://dx.doi.org/10.1111/all.14244DOI Listing
August 2020

The Role of Lung and Gut Microbiota in the Pathology of Asthma.

Immunity 2020 02;52(2):241-255

Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of disease management. Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment. Bacteria and viruses are the most extensively studied microorganisms relating to asthma pathogenesis, but other microbes, including fungi and even archaea, can potently influence airway inflammation. This review focuses on recently discovered connections between lung and gut microbiota, including bacteria, fungi, viruses, and archaea, and their influence on asthma.
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http://dx.doi.org/10.1016/j.immuni.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128389PMC
February 2020

Dynamics of expression, secretion and translocation of type III effectors during enteropathogenic Escherichia coli infection.

Curr Opin Microbiol 2020 04 12;54:67-76. Epub 2020 Feb 12.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Enteropathogenic Escherichia coli (EPEC) is an important cause of infant diarrhea and mortality worldwide. The locus of enterocyte effacement (LEE) pathogenicity island in the EPEC genome encodes a type 3 secretion system (T3SS). This nanomachine directly injects a sophisticated arsenal of effectors into host cells, which is critical for EPEC pathogenesis. To colonize the gut mucosa, EPEC alters its gene expression in response to host environmental signals. Regulation of the LEE has been studied extensively, revealing key mechanisms of transcriptional regulation, and more recently at the posttranscriptional and posttranslational levels. Moreover, the T3SS assembly and secretion is a highly coordinated process that ensures hierarchical delivery of effectors upon cell contact. EPEC effectors and virulence factors not only manipulate host cellular processes, but also modulate effector translocation by controlling T3SS formation. In this review, we focus on the regulation of EPEC virulence genes and modulation of effector secretion and translocation.
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http://dx.doi.org/10.1016/j.mib.2019.12.001DOI Listing
April 2020

Establishing or Exaggerating Causality for the Gut Microbiome: Lessons from Human Microbiota-Associated Rodents.

Cell 2020 01;180(2):221-232

Department of Medicine and APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland.

Human diseases are increasingly linked with an altered or "dysbiotic" gut microbiota, but whether such changes are causal, consequential, or bystanders to disease is, for the most part, unresolved. Human microbiota-associated (HMA) rodents have become a cornerstone of microbiome science for addressing causal relationships between altered microbiomes and host pathology. In a systematic review, we found that 95% of published studies (36/38) on HMA rodents reported a transfer of pathological phenotypes to recipient animals, and many extrapolated the findings to make causal inferences to human diseases. We posit that this exceedingly high rate of inter-species transferable pathologies is implausible and overstates the role of the gut microbiome in human disease. We advocate for a more rigorous and critical approach for inferring causality to avoid false concepts and prevent unrealistic expectations that may undermine the credibility of microbiome science and delay its translation.
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http://dx.doi.org/10.1016/j.cell.2019.12.025DOI Listing
January 2020

Are noncommunicable diseases communicable?

Authors:
B B Finlay

Science 2020 01;367(6475):250-251

Michael Smith Laboratories and the Departments of Biochemistry and Molecular Biology, and Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.1126/science.aaz3834DOI Listing
January 2020

Developmental duration as an organizer of the evolving mammalian brain: scaling, adaptations, and exceptions.

Evol Dev 2020 01 3;22(1-2):181-195. Epub 2019 Dec 3.

Institute for Advanced Research, Shanghai, China.

Neurodevelopmental duration plays a central role in the evolution of the retina and neocortex in mammals. In the diurnal primate eye and retina, it is necessary to scale the number of cones versus the number of rods with different exponents to defend their respective functions of spatial acuity and sensitivity in eyes of different sizes. The order of photoreceptor precursor specification, cones specified first, rods second, couples their respective cell numbers at maturity to the kinetics of embryonic stem cell proliferation. Different durations of retinogenesis change the ratio of rods to cones produced so as to defend both functions over a range of eye diameters. In the evolution of nocturnality, the same coupling of photoreceptor specification to neurogenesis is altered to fewer cones and many more rods in nocturnal eyes, by delaying the onset of retinogenesis. Similarly, the neocortex also shows coupling of the specification of laminar position with duration of neurogenesis. Overall, duration of neurogenesis directly predicts neocortex volume in most mammalian clades. In larger brains with longer neocortical neurogenesis, its organization changes progressively, differentiating the frontal pole from the occipital pole in volume of connectivity and number of neurons per unit column. This permits greater, hierarchically organized information abstraction with increasing neocortex volume. Exceptions do exist, however, in species of three separate taxa, marsupials, naked mole rats, and bats, which break the correlation of neurodevelopmental duration and brain size. Naked mole rats and bats both have small brains and unusual longevity, coupled with neurodevelopmental periods characteristic of much bigger-brained animals, raising the possibility that developmental duration and lifespan have some genetic or mechanistic control in common. The role of duration of development in mediating between the mechanistic levels of construction of retinal and cortical organization, and the different life histories associated with larger brains, such as duration of parental care, learning and overall longevity are discussed.
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http://dx.doi.org/10.1111/ede.12329DOI Listing
January 2020

Gender-Specific Beneficial Effects of Docosahexaenoic Acid Dietary Supplementation in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice.

Neurotherapeutics 2020 01;17(1):269-281

Departament de Medicina Experimental, Institut de Recerca Biomèdica de Lleida-Universitat de Lleida, Av. Rovira Roure 80, 25198, Lleida, Spain.

Docosahexaenoic acid (DHA) is an essential fatty acid modulating key nervous system functions, including neuroinflammation, and regulation of pre- and postsynaptic membrane formation. DHA concentration decreases in the lumbar spinal cord (LSC) of amyotrophic lateral sclerosis (ALS) patients and murine preclinical models. Using a dietary supplementation, we increased DHA levels (2% mean increase, p < 0.01) in the LSC of the familial ALS murine model B6SJL-Tg(SOD1*G93A)1Gur/J. This DHA-enriched diet significantly increases male mouse survival by 7% (average 10 days over 130 days of life expectancy), and delays motor dysfunction (based on stride length) and transgene-associated weight loss (p < 0.01). DHA supplementation led to an increased anti-inflammatory fatty acid profile (ca 30%, p < 0.01) and a lower concentration of circulating proinflammatory cytokine TNF-α (p < 0.001 in males). Furthermore, although DHA-treated mice did not exhibit generally decreased protein oxidative markers (glutamic and aminoadipic semialdehydes, carboxyethyllysine, carboxymethyllysine, and malondialdehydelysine), dietary intake of DHA reduced immunoreactivity towards DNA oxidative damage markers (8-oxo-dG) in the LSC. In vitro we demonstrate that DHA and α-tocopherol addition to a model of motor neuron demise (neonatal rat organotypic spinal cord model under chronic excitotoxicity) also preserves motor neuron number, in comparison with untreated spinal cords. Also, beneficial effects on cell viability were evidenced for the motor neuron cell line NSC-34 in front of HO insult (p < 0.001). Globally we show a sex-specific benefit of dietary DHA supplementation in the G93A ALS mouse model, compared with mice fed an isocaloric control or a n-3-depleted diet. These changes were associated with an increased DHA concentration in the LSC and were compatible with in vitro results showing DHA neuroprotective properties. These results suggest the need for further study on the interaction of gender-influenced biological parameters and DHA in ALS pathogenesis.
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http://dx.doi.org/10.1007/s13311-019-00808-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007454PMC
January 2020

Lessons learned from relocating an acute surgical unit to a new quaternary referral centre in Adelaide, South Australia: a tale of two hospitals.

ANZ J Surg 2019 12 21;89(12):1620-1625. Epub 2019 Oct 21.

Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Background: On 4 September 2017, patient care was relocated from one quaternary hospital that was closing, to another proximate greenfield site in Adelaide, Australia, this becoming the new Royal Adelaide Hospital. There are currently no data to inform how best to transition hospitals. We conducted a 12-week prospective study of admissions under our acute surgical unit to determine the impact on our key performance indicators. We detail our results and describe compensatory measures deployed around the move.

Methods: Using a standard proforma, data were collected on key performance indicators for acute surgical unit patients referred by the emergency department (ED). This was supplemented by data obtained from operative management software and coding data from medical records to build a database for analysis.

Results: Five hundred and eight patients were admitted during the study period. Significant delays were seen in times to surgical referral, surgical review and leaving the ED. Closely comparable was time spent in the surgical suite. Uptake of the Ambulatory Care Pathway fell by 67% and the Rapid Access Clinic by 46%. Overall mortality and patient length of stay were not affected.

Conclusion: We found the interface with ED was most affected. Staff encountered difficulties familiarizing with a new environment and an anecdotally high number of ED presentations. Delays to referral and surgical review resulted in extended patient stay in ED. Once in theatre, care was comparable pre- and post-transition. This was likely from early identification of patients requiring an emergency operation, close consultant surgeon involvement and robust working relationships between surgeons, anaesthetists and nurses.
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http://dx.doi.org/10.1111/ans.15498DOI Listing
December 2019