Interdisciplinary intervention for the management of nonmedical opioid use among patients with cancer pain.

BACKGROUND: Few studies have assessed interventions aimed at managing nonmedical opioid use (NMOU) behavior among patients with cancer. The authors developed the Compassionate High-Alert Team (CHAT) intervention to manage patients receiving opioids for cancer pain who demonstrate NMOU behavior. The objective of this study was to determine the change in frequency of NMOU behaviors, pain intensity, and opioid requirements among those who received the intervention. METHODS: A total of 130 patients receiving opioids for cancer pain that had documented evidence of NMOU and received the CHAT intervention were reviewed. Demographic and clinical information such as NMOU behaviors, pain scores, and morphine equivalent daily dose at baseline, 3, and 6 months post-intervention was obtained. RESULTS: NMOU behaviors significantly decreased from a median (interquartile range) of 2 (1-3) at baseline to 0 (0-1) at both 3 and 6 months post-intervention (p < .001). A total of 45 of 75 (60%) and 31 of 50 (62%) of CHAT recipients achieved complete response to the intervention at 3 and 6 months, respectively. Higher baseline number of NMOU behaviors was independently associated with patient response to the intervention (odds ratio [OR], 1.97; 95% confidence interval [CI],1.09-4.28, p = .049 at 3 months; OR, 2.5; 95% CI, 1.20-6.47, p = .03 at 6 months). The median pain score decreased from 7 at baseline to 6 at both 3 and 6 months (p = .01). Morphine equivalent daily dose did not significantly change during that same period (143 mg/day vs. 139 mg/day, p = .13). CONCLUSIONS: Most patients who received the CHAT intervention improved in their NMOU behaviors and pain intensity scores 3 and 6 months post-intervention. These preliminary findings support the efficacy of CHAT in managing patients receiving opioids for cancer pain who demonstrate NMOU behavior.

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis.

Yorkie (Yki), the transcriptional co-activator of the Hippo signaling pathway, has well-characterized roles in balancing apoptosis and cell division during organ growth control. Yki is also required in diverse tissue regenerative contexts. In most cases this requirement reflects its well-characterized roles in balancing apoptosis and cell division. Whether Yki has repair functions outside of the control of cell proliferation, death, and growth is not clear. Here we show that Yki and Scalloped (Sd) are required for epidermal wound closure in the Drosophila larval epidermis. Using a GFP-tagged Yki transgene we show that Yki transiently translocates to some epidermal nuclei upon wounding. Genetic analysis strongly suggests that Yki interacts with the known wound healing pathway, Jun N-terminal kinase (JNK), but not with Platelet Derived Growth Factor/Vascular-Endothelial Growth Factor receptor (Pvr). Yki likely acts downstream of or parallel to JNK signaling and does not appear to regulate either proliferation or apoptosis in the larval epidermis during wound repair. Analysis of actin structures after wounding suggests that Yki and Sd promote wound closure through actin regulation. In sum, we found that Yki regulates an epithelial tissue repair process independently of its previously documented roles in balancing proliferation and apoptosis.

The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development.

In vitro data suggest that the human RbAp46 and RbAp48 genes encode proteins involved in multiple chromatin remodeling complexes and are likely to play important roles in development and tumor suppression. However, to date, our understanding of the role of RbAp46/RbAp48 and its homologs in metazoan development and disease has been hampered by a lack of insect and mammalian mutant models, as well as redundancy due to multiple orthologs in most organisms studied. Here, we report the first mutations in the single Drosophila RbAp46/RbAp48 homolog Caf1, identified as strong suppressors of a senseless overexpression phenotype. Reduced levels of Caf1 expression result in flies with phenotypes reminiscent of Hox gene misregulation. Additionally, analysis of Caf1 mutant tissue suggests that Caf1 plays important roles in cell survival and segment identity, and loss of Caf1 is associated with a reduction in the Polycomb Repressive Complex 2 (PRC2)-specific histone methylation mark H3K27me3. Taken together, our results suggest suppression of senseless overexpression by mutations in Caf1 is mediated by participation of Caf1 in PRC2-mediated silencing. More importantly, our mutant phenotypes confirm that Caf1-mediated silencing is vital to Drosophila development. These studies underscore the importance of Caf1 and its mammalian homologs in development and disease.

Will the wound-healing field earn its wings?

In a recently published issue of Experimental Dermatology, Dr. Nuria Paricio and colleagues review recent advances using the fruit fly, Drosophila melanogaster, as a wound-healing model. They describe many of the advantages of the fly model for gene discovery and functional analysis, highlighting its particular strengths and limitations for studies of wound healing. This commentary assumes that dermatologist-scientists and fly wound-healing researchers share a common field-wide goal of discovering all of the clinically relevant wound-healing genes and understanding in molecular detail how those genes work. We ask: how can we cooperate to achieve this shared goal?

Frequency and Prediction of Burnout Among Physicians Who Completed Palliative Care Fellowship Training - A 10 Year Survey.

CONTEXT: Palliative Care (PC) physicians are vulnerable to burnout given the nature of practice. Reports suggest that burnout frequency is variable across different countries. OBJECTIVE: The main objective of our study was to determine knowledge, attitudes and frequency of burnout among Hospice and Palliative Medicine (HPM) Fellowship graduates trained at a comprehensive cancer center. METHODS: We conducted a survey to determine the knowledge, attitudes, and frequency of burnout in former fellows, consisting of the Maslach Burnout Inventory (MBI) and 41 custom questions. Palliative care fellows who trained at a Comprehensive Cancer Center from 2008 to 2018 were included in the survey. RESULTS: Eighty-four percent of the 52 eligible physicians completed surveys. Median age was 38 years, with 68% females. Seventy-seven percent practiced PC more than 50% of time. Median practice duration was four years, and 84% were board certified. Most common disease types treated were cancer (89%), cardiac (43%) and pulmonary (43%). Burnout rate was high at 52% (n=20). The median scores for emotional exhaustion were 25.5, depersonalization 9, and personal accomplishment 48. Female gender (P=0.07) and having administration as a component in the job description (P=0.044) were associated with risk of burnout. Clinical care setting, work hours/week, frequency of weekend calls, and size of team were not significantly associated with burnout. CONCLUSION: Burnout among former fellows trained in HPM between 2008 and 2018 is high. More research is needed to develop strategies to better prevent and manage burnout among HPM fellowship trained PC physicians.

Stay Home, Work Safe: Attitudes and Beliefs of Members of a Department of Palliative Care, Rehabilitation, and Integrative Medicine Regarding Remote Work during the COVID-19 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic compelled rapid transition to work from home for the University of Texas MD Anderson Cancer Center Palliative, Rehabilitation, and Integrative Medicine (PRIM) department to ensure social distancing and prevention of transmission. Objectives: To survey the attitudes and beliefs of personnel toward remote work during the COVID-19 pandemic. Methods: One hundred forty-eight clinical, research, and administrative PRIM department employees were invited to participate in an anonymous voluntary survey in May 2020, two months after the beginning of the COVID-19 pandemic and transition to work from home in the geographic location of Houston, Texas. The survey comprised 25 questions, including employee demographics and attitudes and beliefs toward working from home and the COVID-19 pandemic. Results: Ninety-four percent (139) of employees responded, with high response rates among all three employee arms. The majority of respondents were female (74%), between the ages of 30 and 59 years (87%), had broadband Internet (93%), and shared office space before working from home (59%). There were overall positive reports of experience (87%) and emotional response (79%) toward working from home, especially for those more concerned about COVID-19 illness and spread, shared office space, and those reporting adequate resources and equipment for remote work. Clinical role, however, was associated with a less positive response (80%), less productivity (29%), and higher levels of stress (62%). Most of the department also reported increased emotional exhaustion (68%). When surveyed about permanently working from home, most of the department responded favorably (69%). Conclusions: The PRIM rapid transition to remote work was associated with positive perceptions by most members of the clinical, research, and administrative teams. Insight from this survey can serve as a model for future rapid transitions in remote work and merits follow-up studies to prepare us for a postpandemic work environment. Clinical Trial Registration number NCI-2021-01265.

Empowering the Health and Well-Being of the Palliative Care Workforce: Evaluation of a Weekly Self-Care Checklist.

BACKGROUND: Workplace interventions are needed to prevent burnout and support the well-being of the palliative care workforce. MEASURES: We conducted a survey of all palliative care clinical staff to evaluate the usefulness and feasibility of checklist items and the checklist itself. We collected demographics, perceptions of professional satisfaction and burnout, and qualitative feedback aimed at improving the checklist. INTERVENTION: We implemented a 13-item self-care checklist, included in a handbook on palliative care carried in the laboratory coat of all clinical personnel, to remind them to care of their own well-being. OUTCOMES: Of 39 personnel contacted, 32 (82%) responded. Most (20; 62%) found the checklist useful. Exercise was the most highly ranked item, whereas watching visual arts was the lowest ranked item. CONCLUSIONS/LESSONS LEARNED: Numerous opportunities were identified to improve the checklist and facilitate achievement of checklist items. Survey data will be used in the next checklist version.

Rapid Transition to Virtual Care during the COVID-19 Epidemic: Experience of a Supportive Care Clinic at a Tertiary Care Cancer Center.

Background: COVID-19 pandemic necessitated rapid adoption of telemedicine at our supportive care center (SCC) to ensure continuity of care while maintaining social distancing. Objective: To document the process of transition from in-person to virtual care. Design: The charts of 1744 consecutive patients in our SCC located in the United States were retrospectively reviewed during the four weeks before transition (February 14-March 12), four weeks after transition (March 20-April 16), and transition week (March 13-March 19). Patient demographics, vital aspects of a supportive care visit such as assessments (Edmonton Symptom Assessment Scale-Financial and Spiritual [ESAS-FS], Cut-down, Annoyed, Guilty, Eye-opener Screen-Adapted to Include Drugs [CAGE-AID], and Memorial Delirium Assessment Scale [MDAS]), interdisciplinary team involvement, and visit type were recorded. Results: In total 763 patients were seen before transition, 168 during the transition week, and 813 after transitioning to virtual care. Patient characteristics, ESAS-FS, CAGE-AID, and nurse assessment did not significantly differ among the three groups. The after-transition group had a small reduction in counseling intervention compared with before (20.2% vs. 26.2%; p = 0.0068). MDAS completion was higher after transition (99.6% vs. 98%; p = 0.007). In-person visits decreased from 100% before to 12.7% after transition (p < 0.0001) and virtual visits increased to 49.3% (video) and 38% (telephone). In-person visits decreased to 49% in the week one, 3% in week two, and <2% in week four after transition (p < 0.0001). Conclusions: Our supportive care team transitioned from in-person care to virtual visits within weeks while maintaining a high patient volume, continuity of care, and adherence to social distancing. Our transition can serve as a model for other centers.

Genetic Factors Associated With Pain Severity, Daily Opioid Dose Requirement, and Pain Response Among Advanced Cancer Patients Receiving Supportive Care.

BACKGROUND: Current understanding of genetic factors associated with pain severity, and improvement of pain with opioids in advanced cancer patients (AC) is inadequate for delivery of personalized pain therapy (PPT). Therefore, the aim of this study was to determine the genetic factors associated with pain severity, daily opioid dose, and pain response in AC patients receiving supportive care. METHODS: In this prospective study, AC patients were eligible if they had cancer pain ≥4/10 on Edmonton Symptom Assessment Scale (ESAS) - Pain Item and needed opioid rotation for pain control by specialist at the outpatient supportive care center. Association of genetic factors with pain phenotype was assessed using logistic regression models and SKATO (Gene-block) analysis. RESULTS: About 174/178 (98%) patient samples were analyzed. After adjustment for demographic and clinical variables, pain severity was negatively associated with intron variant alleles in OPRM1 rs9322446, P = 0.02; rs2270459, P = 0.038; rs62052210, P = 0.038. Opioid daily dose was positively associated NFKBIA rs2233419, P = 0.008; rs2233417, P = 0.007; rs3138054, P = 0.008; rs1050851, P = 0.015; ORPM1 rs9479759, P = 0.046; rs2003185, P = 0.047; rs636433, P = 0.044; COMT (rs9306234, P = 0.014; rs165728, P = 0.014; rs2020917, P = 0.036; rs165728, P = 0.034); ARRB2 (rs1045280, P = 0.045); and pain response to opioids was negatively associated OPRM1 rs1319339, P = 0.024; rs34427887, P = 0.048; and COMT rs4646316, P = 0.03; rs35478083, P = 0.028, respectively. SKATO analysis showed association between pain severity and CXCL8 (P = 0.0056), and STAT6 (P = 0.0297) genes respectively, and pain response with IL-6 (P = 0.00499). CONCLUSIONS: This study identified that SNPs of OPRM1, COMT, NFKBIA, CXCL8, IL-6, STAT6, and ARRB2 genes were associated with pain severity, opioid daily dose, and pain response in AC receiving supportive care. Additional studies are needed to validate our findings for PPT.

A Comparison of Burnout Frequency Among Oncology Physicians and Nurses Working on the Frontline and Usual Wards During the COVID-19 Epidemic in Wuhan, China.

CONTEXT: The epidemic of coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China and has now spread worldwide. In the affected countries, physicians and nurses are under heavy workload conditions and are at high risk of infection. OBJECTIVES: The aim of this study was to compare the frequency of burnout between physicians and nurses on the frontline (FL) wards and those working in usual wards (UWs). METHODS: A survey with a total of 49 questions was administered to 220 medical staff members from the COVID-19 FL and UWs, with a ratio of 1:1. General information, such as age, gender, marriage status, and the Maslach Burnout Inventory-medical personnel, were gathered and compared. RESULTS: The group working on the FLs had a lower frequency of burnout (13% vs. 39%; P < 0.0001) and were less worried about being infected compared with the UW group. CONCLUSION: Compared with medical staff working on their UWs for uninfected patients, medical staff working on the COVID-19 FL ward had a lower frequency of burnout. These results suggest that in the face of the COVID-19 crisis, both FL ward and UW staff should be considered when policies and procedures to support the well-being of health care workers are devised.

Frequency of Burnout Among Palliative Care Physicians Participating in a Continuing Medical Education Course.

CONTEXT: Palliative care (PC) physicians are vulnerable for burnout given the nature of practice. The burnout frequency may be variable and reported between 24% and 38% across different countries. OBJECTIVE: The main objective of our study was to determine the frequency of burnout among PC physicians participating in PC continuing medical education course. METHODS: A survey including the Maslach Burnout Inventory-General along with 41 custom questions were administered to determine the frequency of burnout among physicians attending the 2018 Hospice and Palliative Medicine Board review course. RESULTS: Of 110 physicians, 91 (83%) completed the survey. The median age was 48 years with 65% being females, 81% married, 46% in community practice, 38% in practice for 6-15 years. PC was practiced ≥50% of the time by 62%, and 76% were doing clinical work. About 73 (80%) reported that PC is appreciated at their work, 58 (64%) reported insurance to be a burden, and 58 (64%) reported that the electronic medical record was a burden. About 82 (90%) felt optimistic about continuing PC in future. Maslach Burnout Inventory results suggest that 35 (38%) participants reported at least one symptom of burnout. Only being single/separated showed trend toward significance with burnout (P = 0.056). CONCLUSION: Burnout among PC physicians who attended a board review course was 38%. Being single/separated showed trend toward association with burnout. Physicians who choose to attend continuing medical education may have unique motivating characteristics allowing them to better cope with stress and avoid burnout.

A genetic screen in Drosophila for genes interacting with senseless during neuronal development identifies the importin moleskin.

Senseless (Sens) is a conserved transcription factor required for normal development of the Drosophila peripheral nervous system. In the Drosophila retina, sens is necessary and sufficient for differentiation of R8 photoreceptors and interommatidial bristles (IOBs). When Sens is expressed in undifferentiated cells posterior to the morphogenetic furrow, ectopic IOBs are formed. This phenotype was used to identify new members of the sens pathway in a dominant modifier screen. Seven suppressor and three enhancer complementation groups were isolated. Three groups from the screen are the known genes Delta, lilliputian, and moleskin/DIM-7 (msk), while the remaining seven groups represent novel genes with previously undefined functions in neural development. The nuclear import gene msk was identified as a potent suppressor of the ectopic interommatidial bristle phenotype. In addition, msk mutant adult eyes are extremely disrupted with defects in multiple cell types. Reminiscent of the sens mutant phenotype, msk eyes demonstrate reductions in the number of R8 photoreceptors due to an R8 to R2,5 fate switch, providing genetic evidence that Msk is a component of the sens pathway. Interestingly, in msk tissue, the loss of R8 fate occurs earlier than with sens and suggests a previously unidentified stage of R8 development between atonal and sens.

Integrin Adhesions Suppress Syncytium Formation in the Drosophila Larval Epidermis.

Integrins are critical for barrier epithelial architecture. Integrin loss in vertebrate skin leads to blistering and wound healing defects. However, how integrins and associated proteins maintain the regular morphology of epithelia is not well understood. We found that targeted knockdown of the integrin focal adhesion (FA) complex components ß-integrin, PINCH, and integrin-linked kinase (ILK) caused formation of multinucleate epidermal cells within the Drosophila larval epidermis. This phenotype was specific to the integrin FA complex and not due to secondary effects on polarity or junctional structures. The multinucleate cells resembled the syncytia caused by physical wounding. Live imaging of wound-induced syncytium formation in the pupal epidermis suggested direct membrane breakdown leading to cell-cell fusion and consequent mixing of cytoplasmic contents. Activation of Jun N-terminal kinase (JNK) signaling, which occurs upon wounding, also correlated with syncytium formation induced by PINCH knockdown. Further, ectopic JNK activation directly caused epidermal syncytium formation. No mode of syncytium formation, including that induced by wounding, genetic loss of FA proteins, or local JNK hyperactivation, involved misregulation of mitosis or apoptosis. Finally, the mechanism of epidermal syncytium formation following JNK hyperactivation and wounding appeared to be direct disassembly of FA complexes. In conclusion, the loss-of-function phenotype of integrin FA components in the larval epidermis resembles a wound. Integrin FA loss in mouse and human skin also causes a wound-like appearance. Our results reveal a novel and unexpected role for proper integrin-based adhesion in suppressing larval epidermal cell-cell fusion--a role that may be conserved in other epithelia.

Rapid clearance of epigenetic protein reporters from wound edge cells in Drosophila larvae does not depend on the JNK or PDGFR/VEGFR signaling pathways.

The drastic cellular changes required for epidermal cells to dedifferentiate and become motile during wound closure are accompanied by changes in gene transcription, suggesting corresponding alterations in chromatin. However, the epigenetic changes that underlie wound-induced transcriptional programs remain poorly understood partly because a comprehensive study of epigenetic factor expression during wound healing has not been practical. To determine which chromatin modifying factors might contribute to wound healing, we screened publicly available fluorescently-tagged reporter lines in Drosophila for altered expression at the wound periphery during healing. Thirteen reporters tagging seven different proteins showed strongly diminished expression at the wound edge. Three downregulated proteins, Osa, Kismet, and Spt6, are generally associated with active chromatin, while four others, Sin3A, Sap130, Mi-2, and Mip120, are associated with repressed chromatin. In all cases reporter down regulation was independent of the Jun N-terminal Kinase and Pvr pathways, suggesting that novel signals control reporter clearance. Taken together, our results suggest that clearance of chromatin modifying factors may enable wound edge cells to rapidly and comprehensively change their transcriptional state following tissue damage.

Autophagy drives epidermal deterioration in a Drosophila model of tissue aging.

Organismal lifespan has been the primary readout in aging research. However, how longevity genes control tissue-specific aging remains an open question. To examine the crosstalk between longevity programs and specific tissues during aging, biomarkers of organ-specific aging are urgently needed. Since the earliest signs of aging occur in the skin, we sought to examine skin aging in a genetically tractable model. Here we introduce a Drosophila model of skin aging. The epidermis undergoes a dramatic morphological deterioration with age that includes membrane and nuclear loss. These changes were decelerated in a long-lived mutant and accelerated in a short-lived mutant. An increase in autophagy markers correlated with epidermal aging. Finally, the epidermis of Atg7 mutants retained younger characteristics, suggesting that autophagy is a critical driver of epidermal aging. This is surprising given that autophagy is generally viewed as protective during aging. Since Atg7 mutants are short-lived, the deceleration of epidermal aging in this mutant suggests that in the epidermis healthspan can be uncoupled from longevity. Because the aging readout we introduce here has an early onset and is easily visualized, genetic dissection using our model should identify other novel mechanisms by which lifespan genes feed into tissue-specific aging.