A study of women in eight English domestic tragedies 1590-1642

This thesis uses the social history of Early Modern England to provide the context for a discussion of tragedy in domestic drama; eight plays from $circa$1590 to 1642. The focus of the discussion is on one female character in each play and how they contribute to their own tragedy. Alice Arden ($Arden$ $of$ $Faversham$) and Anne Frankford ($A$ $Woman$ $Killed$ $with$ $Kindness$) both commit adultery; Alice also plots her husband’s murder. Rachel Merry’s ($Two$ $Lamentable$ $Tragedies$) love of and loyalty to her brother leads her to conceal the murders committed by him. Anne Drury ($A$ $Warning$ $for$ $Fair$ $Women$), in addition to her skills as a cunning woman, uses every piece of information that comes her way to her advantage. Elizabeth Sawyer ($The$ $Witch$ $of$ $Edmonton$) is an intelligent and articulate woman. The treatment she receives at the hands of the villagers of Edmonton leads her to take on the role that they assign her, that of witch. Clandestine marriage, plight troth and wardship bring tragedy to three women, the Wife, ($A$ $Yorkshire$ $Tragedy$), Clare Harcop ($The$ $Miseries$ $of$ $Enforced$ $Marriage$) and Anne Boote ($The$ $Vow-Breaker$). The genre of domestic tragedy often included a strong woman as one of the main characters. This is true of all of these women, despite their being a guilty party to their own tragedy

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology.

Myasthenia gravis (MG) is a prototypical autoantibody mediated disease. The autoantibodies in MG target structures within the neuromuscular junction (NMJ), thus affecting neuromuscular transmission. The major disease subtypes of autoimmune MG are defined by their antigenic target. The most common target of pathogenic autoantibodies in MG is the nicotinic acetylcholine receptor (AChR), followed by muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). MG patients present with similar symptoms independent of the underlying subtype of disease, while the immunopathology is remarkably distinct. Here we highlight these distinct immune mechanisms that describe both the B cell- and autoantibody-mediated pathogenesis by comparing AChR and MuSK MG subtypes. In our discussion of the AChR subtype, we focus on the role of long-lived plasma cells in the production of pathogenic autoantibodies, the IgG1 subclass mediated pathology, and contributions of complement. The similarities underlying the immunopathology of AChR MG and neuromyelitis optica (NMO) are highlighted. In contrast, MuSK MG is caused by autoantibody production by short-lived plasmablasts. MuSK MG autoantibodies are mainly of the IgG4 subclass which can undergo Fab-arm exchange (FAE), a process unique to this subclass. In FAE IgG4, molecules can dissociate into two halves and recombine with other half IgG4 molecules resulting in bispecific antibodies. Similarities between MuSK MG and other IgG4-mediated autoimmune diseases, including pemphigus vulgaris (PV) and chronic inflammatory demyelinating polyneuropathy (CIDP), are highlighted. Finally, the immunological distinctions are emphasized through presentation of biological therapeutics that provide clinical benefit depending on the MG disease subtype

Identifying and overcoming mechanisms of PARP 2 inhibitor resistance in homologous recombination 3 repair-deficient and repair-proficient high grade 4 serous ovarian cancer cells

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib

Disruption of the HLA-E/NKG2X axis is associated with uncontrolled HIV infections

The contribution of the HLA-E/NKG2X axis in NK-mediated control of HIV infection remains unclear. We have studied the relationship between HLA-E expression and phenotypical as well as functional characteristics of NK cells, in the context of chronic HIV infection and in an in vitro model of acute infection. High viremia in HIV+ individuals was related to increased HLA-E expression, and changes in NK subpopulations, especially a reduction of the CD56 bright as well as an increase in adaptive NK subpopulation. Uncontrolled HIV infection was also characterized by a reversion of the NKG2A/NKG2C expression ratio and a loss of positive and negative regulation of NK mediated by HLA-E. This was reflected in a lower cytotoxic, degranulation and cytokine production capacity, especially in CD56 bright and adaptive NK. In line with these results, HLA-E expression showed a positive correlation with viral growth inhibition in an in vitro model of acute infection at day 7, which was lost after 14 days of culture. Using HLA-E expressing K562 cells, we determined that only one out of 11 described HIV-derived HLA-E epitopes increased HLA-E surface stability. In spite of that, eight of the 11 epitopes were capable of increasing degranulation and three drove differences in NK-cell mediated cell lysis or cytokine secretion. In conclusion, our results indicate that HLA-E molecules presenting HIV-derived epitopes may sensitize target cells for NK lysis in early HIV infection. However, prolonged exposure to elevated HLA-E expression levels in vivo may lead to NK cell dysfunction and reduced viral control In chronic infection

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer : patient-reported outcomes from the FLIPPER trial

In the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2− advanced breast cancer (ABC). We assessed health-related quality of life (QoL) using patient-reported outcomes (PROs). In this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively. Of the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales. Although TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2− ABC. Sponsor Study Code: GEICAM/2014-12 EudraCT Number: 2015-002437-21 ClinTrials.gov reference: NCT0269048

Evaluating Alternative Nutrient Sources in Subsistence-Level Aquaponic Systems

Many food production methods are both economically and environmentally unsustainable. Our project investigated aquaponics, an alternative method of agriculture that could address these issues. Aquaponics combines fish and plant crop production in a symbiotic, closed-loop system. We aimed to reduce the initial and operating costs of current aquaponic systems by utilizing alternative feeds. These improvements may allow for sustainable implementation of the system in rural or developing regions. We conducted a multi-phase process to determine the most affordable and effective feed alternatives for use in an aquaponic system. At the end of two preliminary phases, soybean meal was identified as the most effective potential feed supplement. In our final phase, we constructed and tested six full-scale aquaponic systems of our own design. Data showed that soybean meal can be used to reduce operating costs and reliance on fishmeal. However, a more targeted investigation is needed to identify the optimal formulation of alternative feed blends

The concerns of oncology professionals during the COVID-19 pandemic results from the ESMO Resilience Task Force survey II

Background The COVID-19 pandemic has resulted in significant changes to professional and personal lives of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration aimed to provide contemporaneous reports on the impact of COVID-19 on the lived experiences and well-being in oncology. Methods This online anonymous survey (July-August 2020) is the second of a series of global surveys launched during the course of the pandemic. Longitudinal key outcome measures including well-being/distress (expanded Well-being Index—9 items), burnout (1 item from expanded Well-being Index), and job performance since COVID-19 were tracked. Results A total of 942 participants from 99 countries were included for final analysis: 58% (n = 544) from Europe, 52% (n = 485) female, 43% (n = 409) ≤40 years old, and 36% (n = 343) of non-white ethnicity. In July/August 2020, 60% (n = 525) continued to report a change in professional duties compared with the pre-COVID-19 era. The proportion of participants at risk of poor well-being (33%, n = 310) and who reported feeling burnout (49%, n = 460) had increased significantly compared with April/May 2020 (25% and 38%, respectively; P < 0.001), despite improved job performance since COVID-19 (34% versus 51%; P < 0.001). Of those who had been tested for COVID-19, 8% (n = 39/484) tested positive; 18% (n = 7/39) felt they had not been given adequate time to recover before return to work. Since the pandemic, 39% (n = 353/908) had expressed concerns that COVID-19 would have a negative impact on their career development or training and 40% (n = 366/917) felt that their job security had been compromised. More than two-thirds (n = 608/879) revealed that COVID-19 has changed their outlook on their work-personal life balance. Conclusion The COVID-19 pandemic continues to impact the well-being of oncology professionals globally, with significantly more in distress and feeling burnout compared with the first wave. Collective efforts from both national and international communities addressing support and coping strategies will be crucial as we recover from the COVID-19 crisis. In particular, an action plan should also be devised to tackle concerns raised regarding the negative impact of COVID-19 on career development, training, and job security

A randomized trial to assess the impact of an antithrombotic decision aid in patients with nonvalvular atrial fibrillation: the DAAFI trial protocol [ISRCTN14429643]

BACKGROUND: Decision aids are often advocated as a means to assist patient and health care provider decision making when faced with complicated treatment or screening decisions. Despite an exponential growth in the availability of decision aids in recent years, their impact on long-term treatment decisions and patient adherence is uncertain due to a paucity of rigorous studies. The choice of antithrombotic therapy for nonvalvular atrial fibrillation (NVAF) is one condition for which a trade-off exists between the potential risks and benefits of competing therapies, and the need to involve patients in decision making has been clearly identified. This study will evaluate whether an evidence-based patient decision aid for patients with NVAF can improve the appropriateness of antithrombotic therapy use by patients and their family physicians. DESIGN: A multi-center, two-armed cluster randomized trial based in community family practices in which patients with NVAF will be randomized to decision aid or usual care. Patients will receive one of four decision aids depending on their baseline stroke risk. The primary outcome is the provision of "appropriate antithrombotic therapy" at 3 months to study participants (appropriateness defined as per the 2001 American College of Chest Physicians recommendations for NVAF). In addition, the impact of this decision aid on patient knowledge, decisional conflict, well-being, and adherence will be assessed after 3 months, 6 months, and 12 months