An “imperfect” Model of Authorship in Dorothy Wordsworth’s Grasmere Journal

This essay explores Dorothy Wordsworth’s collaborative, “pluralist” model of selfhood and authorship as it is elaborated in her Grasmere journal (1800-03). Nature and community, for her, are extensions of the self rather than (as they often are for her brother William) external forces to be subsumed by the self of the solitary artist. This model, however, is the site of ambivalence and conflict, and is therefore “imperfect” – a word Wordsworth herself uses to qualify the “summary” she believes her journal as a whole provides. It is “imperfect” not because it is inferior, weak, or deficient in some way, but because it is riddled with tension and inconsistency. Wordsworth embraces processes of collaborative creativity, but she also expresses – largely through her narrations of illness – dissatisfaction with such processes, and she sometimes finds relief in her solitary, melancholic musings. In these ways, she at once subverts, reworks, and reinforces conventional, ‘solitary genius’ paradigms of authorship

Evaluating Bioinformatic Pipeline Performance for Forensic Microbiome Analysis*,†,‡

Microbial communities have potential evidential utility for forensic applications. However, bioinformatic analysis of high‐throughput sequencing data varies widely among laboratories. These differences can potentially affect microbial community composition and downstream analyses. To illustrate the importance of standardizing methodology, we compared analyses of postmortem microbiome samples using several bioinformatic pipelines, varying minimum library size or minimum number of sequences per sample, and sample size. Using the same input sequence data, we found that three open‐source bioinformatic pipelines, MG‐RAST, mothur, and QIIME2, had significant differences in relative abundance, alpha‐diversity, and beta‐diversity, despite the same input data. Increasing minimum library size and sample size increased the number of low‐abundant and infrequent taxa detected. Our results show that bioinformatic pipeline and parameter choice affect results in important ways. Given the growing potential application of forensic microbiology to the criminal justice system, continued research on standardizing computational methodology will be important for downstream applications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154468/1/jfo14213_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154468/2/jfo14213.pd

Repertoires of governance among members of Australian university governing boards

Recent corporate collapses have focused public attention on the roles and responsibilities of governing boards. These issues are also significant for Australian universities. This research examines the repertoires of ideas that public university governing body members use to make sense of their governance functions. Through a qualitative study of the language of members of five university governing boards (councils), it identifies the repertoires, or 'regimes of justification' (Boltanksi & Thevenot 1991), used by board members to interpret the principles and practices of university governance. My thesis is that board members of university councils in Australia use several distinct repertoires - of business, of the community, of traditional university values and of professionalism - to express their ideas about university governance. Analysis of these repertoires, each of which implies a different 'logic of action' (Bacharach, Bamberger, & Sonnenstuhl 1996), illuminates our understanding of why board members interpret governance functions in different and sometimes contradictory ways. It also provides a means to assess the influence of 'managerialist' ideas on Australian university governance and the extent to which Australian university governance is yet to become professionalised. The theoretical basis for the research is drawn from the sociology of Pierre Bourdieu, coupled with the discourse analytical method of interpretative repertoires (Wetherell & Potter 1988). By viewing board governance as a locus of discursive struggles over differing systems of value, it becomes possible to analyse the impact on 'practical politics' (Heffernan 1997) of the repertoires of key ideas revealed in discourse by governing board members. This research affirms the significance of organisational and wider societal values in non-for-profit governance. Broad concepts of the public good, participation and the university ideal are used to counterbalance an extreme managerialist view that universities are no more than a particular type of business. It is noted that certain repertoires may be more commonly employed in particular institutions such as regional universities. Reflexive consideration of these differing repertoires by council members could contribute to more effective university governance

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

The Deep Historical Roots of Macroeconomic Volatility

We present cross-country evidence that a country's macroeconomic volatility, measured either by the standard deviation of output growth or the occurrence of trend-growth breaks, is significantly affected by the country's historical variables. In particular, countries with longer histories of state-level political institutions experience less macroeconomic volatility in postwar periods. Robustness checks reveal that the effect of this historical variable on volatility remains significant and substantial after controlling for a host of structural variables investigated in previous studies. We also find that the state history variable is more important in countries with a higher level of macroeconomic volatility

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Of Wandering Wombs and Wrongs of Women: Evolving Conceptions of Hysteria in the Age of Reason

Of Wandering Wombs and Wrongs of Women: Evolving Conceptions of Hysteria in the Age of Reaso

Application of the Beers Criteria to Alternate Level of Care Patients in Hospital Inpatient Units

ABSTRACTBackground: The Beers criteria were developed to help in identifying potentially inappropriate medications (PIMs) for elderly patients. These medications are often associated with adverse events and limited effectiveness in older adults. Patients awaiting an alternate level of care (ALC patients) are those who no longer require acute care hospital services and are waiting for placement elsewhere. They are often elderly, have complex medication regimens, and are at high risk of adverse events. At the time of this study no studies had applied the Beers criteria to ALC patients in Canadian hospitals.Objectives: To determine the proportion of ALC patients receiving PIMs and the proportion experiencing selected PIM-related adverse events. Methods: A retrospective chart review of ALC patients 65 years of age or older was performed to identify PIMs and the occurrence of selected adverse events (specifically central nervous system [CNS] events, falls, bradycardia, hypoglycemia, seizures, insomnia, gastrointestinal bleeding, and urinary tract infections). A logistic regression model with a random intercept for each patient was constructed to estimate odds ratios and probabilities of adverse events.Results: Fifty-two ALC patients were included in the study. Of these, 48 (92%) were taking a PIM. Of the 922 adverse events evaluated, 407 (44.1%) were associated with a regularly scheduled PIM. Among patients who were taking regularly scheduled PIMs, there was a significantly increased probability of an adverse CNS event and of a fall (p &lt; 0.001 for both). The most common PIM medication classes were first-generation antihistamines (24 [46%] of the 52 patients), antipsychotics (21 patients [40%]), short-acting benzodiazepines (15 patients [29%]), and nonbenzodiazepine hypnotics (14 patients [27%]).Conclusions: A high proportion of ALC patients were taking PIMs and experienced an adverse event that may have been related to these drugs. These findings suggest that the ALC population might benefit from regular medication review and monitoring to prevent or detect adverse events.RÉSUMÉContexte : Les critères de Beers ont été élaborés afin d’aider à détecter l’utilisation de médicaments potentiellement inappropriés (MPI) auprès des patients âgés. L’on associe souvent les MPI à des événements indésirables, et leur efficacité chez les personnes âgées est limitée. Les patients en attente d’un autre niveau de soins (patients ANS) sont ceux qui ne nécessitent plus de soins de courte durée de l’hôpital et qui attendent d’être déplacés vers un autre établissement. Il s’agit souvent de personnes âgées ayant une panoplie complexe de traitements médicamenteux et présentant un risque élevé de subir des événements indésirables. Au moment de la présente recherche, aucune étude n’avait appliqué les critères de Beers aux patients ANS des hôpitaux canadiens.Objectifs : Déterminer quelles sont les proportions de patients ANS qui reçoivent des MPI et qui subissent certains événements indésirables choisis liés à ces médicaments.Méthodes : Une analyse rétrospective des dossiers médicaux de patients ANS âgés de 65 ans et plus a été réalisée dans le but de relever les MPI ainsi que les cas de certains événements indésirables choisis (particulièrement les événements liés au système nerveux central, les chutes, la bradycardie, l’hypoglycémie, les convulsions, l’insomnie, les hémorragies gastro-intestinales et les infections urinaires). On a mis au point un modèle de régression logistique avec ordonnée à l’origine aléatoire pour chaque patient afin d’estimer les risques relatifs approchés ainsi que les probabilités d’événements indésirables.Résultats : Au total, 52 patients ANS ont été admis à l’étude. De ceuxci, 48 (92 %) prenaient un MPI. Des 922 événements indésirables analysés, 407 (44,1 %) ont été associés à un MPI administré régulièrement. Parmi les patients prenant des MPI à une fréquence régulière, la probabilité de subir une chute ou un événement indésirable lié au système nerveux central était grandement accrue (p &lt; 0,001 pour chacun). Les MPI les plus fréquents étaient : les antihistaminiques de première génération (24 [46 %] des 52 patients), les antipsychotiques (21 patients [40 %]), les benzodiazépines à action brève (15 patients [29 %]) et les hypnotiques non-benzodiazépines (14 patients [27 %]).Conclusions : Un grand nombre de patients ANS prenaient des MPI et avaient subi un événement indésirable qui ouvait avoir été en lien avec ces médicaments. Ces résultats laissent croire que les patients ANS pourraient tirer avantage d’évaluations fréquentes de la pharmacothérapie et de surveillance afin de prévenir les événements indésirables ou de les détecter

Application of the Beers Criteria to Alternate Level of Care Patients in Hospital Inpatient Units

BACKGROUND: The Beers criteria were developed to help in identifying potentially inappropriate medications (PIMs) for elderly patients. These medications are often associated with adverse events and limited effectiveness in older adults. Patients awaiting an alternate level of care (ALC patients) are those who no longer require acute care hospital services and are waiting for placement elsewhere. They are often elderly, have complex medication regimens, and are at high risk of adverse events. At the time of this study no studies had applied the Beers criteria to ALC patients in Canadian hospitals. OBJECTIVES: To determine the proportion of ALC patients receiving PIMs and the proportion experiencing selected PIM-related adverse events. METHODS: A retrospective chart review of ALC patients 65 years of age or older was performed to identify PIMs and the occurrence of selected adverse events (specifically central nervous system [CNS] events, falls, bradycardia, hypoglycemia, seizures, insomnia, gastrointestinal bleeding, and urinary tract infections). A logistic regression model with a random intercept for each patient was constructed to estimate odds ratios and probabilities of adverse events. RESULTS: Fifty-two ALC patients were included in the study. Of these, 48 (92%) were taking a PIM. Of the 922 adverse events evaluated, 407 (44.1%) were associated with a regularly scheduled PIM. Among patients who were taking regularly scheduled PIMs, there was a significantly increased probability of an adverse CNS event and of a fall (p < 0.001 for both). The most common PIM medication classes were first-generation antihistamines (24 [46%] of the 52 patients), antipsychotics (21 patients [40%]), short-acting benzodiazepines (15 patients [29%]), and nonbenzodiazepine hypnotics (14 patients [27%]). CONCLUSIONS: A high proportion of ALC patients were taking PIMs and experienced an adverse event that may have been related to these drugs. These findings suggest that the ALC population might benefit from regular medication review and monitoring to prevent or detect adverse events