Speaking about the War of 1812: Reinterpreting History in the Rhetoric Surrounding Canada's Inter-War Diplomacy (1919-1939)

A remarkable feature of Canada's external relations in the years between the two world wars of the twentieth century is the extent to which Canada's conduct and speeches by its representatives on international affairs were dominated by imagery of North American harmony. Past clashes, most notably the War of 1812, or simply differences of views were forgotten or overlooked in the construction of a myth that served to justify inaction and the denial of commitments in imperial and world affairs. An aloof, unhelpful stance internationally was depicted more positively as a worthy example of peaceful attitudes and conduct. Thus, the interwar period was dominated by rhetoric about 'the longest undefended border in the world,' '[more than a] century of peace in North America,' and the contrast between the 'New World' and the 'Old World' in world affairs. No Canadian speech in an international forum seemed complete without some variation on these themes and without an admonition to Europeans and other miscreants to settle disputes by conciliation, negotiation and arbitration – rather than resort to war – as was the tradition in relations between Canada and the United States. This paper deals with the development, application and effect in the inter-war period of the lessons supposedly drawn from the experience and especially the aftermath of the War of 1812

Use of opium in the treatment of melancholia

The use of opium as a nerve sedative, as an anodyne, a hypnotic, and as a reducer of mental excitement in delirium, whether due to alcohol, fevers or brain lesions, has been recognised by all physicians in all ages. Within recent times it has been largely supplanted by newer drugs; but it has never been allowed to drop into desuetude, because it is the most powerful of all hypnotics, and the most reliable of all sedatives and anodynes. In idiopathic mental excitement it has in this country and in other parts I of Europe lost favour as an unfailing and reliable remedy, although many eminent physicians on the ContiInent still believe it to be unsurpassed in its power of alleviating the excitement in certain cases of melancholia. A knowledge of this fact has led me to enquire into the efficacy of the drug in the treatment of melancholia; and after a lengthy trial of it in over forty cases of that affection, I have come to the conclusion, which I hope to show in the following thesis, that it is a drug of the utmost value, not only in ameliorating the symptoms of melancholia and there by rendering the patients more manageable and less suicidal, but also in shortening the duration of the disease and promoting the recovery of the patients

The Path to Temptation: The Negotiation of Canada’s Reconstruction Loan to Britain in 1946

Pendant la Deuxième Guerre Mondiale, la dépendance économique du Canada vis-à-vis du commerce international augmenta considérablement. En 1944, en effet, les exportations canadiennes comptaient pour 31 pour cent du revenu national. La bonne part de ces exportations, toutefois, était dirigée vers le Royaume-Uni et était surtout constituée des contributions canadiennes à ce qu'il était convenu d'appeler, à l'époque, l'effort de guerre. Conséquemment, tout au long des années de guerre, le marché britannique exerça une influence certaine, voire souvent décisive, sur les politiques économiques extérieures du Canada. On comprend, dès lors, que le Canada ait surveillé de près les politiques commerciales de Whitehall, préoccupé qu'il était des problèmes que poserait le financement des échanges commerciaux entre les pays pendant la période de transition entre la guerre et la paix et de la nécessité qu'il y avait de s'assurer un marché stable et prospère dans le futur.L'auteur étudie ici une des ententes qui résulta de ces préoccupations, soit celle d'un prêt consenti par le Canada au Royaume-Uni, en 1946, en vue de sa reconstruction. En replaçant toute la question dans le contexte des intérêts économiques et politiques du gouvernement canadien de l'époque, l'auteur examine l'arrière-plan de la démarche et retrace minutieusement les diverses négociations qui aboutirent à l'entente finale

maths inside Resource Suite with Interdisciplinary Learning Activities

Maths inside (https://mathsinside.com/) is a photo competition open to everyone living in Scotland, hosted by the University of Glasgow. The maths inside project seeks to nourish a love for mathematics by embarking on a journey of discovery through a creative lens. This suite of resources have been created to inspire entrants, and support families, teachers and those out-of-school to make deeper connections with their surroundings. The maths inside is waiting to be discovered! Also contained in the suite is an example to inspire and support you to design your own interdisciplinary learning (IDL) activity matched to Education Scotland experiences and outcomes (Es+Os), to lead pupils towards the creation of their own entry. These resources are not prescriptive, and are designed with a strong creativity ethos for them to be adapted and delivered in a manner that meets the specific needs of those participating. The competition and the activities can be tailored to meet all and each learners' needs. We recommend that those engaging with maths inside for the first time complete their own mapping exercise linking the designed activity to the Es+Os. To create a collaborative resource bank open to everyone, we invite you to treat these resources as a working document for entrants, parents, carers, teachers and schools to make their own. Please share your tips, ideas and activities at [email protected] and through our social media channels (https://mathsinside.com/#contact). Past winning entries of the competition are also available for inspiration and for using as a teaching resource (https://mathsinside.com/pastwinners/). Already inspired? Enter the competition! (https://mathsinside.com/submit/enter/

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood

A finer grained approach to psychological capital and work performance

Purpose Psychological capital is a set of personal resources comprised by hope, efficacy, optimism, and resilience, which previous research has supported as being valuable for general work performance. However, in today’s organizations, a multidimensional approach is required to understanding work performance, thus, we aimed to determine whether psychological capital improves proficiency, adaptivity, and proactivity, and also whether hope, efficiency, resilience, and optimism have a differential contribution to the same outcomes. Analyzing the temporal meaning of each psychological capital dimension, this paper theorizes the relative weights of psychological capital dimensions on proficiency, adaptivity, and proactivity, proposing also that higher relative weight dimensions are helpful to cope with job demands and perform well. Methodology Two survey studies, the first based on cross-sectional data and the second on two waves of data, were conducted with employees from diverse organizations, who provided measures of their psychological capital, work performance, and job demands. Data was modeled with regression analysis together with relative weights analysis. Findings Relative weights for dimensions of psychological capital were supported as having remarkable unique contributions for proficient, adaptive, and proactive behavior, particularly when job demands were high. Originality/Value We concluded that organizations facing high job demands should implement actions to enhance psychological capital dimensions; however, those actions should focus on the specific criterion of performance of interest

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)