The art of living\u27: The aesthetics of everyday life in Dorothy Canfield Fisher\u27s novels

In 1924, Dorothy Canfield Fisher (1879-1958) wrote, I have always conceived of everyday life as needing very much the sort of constant effort at composition--that is shapeliness, elimination of unnecessary details, choice of details--as any other work of art. This quotation is the epigraph to my study of five of Fisher\u27s early novels because it reveals a central theme of her fiction: that art is the creation of a daily life that successfully negotiates the problems of living (Fisher\u27s phrase) that plague modern America. The five novels that I analyze--The Squirrel-Cage (1912), The Bent Twig (1915), The Brimming Cup (1921), The Home-maker (1924) and The Deepening Stream (1930)--show that Fisher defines these problems as finding meaningful work and creating sustaining marriages and family lives. Her protagonists\u27 solutions to these problems comprise an art of living, a phrase Fisher uses to summarize the lessons her protagonists learn in their quests to shape their lives. As I explain in my introduction, Fisher\u27s relationship with her mother was a defining element in her artistic development. Although her mother embraced an art for art\u27s sake credo, Fisher felt that art should have a social purpose. Her fiction is rich with debates about art that reenact this split with her mother. Fisher forges a connection between two different artistic processes in her fiction: the ritualized shaping of domestic life, and the rigorous training of creating high art. Therefore, I argue that her position in American women\u27s literature is transitional because she blends two women\u27s literary traditions, regionalism and the kunstlerroman, broadening their boundaries. Throughout my study, I structure my chapters according to the domestic processes that Fisher invokes in her fiction--carpentry, gardening and sewing--illuminating how her protagonists combine these domestic processes with their musical careers. I also describe the social movements that Fisher was interested in--the Arts and Crafts Movement, the Montessori method of education, Freudian psychology and daycare--and show how they partially provide Fisher with the solutions she seeks in remodeling family life for modern America

Randomised controlled trial of the Community Navigator programme to reduce loneliness and depression for adults with treatment-resistant depression in secondary community mental health services: trial protocol

BACKGROUND: New treatments are needed for people with treatment-resistant depression (TRD), who do not benefit from anti-depressants and many of whom do not recover fully with psychological treatments. The Community Navigator programme was co-produced with service users and practitioners. It is a novel social intervention which aims to reduce loneliness and thus improve health outcomes for people with TRD. Participants receive up to 10 individual meetings with a Community Navigator, who helps them to map their social world and set and enact goals to enhance their social connections and reduce loneliness. Participants may also access group meet-ups with others in the programme every 2 months, and may be offered modest financial support to enable activities to support social connections. METHODS: A researcher-blind, multi-site, 1:1 randomised controlled trial with N = 306 participants will test the effectiveness of the Community Navigator programme for people with TRD in secondary community mental health teams (CMHTs). Our primary hypothesis is that people who are offered the Community Navigator programme as an addition to usual CMHT care will be less depressed, assessed using the PHQ-9 self-report measure, at 8-month, end-of-treatment follow-up, compared to a control group receiving usual CMHT care and a booklet with information about local social groups and activities. We will follow participants up at end-of-treatment and at 14 months, 6 months after end-of-treatment follow-up. Secondary outcomes include the following: loneliness, anxiety, personal recovery, self-efficacy, social network, social identities. We will collect data about health-related quality of life and service use to investigate the cost-effectiveness of the Community Navigator programme. DISCUSSION: This trial will provide definitive evidence about the effectiveness and cost-effectiveness of the Community Navigator programme and whether it can be recommended for use in practice. The trial is due to finish in August 2025. TRIAL REGISTRATION: Prospectively registered on 8th July 2022 at: ISRCTN13205972

Randomised controlled trial of the Community Navigator programme to reduce loneliness and depression for adults with treatment-resistant depression in secondary community mental health services : trial protocol

BACKGROUND: New treatments are needed for people with treatment-resistant depression (TRD), who do not benefit from anti-depressants and many of whom do not recover fully with psychological treatments. The Community Navigator programme was co-produced with service users and practitioners. It is a novel social intervention which aims to reduce loneliness and thus improve health outcomes for people with TRD. Participants receive up to 10 individual meetings with a Community Navigator, who helps them to map their social world and set and enact goals to enhance their social connections and reduce loneliness. Participants may also access group meet-ups with others in the programme every 2 months, and may be offered modest financial support to enable activities to support social connections. METHODS: A researcher-blind, multi-site, 1:1 randomised controlled trial with N = 306 participants will test the effectiveness of the Community Navigator programme for people with TRD in secondary community mental health teams (CMHTs). Our primary hypothesis is that people who are offered the Community Navigator programme as an addition to usual CMHT care will be less depressed, assessed using the PHQ-9 self-report measure, at 8-month, end-of-treatment follow-up, compared to a control group receiving usual CMHT care and a booklet with information about local social groups and activities. We will follow participants up at end-of-treatment and at 14 months, 6 months after end-of-treatment follow-up. Secondary outcomes include the following: loneliness, anxiety, personal recovery, self-efficacy, social network, social identities. We will collect data about health-related quality of life and service use to investigate the cost-effectiveness of the Community Navigator programme. DISCUSSION: This trial will provide definitive evidence about the effectiveness and cost-effectiveness of the Community Navigator programme and whether it can be recommended for use in practice. The trial is due to finish in August 2025. TRIAL REGISTRATION: Prospectively registered on 8th July 2022 at: ISRCTN13205972

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The male germ cell response to CPA treatment: A potential role for zinc

Male factor infertility accounts for a large proportion of infertility cases and for the most part may in fact be related to lifestyle and/or exposure to toxic substances. Cyclophosphamide (CPA) is an alkylating agent commonly used in chemo- and immunosuppressive therapies and is a known germ cell toxicant. Men often become infertile after being treated with this drug. In rats, paternal CPA treatment leads to decreased sperm quality as well as defective early embryo development and negative progeny outcomes. The goal of the studies presented in this thesis was to evaluate the effect of chronic CPA treatment on the male germ cell transcriptome in order to gain a better understanding of how these cells respond to such an insult. In the first objective, we evaluated the effect of CPA treatment on the expression of microRNAs in isolated pachytene spermatocytes and round spermatids. We showed for the first time that a therapeutic drug such as cyclophosphamide alters the expression of miRNAs in male germ cells and that these may be involved in the germ cell response to toxic exposures. In the second objective we evaluated the effect of CPA treatment on genome wide gene expression in male germ cells. In addition to many transcripts involved in zinc binding being altered in both cell types following CPA treatment, we found that the expression of members of ZIP family of zinc transporters and zinc transport was increased in pachytene spermatocytes. This led us to believe that zinc may play an important role in the male germ cell response to CPA. In the third objective we examined whether zinc could protect male germ cells from CPA toxicity. We found that zinc supplementation decreased CPA induced oxidative stress and DNA damage in male germ cells. Collectively, the studies presented in this thesis contribute to our basic understanding of male germ cell responses to toxic substances and suggest a potential role for zinc in protecting male germ cells against detrimental effects of CPA treatment.Une large proportion des cas d'infertilité dans les couples peut être attribuée à un facteur mâle, souvent causé par le mode de vie ou l'exposition à des substances toxiques. Parmi ces substances, la cyclophosphamide (CPA), agent alkylant antinéoplastique et immunosuppresseur, est reconnue pour ses effets toxiques sur les gamètes mâles. De nombreux troubles de la fertilité sont en effet rapportés chez les hommes ayant été traités à la CPA. En outre, l'exposition de rats mâles à la CPA altère la qualité de leurs spermatozoïdes, entraînant des effets néfastes sur leur progéniture dès le début du développement embryonnaire. Le but de ces travaux de thèse était de mieux comprendre comment réagissent les cellules germinales mâles face à un traitement chronique à la CPA en faisant l'analyse de leur transcriptome. Notre premier objectif était d'évaluer l'effet de la CPA sur l'expression des microARNs dans les spermatocytes pachytènes et les spermatides rondes. Nous avons ainsi démontré pour la première fois qu'une exposition à une substance thérapeutique peut altérer l'expression des microARNs, des changements potentiellement associés à la réponse physiologique des cellules germinales aux substances toxiques. Dans un deuxième temps, nous avons évalué l'effet de la CPA sur l'expression des ARN messagers dans les spermatocytes pachytènes et spermatides rondes. Nous avons non seulement démontré que la CPA modifiait l'expression de transcrits impliqués dans les complexes de zinc, mais surtout que l'expression de transporteurs de zinc de la famille ZIP et le transport de zinc lui-même étaient accrus dans les spermatocytes pachytènes. Ces résultats établissent le rôle fondamental du zinc dans la réponse physiologique des cellules germinales à la CPA. Enfin, dans un troisième objectif, nous avons évalué le potentiel du zinc dans la protection des cellules germinales contre les dommages causés par la CPA. Nous avons ainsi pu observer que, dans les cellules germinales mâles, une supplémentation en zinc produit une diminution des niveaux de stress oxydant et des dommages à l'ADN associés au traitement à la CPA. Considérés dans leur ensemble, ces résultats permettent une meilleure compréhension de la réponse physiologique des cellules germinales face aux substances toxiques, et mettent en lumière le potentiel du zinc dans la protection des cellules contre les effets nocifs de la CPA

Zygotic chromosomal structural aberrations after paternal drug treatment

In recent years, the field of male-mediated reproductive toxicology has received growing attention. It is now well-established that many drugs, chemicals, and environmental factors can harm male germ cells by inducing DNA damage. Male germ cells have extensive repair mechanisms that allow detection and repair of damaged DNA during the early phases of spermatogenesis. However, during the later phase of spermiogenesis, when the haploid spermatids undergo chromatin condensation and become transcriptionally quiescent, their ability to repair damaged DNA is lost. [1] ,[2] It is also thought that the highly compacted chromatin of the sperm can protect DNA against damage. [3] Therefore, it is expected that late spermatids will be most susceptible to DNA damaging agents. Unrepaired or misrepaired damage in the germ cells leads to the generation of spermatozoa with DNA damage that can be transmitted to the next generation. Fortunately, the maternal DNA repair machinery is capable of recognizing and repairing, at least to some degree, damaged paternal DNA after fertilization in the zygote. Therefore, the efficiency of the maternal repair machinery will greatly influence the risk of transmitting paternal DNA damage to offspring. [4

Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease.

In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients

Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets

Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD).In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications.Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD.When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects.We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic