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Increased Gut Permeability and Microbiota Change Associate with Mesenteric Fat Inflammation and Metabolic Dysfunction in Diet-Induced Obese Mice
We investigated the relationship between gut health, visceral fat dysfunction and metabolic disorders in diet-induced obesity. C57BL/6J mice were fed control or high saturated fat diet (HFD). Circulating glucose, insulin and inflammatory markers were measured. Proximal colon barrier function was assessed by measuring transepithelial resistance and mRNA expression of tight-junction proteins. Gut microbiota profile was determined by 16S rDNA pyrosequencing. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 mRNA levels were measured in proximal colon, adipose tissue and liver using RT-qPCR. Adipose macrophage infiltration (F4/80⁺) was assessed using immunohistochemical staining. HFD mice had a higher insulin/glucose ratio (P = 0.020) and serum levels of serum amyloid A3 (131%; P = 0.008) but reduced circulating adiponectin (64%; P = 0.011). In proximal colon of HFD mice compared to mice fed the control diet, transepithelial resistance and mRNA expression of zona occludens 1 were reduced by 38% (P<0.001) and 40% (P = 0.025) respectively and TNF-α mRNA level was 6.6-fold higher (P = 0.037). HFD reduced Lactobacillus (75%; P<0.001) but increased Oscillibacter (279%; P = 0.004) in fecal microbiota. Correlations were found between abundances of Lactobacillus (r = 0.52; P = 0.013) and Oscillibacter (r = -0.55; P = 0.007) with transepithelial resistance of the proximal colon. HFD increased macrophage infiltration (58%; P = 0.020), TNF-α (2.5-fold, P<0.001) and IL-6 mRNA levels (2.5-fold; P = 0.008) in mesenteric fat. Increased macrophage infiltration in epididymal fat was also observed with HFD feeding (71%; P = 0.006) but neither TNF-α nor IL-6 was altered. Perirenal and subcutaneous adipose tissue showed no signs of inflammation in HFD mice. The current results implicate gut dysfunction, and attendant inflammation of contiguous adipose, as salient features of the metabolic dysregulation of diet-induced obesity.
Journal Article
The Atomic Bomb and the Origins of the Cold War
After a devastating world war, culminating in the obliteration of Hiroshima and Nagasaki, it was clear that the United States and the Soviet Union had to establish a cooperative order if the planet was to escape an atomic World War III.
In this provocative study, Campbell Craig and Sergey Radchenko show how the atomic bomb pushed the United States and the Soviet Union not toward cooperation but toward deep bipolar confrontation. Joseph Stalin, sure that the Americans meant to deploy their new weapon against Russia and defeat socialism, would stop at nothing to build his own bomb. Harry Truman, initially willing to consider cooperation, discovered that its pursuit would mean political suicide, especially when news of Soviet atomic spies reached the public. Both superpowers, moreover, discerned a new reality of the atomic age: now, cooperation must be total. The dangers posed by the bomb meant that intermediate measures of international cooperation would protect no one. Yet no two nations in history were less prepared to pursue total cooperation than were the United States and the Soviet Union. The logic of the bomb pointed them toward immediate Cold War.
eBook
Evaluation of continuous quality improvement in accreditation for medical education
Background
Accreditation systems are based on a number of principles and purposes that vary across jurisdictions. Decision making about accreditation governance suffers from a paucity of evidence. This paper evaluates the pros and cons of continuous quality improvement (CQI) within educational institutions that have traditionally been accredited based on episodic evaluation by external reviewers.
Methods
A naturalistic utility-focused evaluation was performed. Seven criteria, each relevant to government oversight, were used to evaluate the pros and cons of the use of CQI in three medical school accreditation systems across the continuum of medical education. The authors, all involved in the governance of accreditation, iteratively discussed CQI in their medical education contexts in light of the seven criteria until consensus was reached about general patterns.
Results
Because institutional CQI makes use of early warning systems, it may enhance the reflective function of accreditation. In the three medical accreditation systems examined, external accreditors lacked the ability to respond quickly to local events or societal developments. There is a potential role for CQI in safeguarding the public interest. Moreover, the central governance structure of accreditation may benefit from decentralized CQI. However, CQI has weaknesses with respect to impartiality, independence, and public accountability, as well as with the ability to balance expectations with capacity.
Conclusion
CQI, as evaluated with the seven criteria of oversight, has pros and cons. Its use still depends on the balance between the expected positive effects—especially increased reflection and faster response to important issues—versus the potential impediments. A toxic culture that affects impartiality and independence, as well as the need to invest in bureaucratic systems may make in impractical for some institutions to undertake CQI.
Journal Article
An international comparative analysis of public reimbursement of orphan drugs in Canadian provinces compared to European countries
Background
The Canadian government has committed to developing a national strategy for drugs for rare diseases starting in 2022. Considering this announcement, we conducted a comparative analysis to examine patient access to therapies for rare disease in Canada relative to Europe and the U.S.
Methods
Given its similarity to the Canadian health care system, we used Europe as the reference point to analyze all of the therapies with an orphan drug designation approved by the European Medicine Agency (EMA) from 1 January 2015 to 31 March 2020. We then contrasted access to these drugs in Canada (Health Canada) and the U.S. (Food and Drug Administration, FDA). We focused on: (1) the number of therapies for rare diseases entering the Canadian market; (2) the percentage of these therapies that are publicly available to Canadians; and (3) the timelines for patients to access these therapies in Canada.
Results
Sixty-three approved therapies with an orphan drug designation from the EMA were identified. Fifty-three (84%) of these drugs had also been submitted to the FDA for approval, and 41 (65%) were submitted to Health Canada for approval. In Europe, Germany, Denmark, and the U.K. had the highest percentage of publicly reimbursed orphan drugs (84%, 70%, 68%, respectively). In comparison, Ontario (32%), Quebec (25%), and Alberta (25%) had the highest percentage of drugs reimbursed among the Canadian provinces. The shortest median duration (in months) from EMA approval to jurisdictional decision on reimbursement was in Austria (3.2), followed by Germany (4.1), and Finland (6.0). In Canada, the shortest median duration (in months) from regulatory approval to reimbursement was in British Columbia (17.3), Quebec (19.6) and Manitoba (19.6), while the longest duration was in P.E.I (38.5), followed by Nova Scotia (25.9), and Newfoundland (25.1).
Conclusions
Our comparative analysis found that relative to the EU Canadians had less frequent and timely access to therapies for rare diseases. This highlights the need for a rare disease strategy in Canada that allows for clear identification and transparent tracking of the pathway for rare disease drugs, and ultimately optimizes the number of patients with access to these therapies.
Journal Article
Pathogenesis of Chytridiomycosis, a Cause of Catastrophic Amphibian Declines
The pathogen Batrachochytrium dendrobatidis (Bd), which causes the skin disease chytridiomycosis, is one of the few highly virulent fungi in vertebrates and has been implicated in worldwide amphibian declines. However, the mechanism by which Bd causes death has not been determined. We show that Bd infection is associated with pathophysiological changes that lead to mortality in green tree frogs (Litoria caerulea). In diseased individuals, electrolyte transport across the epidermis was inhibited by >50%, plasma sodium and potassium concentrations were respectively reduced by approximately 20% and approximately 50%, and asystolic cardiac arrest resulted in death. Because the skin is critical in maintaining amphibian homeostasis, disruption to cutaneous function may be the mechanism by which Bd produces morbidity and mortality across a wide range of phylogenetically distant amphibian taxa.
Journal Article
P2Y6 receptors are involved in mediating the effect of inactivated avian influenza virus H5N1 on IL-6 & CXCL8 mRNA expression in respiratory epithelium
One of the key pathophysiologies of H5N1 infection is excessive proinflammatory cytokine response (cytokine storm) characterized by increases in IFN-β, TNF-α, IL-6, CXCL10, CCL4, CCL2 and CCL5 in the respiratory tract. H5N1-induced cytokine release can occur via an infection-independent mechanism, however, detail of the cellular signaling involved is poorly understood. To elucidate this mechanism, the effect of inactivated (β-propiolactone-treated) H5N1 on the cytokine and chemokine mRNA expression in 16HBE14o- human respiratory epithelial cells was investigated. We found that the inactivated-H5N1 increased mRNA for IL-6 and CXCL8 but not TNF-α, CCL5 or CXCL10. This effect of the inactivated-H5N1 was inhibited by sialic acid receptor inhibitor (α-2,3 sialidase), adenosine diphosphatase (apyrase), P2Y receptor (P2YR) inhibitor (suramin), P2Y6R antagonist (MRS2578), phospholipase C inhibitor (U73122), protein kinase C inhibitors (BIM and Gö6976) and cell-permeant Ca2+ chelator (BAPTA-AM). Inhibitors of MAPK signaling, including of ERK1/2 (PD98059), p38 MAPK (SB203580) and JNK (SP600125) significantly suppressed the inactivated-H5N1-induced mRNA expression of CXCL8. On the other hand, the inactivated-H5N1-induced mRNA expression of IL-6 was inhibited by SB203580, but not PD98059 or SP600125, whereas SN-50, an inhibitor of NF-κB, inhibited the effect of virus on mRNA expression of both of IL-6 and CXCL8. Taken together, our data suggest that, without infection, inactivated-H5N1 induces mRNA expression of IL-6 and CXCL8 by a mechanism, or mechanisms, requiring interaction between viral hemagglutinin and α-2,3 sialic acid receptors at the cell membrane of host cells, and involves activation of P2Y6 purinergic receptors.
Journal Article
What Alert Thresholds Should Be Used to Identify Critical Risk Results: A Systematic Review of the Evidence
Pathology laboratories are required to immediately report results which indicate a patient is at critical risk, but there is little consensus about what values are deemed critical. The aim of this review was to systematically review the literature on alert thresholds for common chemistry and hematology tests in adults and to provide an explicit and ranked source of this evidence.
The literature search covered the period of 1995-2014. Evidence sources were critically appraised and ranked using the 1999 Stockholm hierarchy for analytical performance specifications in laboratory medicine modified for establishing decision limits.
The 30 most frequently reported laboratory tests with alert thresholds are presented with evidence rankings. Similar thresholds were reported in North America, Europe and Asia. Seventy percent of papers reported thresholds set by individual institutions, while 18% contained thresholds from surveys of laboratories or clinicians. Forty-six percent of the papers referred to 1 or both of the 2 American laboratory surveys from the early 1990s. \"Starter sets\" of alert thresholds were recommended by 6 professional bodies, 3 of which were collaborations between pathologists and clinicians. None of the 9 outcome studies identified dealt with confounding factors.
Recommendations by professional bodies based on outdated surveys of the former state of the art or consensus are currently the best sources of evidence for laboratories to build their alert list. Well-designed outcome studies and greater collaboration between clinicians and the laboratory are needed to identify the most appropriate alert thresholds that signify actionable, critical or significant risk to patient well-being.
Journal Article
Newborn Screening for Spinal Muscular Atrophy: Ontario Testing and Follow-up Recommendations
Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2.
To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result.
An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management.
Ontario's pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.
Journal Article
Developing an Anti-Racism Tool Kit for Medical Education: A Pre-Clerkship Curriculum Audit
Background
Racialized health inequities are poorly addressed in medical education, often presenting race without social context and perpetuating racialized biases. Reframing the understanding of race as a social construct and incorporating anti-racism education into medical curricula are essential to mitigate health inequities. Our study describes an anti-racism curriculum audit conducted for the University of Ottawa Undergraduate Medical Education pre-clerkship program. This audit informed the development of an anti-racism toolkit designed to serve as a systematic guide for medical schools undertaking curriculum reforms.
Methods
A comprehensive anti-racism curriculum audit was conducted on pre-clerkship curriculum content from May 2020 to August 2021. Content flagged for concern was categorized into 4 themes: insufficient representation of racialized populations, race-based generalizations, cultural insensitivities, and reinforcement of stereotypes.
Results
The curriculum audit evaluated 772 course modules, completed by 18 medical students. A total of 224 (31.6%) modules contained one or more racial biases. The most prevalent concern was insufficient representation of racialized populations, identified in 145 flagged comments (55.1%). Curriculum content also perpetuated race-based generalizations (n = 75 flagged comments, 28.5%), racial stereotypes (n = 23 flagged comments, 8.8%), and cultural insensitivities (n = 20 flagged comments, 7.6%).
Conclusions
This anti-racism curriculum audit revealed a lack of diverse representation, alongside the persistence of race-based generalizations, stereotypes, and cultural insensitivities in a large proportion of the pre-clerkship curriculum. An anti-racist lens and curriculum are necessary to reduce bias in medical education and empower medical students to provide equitable care to the diverse Canadian patient population.
Journal Article