Evaluation of antisense oligonucleotide therapy targeting Hsd17b13 in a fibrosis mice model.

Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (CDAHFD)-induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.

Porous Morphology of High Grafting Density Mixed Polyelectrolyte Brushes Grown from a Y-Inimer Coating.

Mixed A/B polyelectrolyte (PE) brushes of opposite charges are grown from a Y-shaped initiator-bearing coating to facilitate intimate mixing of the A and B polyelectrolytes in a 1:1 grafting ratio. The design of the Y-shaped inimer includes both ATRP and NMP initiators attached to a common Y-junction. A copolymer of a Y-shaped inimer with glycidyl methacrylate is cross-linked to the substrate resulting in a stable ultrathin coating decorated with Y-shaped initiators. Weak PE A/B mixed brushes based on poly(methacrylic acid)/poly(2-vinylpyridine) (PMAA/P2VP) with a high grafting density of ∼1 chain/nm2 are grown by surface-initiated ATRP and NMP, respectively. Detailed morphological characterization of the PMAA/P2VP brushes in response to pH changes reveals a nanoporous morphology under conditions that maximize complex coacervate formation between oppositely charged brushes. The charge ratio between the A and B brushes is varied via the composition of the brushes to further study the morphology evolution. The effect of intimate contact between the A and B brushes on the morphology is probed by comparing with a mixed A/B PE system with random fluctuations in grafting composition. A quantitative and qualitative study of the pore evolution with pH as well as charge composition is presented using a combination of atomic force microscopy, water contact angle measurement, and image analysis using Gwyddion software. These studies demonstrate that the porous morphology is enhanced and most uniform when the brushes are grown from the Y-inimer, indicating that a 1:1 grafting ratio and intimate contact between A and B brushes are essential.

Faith and vaccination: a scoping review of the relationships between religious beliefs and vaccine hesitancy.

BACKGROUND: Throughout history, vaccines have proven effective in addressing and preventing widespread outbreaks, leading to a decrease in the spread and fatality rates of infectious diseases. In a time where vaccine hesitancy poses a significant challenge to public health, it is important to identify the intricate interplay of factors exemplified at the individual and societal levels which influence vaccination behaviours. Through this analysis, we aim to shed new light on the dynamics of vaccine hesitancy among religious groups, contributing to the broader effort to promote vaccine uptake, dispel misunderstandings, and encourage constructive dialogue with these groups. METHODS: We used the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) using the 20-point checklist to guide this review. The inclusion criteria for our study were that the literature should be in English, concerned with vaccine hesitancy as the focus of study, study the impact religiosity or religious beliefs as either an outcome or control variable, concerning population levels, and be peer-reviewed. RESULTS: We analysed 14 peer-reviewed articles that included components related to religiosity or religious beliefs and their impact on vaccine hesitancy published until September 2023. All the articles were published in approximately the last decade between 2012 and 2023, with only 4 of the articles published before 2020. Out of the 14 studies included in our review, twelve utilized quantitative methods, while the remaining two employed qualitative approaches. Among the studies included in our analysis, we found various approaches to categorizing religious belief and identity. In most studies when religion is uniformly regarded as the sole determinant of vaccine hesitancy, it consistently emerges as a significant factor in contributing to vaccine hesitancy. All studies in our review reported sociodemographic factors to some degree related to vaccine hesitancy within their sample populations. Our analysis underscored the need for nuanced approaches to addressing vaccine hesitancy among religious groups. CONCLUSION: Vaccine hesitancy is a complex issue and driven by a myriad of individual and societal factors among which religious beliefs is commonly associated to be a driver of higher levels among populations.

Gendered and racial experiences of moral distress: A scoping review.

AIM: To inform efforts to integrate gender and race into moral distress research, the review investigates if and how gender and racial analyses have been incorporated in such research. DESIGN: Scoping review. METHODS: The PRISMA (Preferred Reporting Items for Systematic and Meta-Analysis) Extension for Scoping Reviews was adopted. DATA SOURCES: Systematic literature search was conducted through PubMed, CINAHL and Web of Science databases. Boolean operators were used to identify moral distress literature which included gender and/or race data and published between 2012 and 2022. RESULTS: After screening and full-text review, 73 articles reporting on original moral distress research were included. Analysis was conducted on how gender and race were incorporated in research and interpretation of moral distress experiences among healthcare professionals. IMPACT: This study found that while there is an upward trend in including gender and race-disaggregated data in moral distress research, over half of such research did not conduct in-depth analysis of such data. Others only highlighted differential experiences such as moral distress levels of women vis-à-vis men. Only about 20% of publications interrogated how experiences of moral distress differed and/or explored factors behind their findings. CONCLUSION: There is a need to not only collect disaggregated data in moral distress research but also engage this data through gender and race-based analysis. Particularly, we highlight the need for intersectional analysis, which can elucidate how social identities and categories (such as gender and race) and structural inequalities (such as those sustained by sexism and racism) interact to influence moral experiences. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Moral distress as experienced by healthcare professionals is increasingly recognized as an important area of research with significant policy implications in the healthcare sector. This study offers insights for nuanced and targeted policy approaches. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.

Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.

Racial Disparities in Pediatric Inflammatory Bowel Disease Care: Differences in Outcomes and Health Service Utilization Between Black and White Children.

OBJECTIVE: To describe racial inequities in pediatric inflammatory bowel disease care and explore potential drivers. METHODS: We undertook a single-center, comparative cohort study of newly diagnosed Black and non-Hispanic White patients with inflammatory bowel disease, aged <21 years, from January 2013 through 2020. Primary outcome was corticosteroid-free remission (CSFR) at 1 year. Other longitudinal outcomes included sustained CSFR, time to anti-tumor necrosis factor therapy, and evaluation of health service utilization. RESULTS: Among 519 children (89% White, 11% Black), 73% presented with Crohn's disease and 27% with ulcerative colitis. Disease phenotype did not differ by race. More patients from Black families had public insurance (58% vs 30%, P < .001). Black patients were less likely to achieve CSFR 1-year post diagnosis (OR: 0.52, 95% CI:0.3-0.9) and less likely to achieve sustained CSFR (OR: 0.48, 95% CI: 0.25-0.92). When adjusted by insurance type, differences by race to 1-year CSFR were no longer significant (aOR: 0.58; 95% CI: 0.33, 1.04; P = .07). Black patients were more likely to transition from remission to a worsened state, and less likely to transition to remission. We found no differences in biologic therapy utilization or surgical outcomes by race. Black patients had fewer gastroenterology clinic visits and 2-fold increased odds for emergency department visits. CONCLUSIONS: We observed no differences by race in phenotypic presentation and medication usage. Black patients had half the odds of achieving clinical remission, but a degree of this was mediated by insurance status. Understanding the cause of such differences will require further exploration of social determinants of health.

Thinking About God Encourages Prosociality Toward Religious Outgroups: A Cross-Cultural Investigation.

Most humans believe in a god or gods, a belief that may promote prosociality toward coreligionists. A critical question is whether such enhanced prosociality is primarily parochial and confined to the religious ingroup or whether it extends to members of religious outgroups. To address this question, we conducted field and online experiments with Christian, Muslim, Hindu, and Jewish adults in the Middle East, Fiji, and the United States (N = 4,753). Participants were given the opportunity to share money with anonymous strangers from different ethno-religious groups. We manipulated whether they were asked to think about their god before making their choice. Thinking about God increased giving by 11% (4.17% of the total stake), an increase that was extended equally to ingroup and outgroup members. This suggests that belief in a god or gods may facilitate intergroup cooperation, particularly in economic transactions, even in contexts with heightened intergroup tension.

External Validation of the eRADAR Risk Score for Detecting Undiagnosed Dementia in Two Real-World Healthcare Systems.

BACKGROUND: Fifty percent of people living with dementia are undiagnosed. The electronic health record (EHR) Risk of Alzheimer's and Dementia Assessment Rule (eRADAR) was developed to identify older adults at risk of having undiagnosed dementia using routinely collected clinical data. OBJECTIVE: To externally validate eRADAR in two real-world healthcare systems, including examining performance over time and by race/ethnicity. DESIGN: Retrospective cohort study PARTICIPANTS: 129,315 members of Kaiser Permanente Washington (KPWA), an integrated health system providing insurance coverage and medical care, and 13,444 primary care patients at University of California San Francisco Health (UCSF), an academic medical system, aged 65 years or older without prior EHR documentation of dementia diagnosis or medication. MAIN MEASURES: Performance of eRADAR scores, calculated annually from EHR data (including vital signs, diagnoses, medications, and utilization in the prior 2 years), for predicting EHR documentation of incident dementia diagnosis within 12 months. KEY RESULTS: A total of 7631 dementia diagnoses were observed at KPWA (11.1 per 1000 person-years) and 216 at UCSF (4.6 per 1000 person-years). The area under the curve was 0.84 (95% confidence interval: 0.84-0.85) at KPWA and 0.79 (0.76-0.82) at UCSF. Using the 90th percentile as the cut point for identifying high-risk patients, sensitivity was 54% (53-56%) at KPWA and 44% (38-51%) at UCSF. Performance was similar over time, including across the transition from International Classification of Diseases, version 9 (ICD-9) to ICD-10 codes, and across racial/ethnic groups (though small samples limited precision in some groups). CONCLUSIONS: eRADAR showed strong external validity for detecting undiagnosed dementia in two health systems with different patient populations and differential availability of external healthcare data for risk calculations. In this study, eRADAR demonstrated generalizability from a research sample to real-world clinical populations, transportability across health systems, robustness to temporal changes in healthcare, and similar performance across larger racial/ethnic groups.

Chain End-Functionalized Dense Polymer Brushes from an Inimer Coating by SI-RAFT.

Polymer brushes with controllable grafting density are grown on an inimer coating bearing Reversible Addition-Fragmentation Chain Transfer polymerization (RAFT) chain transfer agents (CTAs). The inimer coating is cross-linked on the substrate to provide an initiator layer that is stable during exposure to organic solvents at high temperatures. Surface-initiated RAFT is conducted to grow poly(2-vinylpyridine) (P2VP) brushes on the coating at grafting densities approaching the theoretical limits. This methodology allows facile end-group functionalization using an efficient thiol-ene click chemistry. Chain ends were functionalized with low surface energy groups to modulate the location of the untethered chain ends by thermal annealing. At lower grafting densities, the low surface energy groups segregate to the surface upon annealing. This effect is less pronounced at higher grafting densities. Detailed characterization of the brushes at varying grafting densities using X-ray photoelectron spectroscopy (XPS) is presented. In tandem with experiments, Monte Carlo simulations examine the effect of the chain-end group size and selectivity on the conformation of the polymer brush, providing numerical evidence of laterally non-uniform distributions of functional groups at different locations in the brush. Simulations further predict the existence of morphologies with an interlayer formed by spherical micelles rich in functional end groups, demonstrating the possibility of end-group functionalization for synthetic modulation of both brush conformation and chain-end location.

Beyond BRCA: Patterns of risk-reducing surgery for non-BRCA, homologous recombination repair pathway gene variant carriers.

OBJECTIVE: The real-world management of patients with non-BRCA, homologous recombination repair pathway variants with increased or uncertain risks of ovarian cancer is unknown. The objective was to determine the adoption of risk-reducing salpingo-oophorectomy (RRSO) for carriers of variants with increased or uncertain risks of ovarian cancer beyond BRCA. METHODS: This was a retrospective cohort study of patients at three hospitals with non-BRCA, homologous recombination repair pathway variants with increased risk (BRIP1, RAD51C, RAD51D) and uncertain risk (ATM, BARD1, NBN, PALB2) of ovarian cancer. Outcomes of interest were adoption of RRSO and factors associated with adoption of RRSO. Wilcoxon rank-sum, chi-square, and logistic regression were performed with p < 0.05. RESULTS: Of 318 patients, 76 (24%) had pathogenic variants with increased risks of ovarian cancer (BRIP1, 45; RAD51C, 20; RAD51D, 11), and 242 (76%) had variants with uncertain risks of ovarian cancer (ATM, 145; PALB2, 69; NBN, 23; BARD1, 5). Of 64 patients eligible for RRSO by National Comprehensive Cancer Network (NCCN) criteria or family history, 31 (48%) underwent RRSO. Among eligible patients who did not undergo RRSO, 24 (73%) were not referred for gynecologic oncology consultation. Older age at testing (adjusted odds ratio [aOR] 1.08, 95% confidence interval [CI] 1.03-1.13) and referral to gynecologic oncology (aOR 33.48, CI 8.10-138.39) were associated with increased adoption of RRSO when adjusting for personal and family history of breast and ovarian cancer. CONCLUSION: Half of RRSO-eligible patients by NCCN criteria beyond BRCA did not undergo RRSO. Opportunities exist for improving education to increase referrals to facilitate RRSO for these patients.

Multifaceted precarity: pandemic experiences of recent immigrant women in the accommodation and food services sector.

The COVID-19 pandemic disproportionately affected those who face historical and ongoing marginalization. In centering pandemic experience of recent immigrant women in the accommodation and food services sector in Canada, we examine how their precarious work translated to experiences of work precarity and wellbeing. This paper illuminates how pre-existing and ongoing marginalization are reproduced during a health crisis for those at the intersection of gender, race, migration, and labour inequities. Using semi-structured interviews and systematic analysis using the Work Precarity Framework, we found that the pandemic exacerbated pre-existing socio-economic marginalization and resulted in unique experiences of work precarity. The latter was experienced as precarity of work (unpredictable work hours and job or employment insecurity), precarity from work (inadequate incomes), and precarity at work (physical, psychological, and relational unsafety). Work precarity stood out as a social determinant of health in relation to its outcome of degraded mental health and wellbeing. Recognizing the role of policies in producing, reproducing, and distributing precarity, we recommend policy directions to reduce social inequities in pandemic recovery.

Fresh Compared With Frozen Embryo Transfer and Risk of Severe Maternal Morbidity: A Study of In Vitro Fertilization Pregnancies in Ontario, Canada.

OBJECTIVES: To quantify the risk of severe maternal morbidity (SMM) in fresh versus frozen-thawed embryo transfers (ETs) among pregnancies conceived by in vitro fertilization (IVF) and to assess SMM risk according to the number of fresh ETs prior to the index pregnancy. METHODS: Retrospective cohort study using the provincial birth registry in Ontario, Canada. We included 13 929 individuals aged 18-55 years who conceived via IVF between January 1, 2013, and March 5, 2018, and delivered a live or stillborn infant ≥20 weeks gestation. We compared the primary outcome, a composite of SMM or death, between fresh and frozen ETs. RESULTS: A total of 174 individuals who conceived via fresh ETs had SMM (30.7 per 1000), compared with 280 among individuals who received frozen ETs (33.9 per 1000); adjusted risk ratio (aRR) 0.85 (95% CI 0.70-1.04). Compared with frozen ET, fresh ET was associated with a lower risk of severe hemorrhage (aRR 0.63; 95% CI 0.48-0.82) but no difference in risk of preeclampsia. Among individuals with 1 (n = 211) or ≥2 (n = 88) prior fresh cycles, the risk of SMM was not increased compared with having no prior cycles; aRR 0.96 (95% CI 0.78-1.18) and 0.91 (95% CI 0.67-1.25), respectively. CONCLUSION: Fresh ET was associated with a lower risk of severe hemorrhage compared with frozen ET. These findings may be partly explained by the increased popularity of a freeze-all strategy, reserving fresh ETs for patients with fewer comorbidities.

Nursing perspectives about the critical gaps in public health emergency response during the COVID-19 pandemic.

INTRODUCTION: The purpose of this qualitative study was to synthesize frontline U.S. nursing perspectives about the current state of U.S. public health emergency preparedness and response. The study findings may inform public health policy change and improve future national pandemic planning and responses. DESIGN: We conducted a secondary thematic qualitative analysis using grounded theory methodology. METHODS: Data collection occurred through semi-structured, in-depth focus groups between July and December 2020, from 43 frontline nurses working in hospitals in four states (Ohio, California, Pennsylvania, and New York). Data were analyzed deductively, aligned with Khan et al.'s Public Health Emergency Preparedness Framework and inductively for emergent themes. RESULTS: Three themes emerged: (1) Validation of the presence of health disparities and inequities across populations; (2) Perceived lack of consistency and coordination of messaging about pandemic policies and plans across all levels; and (3) challenges securing and allocating nursing workforce resources to areas of need. CONCLUSION: From a frontline nursing perspective, this study demonstrates the critical need to address health inequities and inequalities across populations, a consistent national vehicle for communication, and national plan for securing and allocating nursing workforce resources.

Double distress: women healthcare providers and moral distress during COVID-19.

Background: COVID-19 pandemic has led to heightened moral distress among healthcare providers. Despite evidence of gendered differences in experiences, there is limited feminist analysis of moral distress.Objectives: To identify types of moral distress among women healthcare providers during the COVID-19 pandemic; to explore how feminist political economy might be integrated into the study of moral distress.Research Design: This research draws on interviews and focus groups, the transcripts of which were analyzed using framework analysis.Research Participants and Context: 88 healthcare providers, based in British Columbia Canada, participated virtually.Ethical Considerations: The study received ethical approval from Simon Fraser University.Findings: Healthcare providers experienced moral dilemmas related to ability to provide quality and compassionate care while maintaining COVID-19 protocols. Moral constraints were exacerbated by staffing shortages and lack of access to PPE. Moral conflicts emerged when women tried to engage decision-makers to improve care, and moral uncertainty resulted from lack of clear and consistent information. At home, women experienced moral constraints related to inability to support children's education and wellbeing. Moral conflicts related to lack of flexible work environments and moral dilemmas developed between unpaid care responsibilities and COVID-19 risks. Women healthcare providers resisted moral residue and structural constraints by organizing for better working conditions, childcare, and access to PPE, engaging mental health support and drawing on professional pride.Discussion: COVID-19 has led to new and heightened experiences of moral distress among HCP in response to both paid and unpaid care work. While many of the experiences of moral distress at work were not explicitly gendered, implicit gender norms structured moral events. Women HCP had to take it upon themselves to organize, seek out resources, and resist moral residue.Conclusion: A feminist political economy lens illuminates how women healthcare providers faced and resisted a double layering of moral distress during the pandemic.

Ethics and frontline nursing during COVID-19: A qualitative analysis.

BACKGROUND: Nurses experienced intense ethical and moral challenges during the COVID-19 pandemic. Our 2020 qualitative parent study of frontline nurses' experiences during the COVID-19 pandemic identified ethics as a cross-cutting theme with six subthemes: moral dilemmas, moral uncertainty, moral distress, moral injury, moral outrage, and moral courage. We re-analyzed ethics-related findings in light of refined definitions of ethics concepts. RESEARCH AIM: To analyze frontline U.S. nurses' experiences of ethics during the COVID-19 pandemic. RESEARCH DESIGN: Qualitative analysis using a directed content methodology. PARTICIPANTS AND RESEARCH CONTEXT: The study included 43 nurses from three major metropolitan academic medical centers and one community hospital in the northeastern, mid-Atlantic, midwestern, and western United States. ETHICAL CONSIDERATIONS: Participant privacy and data confidentiality were addressed. FINDINGS: Moral dilemmas arose from many situations, most frequently related to balancing safety and patient care. Moral uncertainty commonly arose from lacking health information or evidence about options. Moral distress occurred when nurses knew the right thing to do, but were prevented from doing so, including with end-of-life issues. Moral injury (accompanied by suffering, shame, or guilt) occurred after doing, seeing, or experiencing wrongdoing, often involving authority figures. Nurses expressed moral outrage at events and people within and outside healthcare. Despite difficult ethical situations, some nurses exemplified moral courage, sometimes by resisting policies they perceived as preventing compassionate care, guided by thinking about what was best for patients. DISCUSSION: This content analysis of ethics-related subthemes revealed conceptual characteristics and clarified distinctions with corresponding exemplars. Conceptual clarity may inform responses and interventions to address ethical quandaries in nursing practice. CONCLUSIONS: Ethics education in nursing must address the moral dilemmas of pandemics, disasters, and other crises. Nurses need time and resources to heal from trying to provide the best care when no ideal option was available.

CCL17 in Inflammation and Pain.

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4+ non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Reflections From the Middle: Exploring the Experience of Nurse Managers Across the United States During the COVID-19 Pandemic.

OBJECTIVE: The objective of this multisite study was to explore the professional and personal experiences of US nurse managers (NMs) during the COVID-19 pandemic. BACKGROUND: NMs are the most accessible and visible nurse leaders to the frontline staff during this pandemic. METHODS: Thirty-nine NMs from 5 health systems across the US participated in focus groups in this qualitative study. Data were analyzed using a constant comparative method. RESULTS: Three major themes were identified: challenges, feelings and emotions, and coping. Subthemes emerged within each major theme. CONCLUSION: NMs across the country accepted considerable responsibility at great professional and personal consequence during the pandemic. NMs experienced challenges, ethical dilemmas, and expressed negative emotions. As the usual coping strategies failed, NMs reported that they are considering alternative career choices. This work provided evidence to help senior leaders strategize about mechanisms for reducing managerial dissonance during times of stress.