FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer.

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Cost avoidance of pharmacist-led deprescribing using STOPPFrail for older adults in nursing homes.

BACKGROUND: The Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy (STOPPFrail) criteria aim to reduce inappropriate/unnecessary medications in frail older adults, which should minimise adverse drug events and additional healthcare expenditure. Little is known about the economic outcomes of applying these criteria as an intervention. AIM: To evaluate cost avoidance of pharmacist-led application of STOPPFrail to frail older nursing home residents with limited life expectancy. METHOD: Pharmacist-identified STOPPFrail-defined potentially inappropriate medications that were deprescribed by patients' general practitioners were assigned a rating by a multidisciplinary panel, i.e. the probability of an adverse drug event occurring if the medication was not deprescribed. The intervention's net cost benefit and cost-benefit ratio were then determined by factoring in adverse drug event cost avoidance (calculated from probability of adverse drug event ratings), direct cost savings (deprescribed medication costs/reimbursement fees), and healthcare professionals' salaries. RESULTS: Of the 176 potentially inappropriate medications deprescribed across 69 patients, 65 (36.9%) were rated as having a medium or high probability of an adverse drug event occurring if not deprescribed. With €27,162 for direct cost savings, €61,336 for adverse drug event cost avoidance, and €2,589 for healthcare professionals' salary costs, there was a net cost benefit of €85,909 overall. The cost-benefit ratio was 33.2 and remained positive in all scenarios in sensitivity analyses. CONCLUSION: Pharmacist-led application of STOPPFrail to frail older nursing home residents is associated with significant cost avoidance. Wider implementation of pharmacist interventions in frail older nursing home residents should be considered to reduce potentially inappropriate medications and patient harm, alongside substantial cost savings for healthcare systems.

Pharmacist-Led Deprescribing Using STOPPFrail for Frail Older Adults in Nursing Homes.

OBJECTIVES: To evaluate the impact of pharmacist-guided deprescribing using the STOPPFrail (Screening Tool of Older Persons' Prescriptions in Frail adults with a limited life expectancy) criteria in frail older nursing home residents. DESIGN: Prospective, unblinded, non-randomized, intervention study. SETTING AND PARTICIPANTS: Adults aged ≥65 years with advanced frailty resident in 6 independent nursing homes in Ireland. METHODS: STOPPFrail-based deprescribing recommendations were developed by a pharmacist and presented to residents' general practitioners (GPs), who decided to implement or not. Measured outcomes included number of prescribed medications, medication costs, anticholinergic cognitive burden (ACB), drug burden index (DBI), modified medication appropriateness index (MMAI), quality of life (QoL), non-elective hospitalizations, emergency department visits, falls, and mortality were measured at baseline, post review, and at 6 months post review. RESULTS: Ninety-nine residents were recruited. Most (94%) were prescribed ≥1 potentially inappropriate medication (PIM). The most frequent PIMs were medications without a clearly documented indication (29.6%) and vitamin D (16.9%). Of 348 recommendations provided to GPs, 203 (58%) were accepted and 193 (55%) were implemented. Relating to baseline, post review, and at 6 months: the mean ± standard deviation (SD) number of medications was 16.0 ± 6.1, 14.6 ± 5.7 (P < .001), and 15.4 ± 5.5 (P < .001). The monthly mean ± SD medication cost per patient was €186.8 ± 123.7, €172.7 ± 119.0 (P < .001), and €186.4 ± 121.2 (P = .95). There were significant post-review decreases in the mean DBI, ACB, and MMAI of 9.7%, 9.6%, and 3.7%, respectively (P < .001), which remained significant at 6 months (P < .001). There were no significant differences in falls, emergency department visits, non-elective hospitalizations, or QoL. CONCLUSIONS AND IMPLICATIONS: STOPPFrail-guided deprescribing led by a pharmacist in nursing homes appeared to significantly reduce PIMs, medication costs (initially), and anticholinergic and sedative burdens, without adversely affecting other patient outcomes. Greater consideration should therefore be given to the wider integration of pharmacists into nursing homes to optimize the medications and health outcomes of frail older adults.

Answering the call: Experiences of nurses of color during COVID-19.

In the years following the COVID-19 pandemic, issues such as high job demands, burnout, and turnover continue to influence the nursing workforce, with heavier impacts to marginalized groups. Understanding the work and life contexts of nurses of color can help guide strategies for workplace equity and meaningful support. This qualitative study explored the experiences of nurses of color in the United States during the pandemic, focusing on feelings about the profession and job decisions. The overarching theme was "answering the call," with subthemes of "COVID shone a light," "being consumed by COVID," and "is it worth it?" Participants shared how their racial identities shaped their perceptions and job decisions in positive and negative ways, noting how racism impacted many facets of their work and added to the stressors felt in the workplace and the community. Findings provide insight into the underrepresented perspectives of nurses of color and suggest strategies to eliminate racism in nursing.

Solving the Autism Puzzle: Creating a Broad-Spectrum Tool to Improve Care Delivery in the Clinical Setting.

PURPOSE: The purpose of this quality improvement (QI) project was to develop and implement an assessment tool to identify a patient's specific needs due to autism spectrum disorder (ASD). The use of an individualized plan of care related to sensory and behavioral differences correlates with improved experiences in the perioperative setting for patients with ASD. DESIGN: Mixed methods, pre-post survey, retrospective data comparison. METHODS: Metrics planned to evaluate intervention outcomes included: (1) Comparison of pre and postsurvey data obtained from perioperative staff members following ASD education, (2) Evaluation of the number of behavior response team calls made compared to retrospective data, and (3) Survey response data from families assessing the perceived experience of perioperative stay. FINDINGS: Two hundred and fifty staff members responded to the learning needs survey; 164 in the preperiod and 86 in the postperiod. The perioperative process for these patients improved from the pre- to the postperiod in its ability to meet the needs of patients with autism (P < .001). Overall, respondents rated the sensory aids and the behavioral and sensory assessment tool as very useful (Median = 5, IQR = 2) and stated that they are likely to continue to use the tools in the future when caring for patients with autism (Median = 5, IQR = 1). CONCLUSIONS: The caregivers of study patients felt they had a high level of satisfaction with their surgery or procedure experience. Health care providers also reported increased confidence working with individuals with ASD in the perioperative environment and satisfaction with the intervention program.

Serum Hormone Concentrations in Transgender Youth Receiving Estradiol.

OBJECTIVE: This study aimed to evaluate the serum estradiol levels in gender-diverse youth to compare the efficacy of different estradiol routes in achieving therapeutic blood levels and suppressing serum testosterone levels. METHODS: This was a retrospective chart review of patients who initiated estradiol at an adolescent gender clinic between 2010 and 2019. Data on the route of estradiol administration and antiandrogen use (spironolactone or gonadotropin-releasing hormone agonist) were collected, and laboratory data were analyzed. Scatterplots were used to visualize the relationship between the estradiol dose and testosterone and estradiol laboratory values. RESULTS: A total of 118 patients were included, with a mean (standard deviation [SD]) age of 17.2 (1.6) years. The most common route of estradiol administration was oral only (62.7%), followed by transdermal only (23.7%), multiple routes excluding subcutaneous (8.5%), and any subcutaneous (5.1%). Notable variability was observed in the serum estradiol levels, with means (SDs) of 131.9 (120.4) pg/mL for those on oral estrogen 6 to 8 mg per day, 62.6 (40.3) pg/mL for those on transdermal estrogen 0.1 to 0.15 mg every 24 hours, and 53.6 (42.4) pg/mL for those on subcutaneous estradiol. In patients who received spironolactone, transdermal estradiol was associated with lower testosterone levels than estradiol administered orally or subcutaneously. CONCLUSION: Oral, transdermal, and subcutaneous administrations of estrogen all lead to increased serum estradiol levels and are effective for use in gender-affirming care for youth. Patients on transdermal estrogen tended to have lower serum estradiol levels but also had more suppression of serum testosterone levels.

Temporal Daily Relationships Between Sleep and Pain in Adolescents With Systemic Lupus Erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by recurrent episodes of pain. This study aimed to describe the temporal daily relationships between sleep and pain in adolescents with SLE. METHOD: Twenty-three adolescents with SLE recruited from a pediatric hospital wore actigraphy and completed diaries. Generalized estimating equation models were used. RESULTS: On average, evening pain negatively predicted subsequent sleep quality that night, and, on average, sleep quality negatively predicted morning pain. Shorter total sleep time significantly predicted higher morning pain (95% confidence intervals [CI], -0.38 to -0.03, p = .02), whereas sleep efficiency and sleep quality were not significantly associated with morning pain (95% CI, -0.03 to 0.03; 95% CI, -0.08 to 0.06, respectively). Subsequent evening pain did not predict daily nighttime sleep DISCUSSION: Our findings suggest that sleep is a target for pain interventions to include among adolescents with SLE.

GPs' perceptions of pharmacists working in general practices: A mixed methods survey study.

BACKGROUND: Pharmacists are increasingly incorporated into general practice teams globally and have been shown to positively impact patient outcomes. However, little research to date has focused on determining general practitioners' (GPs') perceptions of practice-based pharmacist roles in countries yet to establish such roles. OBJECTIVES: To explore GPs' perceptions towards integrating pharmacists into practices and determine if any significant associations were present between GPs' perceptions and their demographic characteristics. METHODS: In June 2022, a survey was disseminated to GPs in Ireland via post (n = 500 in Munster region), Twitter, WhatsApp, and an online GP support and education network. Quantitative data were captured through multiple option and Likert-scale questions and analysed using descriptive and inferential statistics. Qualitative data were captured via free-text boxes, with the open comments analysed using reflexive thematic analysis. RESULTS: A total of 152 valid responses were received (24.6% response to postal survey). Overall, GPs welcomed the role of practice-based pharmacists and perceived that they would increase patient safety. Most agreed with practice pharmacists providing medicine information (98%) vs. 23% agreeing with practice pharmacists prescribing independently. Most agreed they would partake in a practice pharmacist pilot (78.6%). The free-text comments described current pressures in general practice, existing relationships with pharmacists, funding and governance strategies, potential roles for pharmacists in general practice, and anticipated outcomes of such roles. CONCLUSION: This study provides a deeper understanding of GPs' perceptions of integrating pharmacists into practices and the demographic characteristics associated with different perceptions, which may help better inform future initiatives to integrate pharmacists into practices.

The Resilience of Pediatric Nurses in Context: A Mixed Methods Study.

BACKGROUND: Resilience, an individual's ability to cope with and recover from stressors, is supported by contextually specific factors. Factors in the work environment may support or hinder nurses' resilience to the specific stressors present in pediatric nursing, an understudied population. OBJECTIVE: We aimed to explore the contextual factors in the work environment of pediatric nurses with varying levels of resilience, including social support, the work environment, and opportunities for coping from an individual approach. METHODS: This study is a secondary mixed-methods analysis using ordinal logistic regression and a meta-matrix of survey responses and semi-structured interview transcripts from 30 pediatric nurses. RESULTS: 5 themes, 3 supporting and 2 hindering resilience, emerged from the interviews. Nurses described their resilience as supported by sharing the burden, support from administration, and taking a break. Participants described resilience as hindered when they found it challenging to provide quality nursing care and when they felt unappreciated or undervalued. No theme significantly changed the odds of having higher resilience. CONCLUSIONS: Our findings suggest that nurses recognize resources and conditions within their work environment as influencing their resilience. However, workplace resources and conditions are only one contributor to pediatric nurse resilience. Encouraging breaks and informal opportunities for nurses to support each other may support resilience in pediatric nurses. In addition, nursing leaders can support pediatric nurse resilience by regularly spending time connecting with nurses. Finally, health care organizations should consider how changes in the work environment may hinder nurse resilience by adding stress or changing access to supportive factors.

A Contemporary Model for Improving RN Job Outcomes.

The pandemic has highlighted three critical nursing workforce issues: turnover, wellbeing, and equity. A comprehensive framework is needed to understand the interactions between these concepts. This paper proposes a model that allows for more inclusive understanding of professional outcomes for RNs, with attention not just to job outcomes, but also to equity for underrepresented groups in the workforce and individual wellbeing. The model highlights the importance of systems and societal elements, contextual elements, and individual responses to the dynamic conditions of work and life, and can be used to advance research and practice to create effective retention and support strategies.

COVID-19 Related Job Outcomes for Nurses of Color in the United States.

The purpose of this study was to examine factors associated with negative job outcomes for nurses during the initial phase of the COVID-19 pandemic, with a focus on nurses of color. The study used data from 3,782 nurses in the Current Population Survey to examine the relationship between nurse characteristics and COVID-19-related inability to work or look for work during May through December 2020. The analysis showed that race and gender did not significantly impact nurses' job outcomes. The odds of a negative impact were increased by age (1.5% per year, p < .05), having a child in the home (43%, p < .01), having no spouse present (36%, p < .01), and working in an outpatient role (48%, p < .001). While race alone was not linked to negative outcomes, nurses of color had higher rates of other factors that were associated with negative outcomes, indicating a need for a more nuanced examination of their work and life contexts and job outcomes throughout the pandemic.

Tobacco-free campuses - a pipe dream? A survey of current smoking cessation practice in mental health units in Ireland.

AIMS AND METHOD: Smoking and vaping are prohibited on Ireland's Health Service Executive (HSE) campuses. The HSE states that there is no evidence to suggest vaping is less damaging than cigarettes. Recent meta-analyses have shown that e-cigarettes are in fact less dangerous and can help smokers quit. Our study analyses the current smoking policies in place in mental health 'approved centres' in Ireland, what is being done to help smokers quit while in-patients and the level of support among staff for the introduction of e-cigarettes as a harm reduction tool. Clinical nurse managers from each mental health approved centre were surveyed to assess adherence to smoking policies. RESULTS: Only 5% of surveyed units enforce the HSE's Tobacco Free Campus Policy; 55% of units supported the idea of using e-cigarettes to help patients quit cigarettes. CLINICAL IMPLICATIONS: Ireland's hospital campuses are not tobacco free. Changes need to be made to our smoking policies and their enforcement.

General practitioners' perceptions of pharmacists working in general practice: a qualitative interview study.

INTRODUCTION: Pharmacists in general practice have been shown to enhance patient care and are becoming increasingly prevalent worldwide. Yet, little is known about general practitioners' (GPs') perceptions of pharmacists prior to potentially working alongside them in this setting. Therefore, this study aimed to investigate these GP perceptions to inform future efforts to integrate pharmacists into general practice. METHODS: Semi-structured interviews were conducted with GPs practising in the Republic of Ireland between October and December 2021. Content analysis was used to identify the most relevant Theoretical Domains Framework (TDF) domains that affected the theoretical integration of pharmacists into general practice. RESULTS: Fifteen GPs were interviewed. Five TDF domains were found to be most relevant in affecting pharmacist integration: (1) 'environmental context and resources' (space, government funding, information technology, current workplace pressures, increasing patient complexity, indemnity, moves towards group practices); (2) 'skills' (GP mentors, practical in-service training, consultation skills development); (3) 'social professional role and identity' (role definition, clinical governance, pharmacist prescribing, medication review and monitoring); (4) 'beliefs about consequences' (patient safety, cost savings, workload); and (5) 'knowledge' (pharmacists as medication experts, lack of knowledge of pharmacist undergraduate training). DISCUSSION: This is the first qualitative interview study to focus on exploring GPs' perceptions of pharmacists working in general practice outside of private practice settings. It has provided a deeper understanding of GPs' considerations regarding the integration of pharmacists into general practice. In addition to informing future research, these findings should help optimise future service design and aid pharmacist integration into general practice.

School Nurses' Diabetes-Related Attitudes and Self-efficacy in Diabetes Education and Management.

This study explored relationships between school nurses' diabetes-related attitudes, self-efficacy in diabetes management and education, and care practices. One-hundred fourteen school nurses who have taken care of students with type 1 diabetes in public schools comprised this descriptive study sample. Participants completed online surveys. School nurses' diabetes-related attitudes were not related to their self-efficacy in diabetes education, but nurses' attitudes towards the psychosocial impact of diabetes were significantly related to their self-efficacy in diabetes management, and the number of students with diabetes was a significant contributor to this relationship. Nurses' full-time status and the type of school they worked in were significantly related to their self-efficacy in providing diabetes education. School nurses' positive attitudes about providing care for students with diabetes were related to having a higher level of self-efficacy in providing diabetes management. Based on the findings, recommendations are made for health consolidated schools and full-time school nurses.

General practitioners' perceptions of pharmacists working in general practice: a qualitative interview study.

BACKGROUND: Pharmacists are being increasingly employed as part of general practice teams globally, and their input has been associated with several clinical and economic benefits. However, there is a paucity of research focussing on general practitioners' (GPs') perceptions of pharmacist integration into practices in countries where this novel role for pharmacists is yet to become commonplace. OBJECTIVE: To explore GPs' perceptions of integrating pharmacists into general practices and to identify the behavioural determinants of GPs integrating pharmacists into practices. METHODS: Semistructured interviews were conducted with GPs practising in Ireland, who were sampled using a combination of purposive, convenience, and snowball sampling. Interviews were audio-recorded and transcribed verbatim, which then were analysed using conventional content analysis and directed content analysis employing the Theoretical Domains Framework (TDF). RESULTS: Seventeen GPs were interviewed between November 2021 and February 2022. Seven TDF domains were identified as predominant in influencing GPs' perceptions of pharmacist integration into general practices. These perceptions were mostly positive, especially regarding patient outcomes, cost savings, and improving access to care. However, there were concerns about funding the role, affecting others' workloads, and pharmacists' training needs to work in practices. CONCLUSION: This study's theory-informed insight provides a deeper understanding of GPs' perceptions of pharmacists working in general practice and behaviours which can be targeted to help optimize integration. These findings should be utilized in future service development to preempt and address GPs' concerns ahead of pharmacist integration, as well as to inform the development of general practice-based pharmacist roles going forward.

This interview study focusses on, for the first time, general practitioners' (GPs') perceptions of pharmacist integration into general practices outside of a private practice setting. Pharmacists working in general practices have demonstrated several benefits for patients, GPs, practices, and for wider society. However, pharmacist roles in general practices have thus far been confined to a small number of countries; little is known about the perceptions of GPs who have not previously worked alongside a pharmacist in general practice regarding pharmacist integration in this setting. GPs interviewed in this study were broadly optimistic about aspects of pharmacists working in practices and potential outputs. However, GPs had concerns about pharmacists' impact on others' roles and workloads, funding, and training pharmacists to perform roles in this setting. This study therefore provides a useful insight into GPs' perceptions on the subject so that their views, concerns, and ideas can be anticipated and taken on board in advance of trying to integrate pharmacists into practices.

Musculoskeletal manifestations of lymphoma: a case series.

Lymphomas are a heterogenous group of cancers of the lymphatic system in which disease primarily arises in lymph nodes. Extranodal disease is common; however, musculoskeletal involvement is rare. Imaging plays an important role in the diagnosis and staging of all lymphomas. In this case series, we present examples of musculoskeletal involvement of lymphoma encountered at our institution. We outline the clinical presentation and imaging findings of each and use these cases to review the features that can help to differentiate lymphoma from other musculoskeletal lesions.

Health Research in a Jail: Methodological Challenges.

Strict regulations are in place for conducting research with prisoners. Published studies are limited that focus on improving the health and well-being of incarcerated persons. Subsequently, institutional review boards established methods to guide researchers in conducting fair and ethical research in carceral settings. The authors of this paper discuss some of the methodological challenges that exist when conducting research with incarcerated persons. Unique methodological challenges were found during the process of conducting a research study inside a jail setting. The authors discuss challenges and provide guidance for future studies. Despite challenges, researchers can conduct studies that can benefit incarcerated persons.

Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.

Accelerating drug development in breast cancer: New frontiers for ER inhibition.

The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field.