Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study.

OBJECTIVE: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3). METHODS: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100). RESULTS: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. CONCLUSION: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.

Factors impacting pediatric registered nurse attitudes toward caring for dying children and their families: A descriptive study.

PURPOSE: The purpose of this study was to gain knowledge of the educational preparation and attitudes of registered nurses at a southeastern pediatric hospital toward caring for dying children and their families. DESIGN AND METHODS: A descriptive study with two independent samples was used to examine the attitudes of registered nurses at a pediatric hospital in southeastern United States. Participants completed the Frommelt Attitude Toward Care of the Dying Scale, Form B, a 30-item survey. Descriptive and inferential statistics were used to analyze data. RESULTS: One hundred and thirty-two registered nurses participated in the study. Results indicated a statistically significant difference in attitudes toward caring for dying pediatric patient scores in registered nurses working in the hematology/oncology and intensive care units compared to the other units (p = 0.0017; 95% CI: 2.39-10.12). CONCLUSIONS: This study described the educational preparation and attitudes of registered nurses who care for children who are dying and their families. Additionally, pediatric end-of-life care is complex and is further influenced by experiences and attitudes. Future research is needed to identify educational needs to care for pediatric patients and their families at the end of life. PRACTICE IMPLICATIONS: Findings from this project indicated end-of-life care education should be integrated into undergraduate curricula. New nurse graduates who are entering the workforce should receive education on end-of-life care, especially if they are entering into a pediatric specific organization. Healthcare organizations should include end-of-life care education as part of the orientation process and annual competency process.

PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors.

OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.

End-of-life care in an Australian acute hospital: a retrospective observational study.

BACKGROUND: There is a gap in knowledge about the kind and quality of care experienced by hospital patients at the end of their lives. AIMS: To document and compare the patterns in end-of-life care for patients dying across a range of different medical units in an acute care hospital. METHODS: A retrospective observational study of consecutive adult inpatient deaths between 1 July 2010 and 30 June 2014 in four different medical units of an Australian tertiary referral hospital was performed. Units were selected on the basis of highest inpatient death rates and included medical oncology, respiratory medicine, cardiology and gastroenterology/hepatology. RESULTS: Overall, 41% of patients died with active medical treatment plans, but significantly more respiratory and cardiology patients died with ongoing treatment (46 and 75% respectively) than medical oncology and gastroenterology patients (each 27%, P < 0.05). More medical oncology and gastroenterology patients were recognised as dying (92 and 88%) compared with 72% of respiratory and only 38% of cardiology patients (P < 0.001). Significantly, more medical oncology patients were referred to palliative care and received comfort care plans than all other patient groups. However, the rate of non-palliative interventions given in the final 48 h was not significantly different between all four groups. CONCLUSIONS: There were differences in managing the dying process between all disciplines. A possible solution to these discrepancies would be to create an integrated palliative care approach across the hospital. Improving and reducing interdisciplinary practice variations will allow more patients to have a high-quality and safe death in acute hospitals.

Supporting health system transformation through an interprofessional education experience focused on population health.

The purpose of the study was to determine the impact of an interprofessional education (IPE) experience on first year students across all schools of a health sciences center on the topic of pediatric immunizations. The authors conducted a pre-/post-test at Louisiana State University Health Sciences Center-New Orleans with 731 first year students from 25 academic programs encompassing all six schools (Allied Health, Dentistry, Graduate Studies, Medicine, Nursing and Public Health). In the four questions related to the Interprofessional Education Collaborative (IPEC) sub-competencies and the three questions related to professional role regarding immunizations, there was a statistically significant difference in the pre-/post-test survey results (P < 0.0001). Student learning related to the collaboration needed to make a larger impact on patient outcomes was demonstrated through assessment of an open-ended question. IPE experiences can improve first-year students' perceptions of IPEC sub-competencies regarding the importance of population health and teamwork. By utilizing a population health focus with IPE activities, novice learners are equipped to learn and apply collaborative practice skills along with recognizing the importance of promoting overall health and well-being instead of just health care.

Complex Task Performance Assessment (CTPA) and Functional Cognition in People With Parkinson's Disease.

OBJECTIVE: The objective of this study was to determine how Parkinson's disease (PD) affects functional cognition as assessed by the Complex Task Performance Assessment (CTPA) and to examine the associations of CTPA performance with other indicators of executive function in people with PD. METHOD: Volunteers with PD without dementia (n = 20) and community control participants (n = 19) completed neuropsychological testing, patient-reported outcome measures, and the CTPA. RESULTS: There were no group differences for CTPA performance accuracy; however, the PD group took longer to complete the CTPA than did the control group. In the PD group, inefficient CTPA performance correlated with poorer cognitive flexibility and worse reported everyday shifting and task monitoring. CONCLUSION: Decreased executive function, namely cognitive flexibility and attentional control, may impair functional cognition in people with PD. Future studies with larger, more diverse samples are warranted to determine the discriminant validity and sensitivity of the CTPA. Use of performance-based assessments such as the CTPA may increase the understanding of functional cognition in people with PD.

Breast and ovarian cancer referrals to the ACT Genetic Service: are we meeting guidelines?

BACKGROUND: The ACT Genetic Service at The Canberra Hospital evaluates the genetic risk of individuals for inherited diseases, and provides counselling and genetic testing where appropriate. AIM: To evaluate the current referral practice for patients with a personal and/or family history of breast and/or ovarian cancer, and to assess whether these referrals are made according to eviQ cancer referral guidelines. METHODS: A retrospective clinical audit of patients seen by the ACT Genetic Service for evaluation of genetic risk of breast and/or ovarian cancer between 1 January 2013 and 30 June 2015. Statistical analysis included Chi-squared and Poisson distribution tests. RESULTS: Of the 711 patients referred during the 30-month period, 671 were seen by the service. The number of patients seen increased steadily over the time period, as did waiting times. The majority of referrals were made by general practitioners (403/711; 57%) and oncologists (172/711; 24%). Of note, 300 of 711 (42%) of all referrals made to the service during this time period did not meet eviQ referral guidelines. Patients who met guidelines for referral were more likely both to be offered genetic testing and to have a positive result. CONCLUSION: Demand on the ACT Genetic Service increased over the time period assessed. As a significant proportion of patients did not meet eviQ cancer referral guidelines, it is worth reviewing the referral process in order to optimise utility of this limited resource.

Aligning interprofessional education collaborative sub-competencies to a progression of learning.

In the United States, the Interprofessional Education Collaborative (IPEC) developed four core competencies for interprofessional collaborative practice. Even though the IPEC competencies and respective sub-competencies were not created in a hierarchal manner, one might reflect upon a logical progression of learning as well as learners accruing skills allowing them to master one level of learning and building on the aggregate of skills before advancing to the next level. The Louisiana State University Health-New Orleans Center for Interprofessional Education and Collaborative Practice (CIPECP) determined the need to align the sub-competencies with the level of behavioural expectations in order to simplify the process of developing an interprofessional education experience targeted to specific learning levels. In order to determine the most effective alignment, CIPECP discussions revolved around current programmatic expectations across the institution. Faculty recognised the need to align sub-competencies with student learning objectives. Simultaneously, a progression of learning existing within each of the four IPEC domains was noted. Ultimately, the faculty and staff team agreed upon categorising the sub-competencies in a hierarchical manner for the four domains into either a "basic, intermediate, or advanced" level of competency.

"Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit?

"Platinum resistant" ovarian cancer was historically defined as disease recurrence within 6months of completion of first-line platinum-based chemotherapy, although this is now more broadly applied to also include patients progressing within 6months after multiple lines of chemotherapy. However, this definition ignores the heterogeneity and complexity of the spectrum of diseases that comprise "platinum resistant ovarian cancer" (PROC) and is innately flawed as it was initially derived using methods of detection of recurrence that would now be regarded as outdated. The outcome of patients with PROC is generally poor, with low response rates to further chemotherapy and a median survival of less than 12months, but this is unpredictable and can be quite variable from study to study. This review outlines the complexity of PROC, examines how this impacts on the interpretation of the results of clinical trials, and explores how the definition may be improved. We also briefly describe the mechanisms of platinum resistance, the results of clinical trials to date as well as treatment options for patients with PROC and highlight the need for better methods of assessing clinical benefit in this poor prognostic sub group of patients.

Gynecologic Cancer InterGroup (GCIG) consensus review for cervical adenocarcinoma.

Cervical adenocarcinoma is known to be less common than squamous cell carcinoma of the cervix comprising approximately 25% of all cervical carcinomas. Differences in associated human papillomavirus types, patterns of spread, and prognosis call for treatments that are not always like those for squamous cancers. In this review, we report a consensus developed by the Gynecologic Cancer InterGroup surrounding cervical adenocarcinoma for epidemiology, pathology, treatment, and unanswered questions. Prospective clinical trials are needed to help develop treatment guidelines.

Gynecologic Cancer InterGroup (GCIG) consensus review for squamous cell carcinoma of the ovary.

Squamous cell carcinoma of the ovary is a rare complication of mature cystic teratoma. The epidemiology, pathology, diagnosis, and management of this rare tumor are reviewed. Clinical characteristics, preoperative imaging, and tumor markers may help to predict malignancy preoperatively. Complete cytoreduction should be the aim of surgery. The prognosis for stage 1A disease is good, but for women with advanced or recurrent disease, it is very poor and has not improved in recent years. At present, there are insufficient data to provide clear guidance on the optimal management strategy for advanced disease, and there is a need to gain an understanding of the biology and to develop novel effective therapies. This will require coordinated international collaboration.

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

A mutant with aberrant extracellular LcrV-YscF interactions fails to form pores and translocate Yop effector proteins but retains the ability to trigger Yop secretion in response to host cell contact.

The plasmid-encoded type three secretion system (TTSS) of Yersinia spp. is responsible for the delivery of effector proteins into cells of the innate immune system, where these effectors disrupt the target cells' activity. Successful translocation of effectors into mammalian cells requires Yersinia to both insert a translocon into the host cell membrane and sense contact with host cells. To probe the events necessary for translocation, we investigated protein-protein interactions among TTSS components of the needle-translocon complex using a chemical cross-linking-based approach. We detected extracellular protein complexes containing YscF, LcrV, and YopD that were dependent upon needle formation. The formation of these complexes was evaluated in a secretion-competent but translocation-defective mutant, the YscFD28AD46A strain (expressing YscF with the mutations D28A and D46A). We found that one of the YscF and most of the LcrV and YopD cross-linked complexes were nearly absent in this mutant. Furthermore, the YscFD28AD46A strain did not support YopB insertion into mammalian membranes, supporting the idea that the LcrV tip complex is required for YopB insertion and translocon formation. However, the YscFD28AD46A strain did secrete Yops in the presence of host cells, indicating that a translocation-competent tip complex is not required to sense contact with host cells to trigger Yop secretion. In conclusion, in the absence of cross-linkable LcrV-YscF interactions, translocon insertion is abolished, but Yersinia still retains the ability to sense cell contact.

Effective contractile response to voltage-gated Na+ channels revealed by a channel activator.

This study investigated the molecular identity and impact of enhancing voltage-gated Na(+) (Na(V)) channels in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the Na(V) channel activator veratridine were examined. Na(V) channel expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC(50) = 5.19 ± 0.20, E(max) = 12.0 ± 2.7 mN), which were inhibited by 1 µM TTX (a blocker of all Na(V) channel isoforms, except Na(V)1.5, Na(V)1.8, and Na(V)1.9), but not by selective blockers of Na(V)1.7 (ProTx-II, 10 nM) or Na(V)1.8 (A-80347, 1 µM) channels. The responses were insensitive to endothelium removal but were partly (~60%) reduced by chemical destruction of sympathetic nerves by 6-hydroxydopamine (2 mM) or antagonism at the α1-adrenoceptor by prazosin (1 µM). KB-R7943, a blocker of the reverse mode of the Na(+)/Ca(2+) exchanger (3 µM), inhibited veratridine contractions in the absence or presence of prazosin. T16A(inh)-A01, a Ca(2+)-activated Cl(-) channel blocker (10 µM), also inhibited the prazosin-resistant contraction to veratridine. Na(V) channel immunoreactivity was detected in freshly isolated mesenteric myocytes, with apparent colocalization with the Na(+)/Ca(2+) exchanger. Veratridine induced similar contractile effects in the femoral artery, and mRNA transcripts for Na(V)1.2 and Na(V)1.3 channels were evident in both vessel types. We conclude that, in addition to sympathetic nerves, NaV channels are expressed in vascular myocytes, where they are functionally coupled to the reverse mode of Na(+)/Ca(2+) exchanger and subsequent activation of Ca(2+)-activated Cl(-) channels, causing contraction. The TTX-sensitive Na(V)1.2 and Na(V)1.3 channels are likely involved in vascular control.

Selective loss of polymorphic mating types is associated with rapid phenotypic evolution during morphic speciation.

Polymorphism may play an important role in speciation because new species could originate from the distinctive morphs observed in polymorphic populations. However, much remains to be understood about the process by which morphs found new species. To detail the steps of this mode of speciation, we studied the geographic variation and evolutionary history of a throat color polymorphism that distinguishes the "rock-paper-scissors" mating strategies of the side-blotched lizard, Uta stansburiana. We found that the polymorphism is geographically widespread and has been maintained for millions of years. However, there are many populations with reduced numbers of throat color morphs. Phylogenetic reconstruction showed that the polymorphism is ancestral, but it has been independently lost eight times, often giving rise to morphologically distinct subspecies/species. Changes to the polymorphism likely involved selection because the allele for one particular male strategy, the "sneaker" morph, has been lost in all cases. Polymorphism loss was associated with accelerated evolution of male size, female size, and sexual dimorphism, which suggests that polymorphism loss can promote rapid divergence among populations and aid species formation.

Evidence-Based Pearls: Falls in the Intensive Care Unit.

Falls in the ICU are multifaceted, affecting patients of all ages. Historically, falls have been associated with patients in the hospital environment, but fall rates after discharge and readmission rates following a fall are now areas of concern. Recent innovations to prevent risks related to sedation and immobility in the hospital have revealed their impact on ICU patients and fall risk. Risk factors for falls in the ICU relate to length of stay and acuity-related care requirements, such as mechanical ventilation, sedation, and prolonged immobilization. Evidence-based fall prevention includes screening tools, prevention bundles/programs, and implementing clinical practice guidelines.

Community sociodemographics and rural hospital survival.

PURPOSE: To determine whether community sociodemographic factors are associated with the survival or closure of rural hospitals at risk of financial distress between 2010 and 2019. METHODS: We use a national sample of 985 rural hospitals at risk of financial distress to analyze the relationship between community sociodemographic characteristics and hospital survival or closure. We control for financial distress using the Financial Distress Index developed by the Sheps Center for Health Services Research. Community characteristics are retrieved from the Census and the Robert Wood Johnson Foundation. We first use Wilcoxon rank-sum tests to demonstrate annual sociodemographic differences between rural communities with financially distressed hospitals that closed between 2010 and 2019, and those that remained open. Multilevel Weibull proportional hazards regressions then uncover which sociodemographic factors are significantly associated with survival. FINDINGS: Our initial results confirm that closures of rural hospitals at risk of financial distress disproportionately affect communities with certain sociodemographic characteristics. However, most of these characteristics are not associated with higher rates of closure in the multivariate survival analysis. The final results suggest that financially distressed hospitals are more likely to experience closure if their communities have higher rates of unemployment (Hazard Ratio = 1.36, P < .05) or uninsured residents under 65 (Hazard Ratio = 1.13, P < .05). CONCLUSIONS: Among financially distressed rural hospitals, specific community-level sociodemographic characteristics (unemployment and uninsurance rates) are positively associated with the likelihood of closure. Social policies addressing these issues should emphasize their broader relationship with the local health sector.

Intervention Fidelity in Pain Pragmatic Trials for Nonpharmacologic Pain Management: Nuanced Considerations for Determining PRECIS-2 Flexibility in Delivery and Adherence.

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, "flexibility in delivery" and "flexibility in adherence," address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate. PERSPECTIVE: This article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable.