Comparative analysis of symptom burdens and influential factors among diverse terminally-ill patients.

BACKGROUND: The suffering experienced by terminally-ill patients encompasses physiological, psychosocial and spiritual dimensions. While previous studies have investigated symptom burden intensity for specific disease groups, such as cancer or heart failure patients, a research gap exists in understanding major distressing symptoms among diverse terminally-ill patients. This study assessed symptom burden intensity and explored its influential factors among diverse patient disease groups. METHODS: This cross-sectional study utilized the baseline Integrated Palliative care Outcome Scale (IPOS) assessment data. The study participants were terminally-ill patients enrolled in an end-of-life care (EoLC) intervention in Hong Kong. Statistical methods including relative importance index (RII), one-way analysis of variance (ANOVA), and generalized linear regression (GLR) were employed. RESULTS: Final sample consisted of 1,549 terminally-ill patients (mean age =77.4 years, SD =11.6). The five top-rated distressing symptoms among these patients, revealed by the RII analysis, were poor mobility (RII =64.4%), family anxiety (RII =63.5%), sharing feelings with family/friends (RII =61.4%), weakness/lack of energy (RII =58.1%), and hardly feeling at peace (RII =50.7%). One-way ANOVA showed significant differences among the eight disease groups in perceived physical and emotional symptom burden intensity (P<0.05). Analysis of RII symptom scores for each disease group revealed that poor mobility was rated as the most distressing symptom (RII =85.1-62.9%) by patients with motor neurone disease, Parkinson's disease, heart failure, dementia, end-stage renal disease and other serious diseases (including stroke, hematological disease, multiple sclerosis and liver diseases). Perceived family anxiety (RII =66.1%) and shortness of breath (RII =63.8%) were the most distressing symptoms for cancer patients and those with chronic obstructive pulmonary disease, respectively. GLR analysis showed that illness type is the most significant factor influencing the perceived burden intensity in terms of the IPOS total and subscale scores of physical symptoms, emotional symptoms and communication/practical issues. Demographic characteristics such as age, gender, marital status and co-residing status were also identified as influential factors of various symptom categories. However, patients' educational level and relationship with primary caregiver did not significantly influence any perceived symptom burden. CONCLUSIONS: This study provides valuable insights into the symptom burdens experienced by diverse patient disease groups at end-stage of life. The findings highlight the major distressing symptoms of poor mobility, family anxiety, and shortness of breath. Addressing these symptoms is crucial in improving the quality of care for terminally-ill patients. Furthermore, the study identifies influential factors that can affect the perceived intensity of symptom burden, primarily the main type of terminal illness and patient's age. Tailored care support and improved clinical care should be implemented, particularly for high-risk groups such as patients with non-cancer terminal illnesses and older aged patients. These findings contribute to existing literature and emphasize the need for comprehensive and individualized care in EoLC.

Influencing factors of nurses' short-term bereavement reactions after patient death.

An online cross-sectional survey was performed among 181 nurses in mainland China who experienced their most recent patient death within the last month. Multivariate linear regressions were used following bivariate analysis to identify influencing factors for their short-term professional bereavement reactions. More intensive reactions were associated with the nurse's fewer experiences of patient death; the nurse's employment in the intensive care unit rather than the emergency, oncology, geriatrics, or internal medicine departments; and the patient experiencing more pain in the last few days. Higher reaction scores were also reported by nurses who lost the patient more than 1 week prior.

Redefining caregiver strain for family caregivers in end-of-life care in Hong Kong.

OBJECTIVES: Caregiving for family members at their end of life is stressful. Caregivers' strain, burden, or stress has been measured in various geographical and sociodemographic contexts. The concept of stress, burden, and strain are sometimes used interchangeably. By analysing the factor structure of the Chinese version of the Modified Caregiver Strain Index (C-M-CSI), this study aimed to examine the caregiving strain concept and its demographic correlates. METHODS: A sample of 453 family caregivers of patients with a terminal illness in Hong Kong was employed. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed. In addition, generalized linear models (GLM) were used to examine the demographic correlates. RESULTS: The EFA yielded a 3-factor model termed "Perception of Caregiving," "Empathetic Strain," and "Adjustment Demand." This 3-factor model explained 50% of the variance and showed good internal consistency. The CFA confirmed the 3-factor construct with satisfactory internal reliability (χ2 [61, N = 226] = 108.86, p < 0.001, CFI = 0.96, TLI = 0.95, SRMR = 0.04, and RMSEA = 0.06). Inspired by this factor structure and concepts of stress and strain from engineering discipline, a new model of caregiver strain is proposed. Additionally, family caregivers of non-cancer patients, who were not living with the patient, or younger were associated negatively with different dimensions of caregiver strain. SIGNIFICANCE OF RESULTS: The results gave insights into the advancement of the conceptualization of caregiver strain, its multidimensional nature, and process of change, which inform directions for future research and practices.

The Physical and Psychosocial Outcomes of a Psychosocial Home-Based end-of-Life Care Intervention in Hong Kong.

OBJECTIVE: Living the final days of life being cared for at home is a preference expressed by many. The data on the effectiveness of home-based end-of-life care (EoLC) intervention to improve the holistic conditions of terminally ill patients are scanty. This study sought to evaluate a psychosocial home-based EoLC intervention for terminally ill patients in Hong Kong. METHODS: A prospective cohort study was conducted, applying the Integrated Palliative Care Outcome Scale (IPOS) at 3 timepoints (service intake, 1-month, and 3-months after enrollment). A total of 485 eligible, consenting terminally ill people (mean age = 75.48, SD = 11.39) were enrolled, with 40.21% (n = 195) providing data at all 3 timepoints for this study. RESULTS: Decreasing symptom severity scores were observed for all IPOS psychosocial symptoms, and most physical symptoms, over the 3 timepoints. Improvements in depression and practical concerns had the highest omnibus time effects (F > 31.92, P < .01) and T0 to T2 paired comparison effects (Cohen's d > 0.54, P < .01). Physical symptoms of weakness/lack of energy, poor mobility, and poor appetite also showed significant improvements at T1 and T2 (Cohen's d: 0.22-0.46, P < .05). Bivariate regression analyses showed that improvements in anxiety, depression, and family anxiety were associated with improvements in physical symptoms of pain, shortness of breath, weakness/lack of energy, nausea, poor appetite, and poor mobility. Patients' demographic and clinical characteristics were not associated with changes in symptoms. CONCLUSIONS: The psychosocial home-based EoLC intervention effectively improved the psychosocial and physical status of terminally ill patients, irrespective of their clinical characteristics or demographics.

The connections of physical and psychosocial symptoms among patients with terminal illnesses: A network analysis.

BACKGROUND: Patients with terminal illnesses have different symptoms. The goal of palliative care is to alleviate the suffering induced by these symptoms. Available research on symptoms has focused on their prevalence or identification of clusters. Little is known about the central symptoms contributing to the maintenance of the whole system of symptoms or the mechanism of influence between symptoms, particularly between physical and psychosocial symptoms. AIM: The study used network analysis to explore symptom clusters among patients with terminal illnesses and identify the central symptoms, the bridge symptoms, and pathways between physical and psychosocial symptoms. DESIGN AND SETTING/PARTICIPANTS: This is a retrospective cohort study using baseline symptom assessment of 677 adults with terminal illnesses receiving care from the Integrated Community End-of-Life Care Support Teams. RESULTS: Three symptom clusters were identified: physical, psychological, and practical clusters. "Weakness or lack of energy" was identified as the crucial symptom affecting the changes of other symptoms, followed by depression and anxiety. Three connections between the psychological and physical symptoms were identified: anxiety-pain, depression-constipation, and perceived family anxiety-poor appetite pathways. Pathways of practical concern-peace and practical concern-depression were indicated between practical and psychological symptoms. CONCLUSIONS: This study is the first of its kind to investigate the connections and mechanism of influence between symptoms among patients with terminal illnesses. It offers clear pathways for intervention with the most influential symptoms of weakness, anxiety, and depression.

What factors facilitate interprofessional collaboration outcomes in interprofessional education? A multi-level perspective.

OBJECTIVES: Interprofessional education (IPE) harnesses the power of teams to facilitate collaborative learning across disciplines. However, prior research has not paid sufficient attention to the role of team-level factors on IPE outcomes, posing a major theoretical and methodological limitation. In response to this, using social interdependence theory (SIT), this study aimed to delineate the independent contributions of both team-level and student-level interprofessional attitudes (teamwork, roles, and responsibilities; patient-centeredness; and community-centeredness) in predicting IPE collaboration outcomes (goal achievement, team effectiveness, and team performance) employing multi-level analysis. METHODS: To test whether interprofessional attitudes at the team and student levels predict IPE collaboration outcomes, conducted multilevel modeling. We used the pretest and posttest data from 323 healthcare students in Hong Kong from Chinese medicine, medicine, nursing, pharmacy, and social work programmes enrolled in the IPE Cancer module. RESULTS: Among the interprofessional attitudes, "teamwork, roles, and responsibilities" was found to be the best predictor of IPE outcomes, both at the student and team levels. Students who recognized the benefits of shared learning had better goal achievement and team effectiveness. Furthermore, teams that emphasized shared learning also had better overall team performance. CONCLUSIONS: Students' attitudes towards teamwork, roles, and responsibilities in interprofessional collaborative practice, both at the student and team levels, are important to attaining positive student- and team-level outcomes. The study contributes to the expansion of existing knowledge in medical education, theoretically, by adopting SIT as a lens through which collaborative learning in healthcare teams can be understood, and methodologically, by applying multi-level approaches and delineating important student- and team-level predictors of IPE outcomes.

Effectiveness of Educational Programs on Palliative and End-of-life Care in Promoting Perceived Competence Among Health and Social Care Professionals.

BACKGROUND: There is a growing need for palliative care for patients near the end of life and their caregivers. Palliative and end-of-life care (EoLC) education are recommended for all health care (e.g., physicians, nurses, and allied health practitioners) and social care professionals (e.g., social workers) to ensure the quality of services. However, less attention has been afforded to generic, in contrast to specialized, EoLC education. This study evaluated the effectiveness of a series of short-term generic EoLC educational programs for health and social care professionals. METHOD: A pre-post survey design was adopted, focusing on different EoLC core competences. RESULTS: Significant improvement was observed in all perceived competences after the educational programs, regardless of participants' occupation or EoLC experience. Perceived competence in self-care was rated significantly higher than all other competences prior to the programs. Healthcare professionals rated significantly higher on competence in symptom management than social workers. Scores on communication skill and self-care competences were significantly higher following longer (i.e., 16-24 hours) than shorter (i.e., 4-8 hours) programs. CONCLUSION: Generalist palliative/EoLC educational programs may enable health and social care professionals to refresh and extend their knowledge and skills and enhance their perceived competence in providing EoLC. Further research on generalist palliative/EoLC education is needed to examine the impact of continuing training on professionals' actual practice in EoLC and palliative care.

Longitudinal Assessment of Quality of Life Following Molecular Testing for Indeterminate Thyroid Nodules.

BACKGROUND: Molecular testing can refine the risk of malignancy in cytologically indeterminate thyroid nodules and can reduce the need for diagnostic thyroidectomy. However, quality of life (QOL) in patients mananged with molecular testing is not well studied. OBJECTIVE: We aimed to assess the QOL of patients undergoing surveillance after a benign molecular test result, or thyroidectomy after a suspicious molecular test result. METHODS: This prospective longitudinal follow-up of the Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules randomized trial utilized the Thyroid-Related Patient-Reported Outcome, 39-item version (ThyPro-39) to assess the QOL of patients with indeterminate cytology on thyroid fine needle aspiration (FNA) biopsy. All patients underwent molecular testing at the time of initial FNA. A mixed-effect model was used to determine changes in QOL over time. RESULTS: Of 252 eligible patients, 174 completed the assessment (69% response rate). Molecular test results included 72% (n = 124) benign and 28% (n = 50) suspicious. ThyPro-39 scores of benign molecular test patients were unchanged from baseline (following initial FNA and molecular test results) to 18 months of ultrasound surveillance. Baseline symptoms of goiter, anxiety, and depression were more severe for patients with suspicious compared with benign molecular test results. At a median of 8 months after thyroidectomy, suspicious molecular test patients reported improved symptoms of goiter, anxiety, and depression. CONCLUSION: A benign molecular test provides sustained QOL throughout ultrasound surveillance, without worsening anxiety or depression relating to the risk of malignancy. Definitive surgery results in improvement of QOL in patients with suspicious molecular tests.

Comparing the efficacy of integrative body-mind-spirit intervention with cognitive behavioral therapy in patient-caregiver parallel groups for lung cancer patients using a randomized controlled trial.

Purposes/objectives: This paper reports the comparative efficacies of integrative body-mind-spirit intervention (I-BMS) and cognitive behavioral therapy (CBT) in patient-caregiver parallel groups for Chinese patients with lung cancer.Design: Randomized controlled trial (RCT).Methods: One hundred and fifty-seven patient-caregiver dyads with no marked functional impairment were randomized into one of the two interventions with eight weekly patient-caregiver parallel groups. Assessments were conducted at baseline, within one, eight- and sixteen-weeks post-intervention. Effects of treatment group across time were analyzed by multilevel modeling.Findings: CBT led to greater reduction in emotional vulnerability than I-BMS. I-BMS resulted in greater increase in overall QoL and spiritual self-care, and more reduction in depression than CBT. Patients in both interventions experienced improvement in physical, emotional and spiritual, except social, domains of QoL.Conclusion: I-BMS was more efficacious for diverse domains of QoL, and CBT was more effective for emotional well-being, despite the relatively small between-group effect sizes.Implications for psychosocial providers/policy: (1) With the expanding repertoire of psychosocial interventions for families facing lung cancer, it has become imperative to investigate the comparative efficacies of empirically supported and culturally adapted interventions. (2) Our findings show that I-BMS was more effective for diverse domains of QoL, while CBT was more efficacious with emotional well-being, although both interventions led to significant improvements in physical, emotional and spiritual domains of patient QoL. (3) Patient-caregiver parallel groups have been shown to be effective for enhancing QoL of Chinese lung cancer patients. (4) Care professionals are encouraged to dispense interventions based on the idiosyncratic needs and preferences of the patients to maximize the treatment effects.

Comparing dyadic cognitive behavioral therapy (CBT) with dyadic integrative body-mind-spirit intervention (I-BMS) for Chinese family caregivers of lung cancer patients: a randomized controlled trial.

PURPOSE: The study adopted a randomized controlled trial to compare the effect of culturally compatible psychosocial interventions on multiple aspects of quality of life (QoL) for family caregivers of lung cancer patients. METHODS: 157 Chinese informal caregivers of lung cancer patients were recruited together with the family members for whom they were providing care, and randomly assigned to either integrative body-mind-spirit intervention (I-BMS) or cognitive behavioral therapy (CBT). Patient-caregiver dyads attended the same arm of intervention in separate groups for 8 weeks. Assessments of generic QoL, anxiety, depression, perceived stress, insomnia, and caregiving burden were measured before intervention (T0), within 1-week (T1), 8-week (T2), and 16-week (T3) post-intervention. RESULTS: Adopting the intention-to-treat analysis, family caregivers in receipt of both I-BMS and CBT exhibited a statistically significant improvement in generic QoL immediately following intervention and at follow-up assessments, with moderate effect size. Improvement of insomnia was found at T1 for both modes, which deteriorated at follow-up; both modes reduced anxiety and perceived stress at follow-up. No intervention effect was observed in depression and domains of caregiving burden. There was no significant interaction effect between intervention type and time. No main or interaction effect between sample background variables and intervention type was found to predict symptomatic changes at T1 and T3. CONCLUSIONS: Culturally attuned I-BMS and CBT exhibited equivalent effectiveness in improving psychological distress and generic QoL for family caregivers of lung cancer patients. To improve the evaluation of outcomes, future study could benefit from incorporating a usual care control.

What Patients, Families, Health Professionals and Hospital Volunteers Told Us about Advance Directives.

OBJECTIVE: An advance directive (AD) is a document that allows mentally competent individuals to make healthcare decisions about their condition that they might no longer be able to make in the future. This study aimed to explore the perceptions of AD decision-making of various stakeholders in the Chinese palliative care setting. METHODS: Patients with life-limiting diseases, family members, health professionals, and hospital volunteers were recruited in the palliative care unit of two hospitals in Hong Kong by purposive sampling on age and sex. Qualitative semi-structured individual interviews were conducted. RESULTS: A total of 96 participants, including 24 participants from each group, completed the study. Most participants were willing to discuss AD but had not heard about it before the interview. Patients regarded the decisions made in the AD as a way to reduce their future sufferings, while they also considered the welfare of their family. Family members were concerned about the psychological burden when discussing about the AD. Health professionals emphasized the logistic and process of the AD. Hospital volunteers pointed out the impact of Chinese culture on AD acceptance and the lack of AD promotion in the community. CONCLUSIONS: The findings of the study indicated the need for more promotion of AD in the society. It is important to consider the opinion of a patient's family during AD discussions in a Chinese culture. Health professionals may need to identify the best timing for the discussion of AD with patients and their families.

Facing death alone or together? Investigating the interdependence of death anxiety, dysfunctional attitudes, and quality of life in patient-caregiver dyads confronting lung cancer.

BACKGROUND: Based on the cognitive theory, anxiety arising from the awareness of death and dying may activate dysfunctional attitudes, which may then reduce quality of life. This study examined the interdependence and the mediating role of dysfunctional attitudes on the relationship between death anxiety and quality of life among patients with lung cancer and their caregivers. METHODS: From March 2016 to April 2017, 173 pairs of patients and their caregivers enrolled in a randomized controlled trial of psychosocial support. Using the baseline data, actor-partner interdependence modeling was used to analyze the relationships among death anxiety, dysfunctional attitudes, and quality of life. RESULTS: In patients, death anxiety was related to dependency (ß = .51) and self-control (ß = -.37); achievement (ß = -.21) and self-control (ß = .34) were related to quality of life. Among caregivers, death anxiety was related to all 3 dysfunctional attitudes of their own (ßs = .23 to.32); dependency (ß = -.22) was associated with quality of life. Caregiver quality of life was also associated with patient self-control (ß = .22) and achievement (ß = -.18). Patient self-control mediated the links between patient death anxiety with both patient and caregiver quality of life. The relationship between death anxiety and quality of life was mediated by dependency in caregivers. DISCUSSION: Death anxiety influences dysfunctional attitudes and quality of life of both patients and caregivers. Our results support the relevance of dysfunctional attitudes in understanding the impact of death anxiety and underscore the need for parallel psychosocial interventions.

Study protocol of a randomized controlled trial comparing integrative body-mind-spirit intervention and cognitive behavioral therapy in fostering quality of life of patients with lung cancer and their family caregivers.

Compared to cancers at other sites, lung cancer often results in greater psychosocial distress to both the patients and their caregivers, due to the poor prognosis and survival rate, as well as the heavy symptom burden. In recent years, making protocols of proposed or on-going studies publicly available via clinical trial registries and/or peer-reviewed journals has benefited health sciences with timely communication of the latest research trends and improved transparency in reporting. However, such practice is yet to be a common sight in evidence-informed social work. Hence, this paper discusses the value of publishing protocols in social work research and presents the protocol of a randomized controlled trial that compares the effectiveness of integrative body-mind-spirit intervention with cognitive behavioral therapy for enhancing quality of life of patients with lung cancer and their family caregivers. The data collection process was still on-going at the time of manuscript submission.

Social workers' involvement in advance care planning: a systematic narrative review.

BACKGROUND: Advance care planning is a process of discussion that enables competent adults to express their wishes about end-of-life care through periods of decisional incapacity. Although a number of studies have documented social workers' attitudes toward, knowledge about, and involvement in advance care planning, the information is fragmented. The purpose of this review was to provide a narrative synthesis of evidence on social workers' perspectives and experiences regarding implementation of advance care planning. METHODS: Six databases were searched for peer-reviewed research papers from their respective inception through December 2016. All of the resulting studies relevant to both advance care planning and social worker were examined. The findings of relevant studies were synthesized thematically. RESULTS: Thirty-one articles met the eligibility criteria. Six research themes were identified: social workers' attitudes toward advance care planning; social workers' knowledge, education and training regarding advance care planning; social workers' involvement in advance care planning; social workers' perceptions of their roles; ethical issues relevant to advance care planning; and the effect of social work intervention on advance care planning engagement. The findings suggest that there is a consensus among social workers that advance care planning is their duty and responsibility and that social workers play an important role in promoting and implementing advance care planning through an array of activities. CONCLUSIONS: This study provides useful knowledge for implementing advance care planning through illustrating social workers' perspectives and experiences. Further studies are warranted to understand the complexity inherent in social workers' involvement in advance care planning for different life-limiting illnesses or within different socio-cultural contexts.

The effects of life review interventions on spiritual well-being, psychological distress, and quality of life in patients with terminal or advanced cancer: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Life review interventions have been used to alleviate psycho-spiritual distress in people near the end of life. However, their effectiveness remains inconclusive. AIM: To evaluate the effects of therapeutic life review on spiritual well-being, psychological distress, and quality of life in patients with terminal or advanced cancer. DESIGN: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. DATA SOURCES: Five databases were searched from their respective inception through February 2017 for relevant randomized controlled trials. The effects of therapeutic life review were pooled across the trials. Standardized mean differences were calculated for the pooled effects. Heterogeneity was assessed using the I2 test. Study quality was assessed using the Cochrane criteria. RESULTS: Eight randomized controlled trials met the inclusion criteria. The pooled results suggested a desirable effect of therapeutic life review on the meaning of life domain of spiritual well-being (standardized mean difference = 0.33; 95% confidence interval, 0.12 to 0.53), general distress (standardized mean difference = -0.32; 95% confidence interval, -0.55 to -0.09), and overall quality of life (standardized mean difference = 0.35; 95% confidence interval, 0.15 to 0.56) when compared to usual care only. Of the three outcomes examined, only the pooled effect on overall quality of life remained statistically significant at follow-ups up to 3 months after the intervention (standardized mean difference = 0.82; 95% confidence interval, 0.47 to 1.18). CONCLUSIONS: Therapeutic life review is potentially beneficial for people near the end of life. However, the results should be interpreted with caution due to the limited number of randomized controlled trials and associated methodological weaknesses. Further rigorously designed randomized controlled trials are warranted.

Dyadic associations between psychological distress and sleep disturbance among Chinese patients with cancer and their spouses.

BACKGROUND: Patients with cancer and their spouses usually both suffer, but the dyadic effects have not been thoroughly investigated. This study examined the dyadic effects of psychological distress on sleep disturbance in Chinese couples affected by cancer. METHODS: Patients with cancer and their spouses (N = 135) participated in this study. The Hospital Anxiety and Depression Scale and Pittsburgh Sleep Quality Index were used to measure anxiety, depression, and sleep disturbance. RESULTS: There were significant patient-spouse associations on anxiety (r = 0.48, P < .01), depression (r = 0.55, P < .01), and sleep disturbance (r = 0.30, P < .01). Analyses using the actor-partner interdependence model showed that anxiety had significant actor effects, rather than partner effects, on sleep disturbance in both patients and their spouses, but depression had both actor and partner effects. In addition to providing evidence for the concordance in distress and sleep disturbance in patients with cancer and their spouses, the findings indicate a mutual influence of depression on sleep disturbance among the couples. CONCLUSIONS: Clinicians and health care providers are suggested to integrate depression management as a component of sleep therapies and involve both patients and their spouses in treatment programs.

Socioeconomic status and utilization of amblyopia services at a tertiary pediatric hospital in Canada.

OBJECTIVE: To evaluate whether socioeconomic status is associated with equal utilization of amblyopia services at The Hospital for Sick Children (SickKids), a pediatric tertiary hospital in Canada. DESIGN: This is a retrospective, cross-sectional study. PARTICIPANTS: The medical records of children aged under 7 years diagnosed with amblyopia at SickKids from 2007 to 2009 were reviewed. METHODS: Socioeconomic status was derived from patients' residential postal codes through linking with income data in the 2006 Canadian census report. Patients were divided into 5 income quintiles to compare with amblyopia service utilization. The main outcome measure was the observed distribution of amblyopia patients by socioeconomic status versus the expected distribution of 20% for each quintile. RESULTS: The analyses included 336 patients. Children with amblyopia at SickKids were more likely to come from the richest neighbourhood (32.5%), whereas children from each of the 3 lowest quintiles (14.6%-15.5%) were less likely to present at SickKids. These results differed significantly from the expected 20% for each quintile (p < 0.0001). All types of amblyopia were significantly under-represented for children from the lower socioeconomic groups. When analyses were stratified by travel distance to the hospital, a significant inequality between the lower and higher income quintiles remained for nonmetropolitan Toronto patients, but not for metropolitan Toronto patients. CONCLUSION: Despite a publicly funded health-care system in Canada, children from lower socioeconomic neighbourhoods in distant areas utilize the amblyopia services in a tertiary pediatric centre less often than those from higher socioeconomic status.

m(6)A RNA methylation promotes XIST-mediated transcriptional repression.

The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues-a reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression.

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis.

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients, and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the premetastatic niche. Mechanistically, cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase. In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that, by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.

Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.

Growing evidence links tumor progression with chronic inflammatory processes and dysregulated activity of various immune cells. In this study, we demonstrate that various types of macrophages internalize microvesicles, called exosomes, secreted by breast cancer and non-cancerous cell lines. Although both types of exosomes targeted macrophages, only cancer-derived exosomes stimulated NF-κB activation in macrophages resulting in secretion of pro-inflammatory cytokines such as IL-6, TNFα, GCSF, and CCL2. In vivo mouse experiments confirmed that intravenously injected exosomes are efficiently internalized by macrophages in the lung and brain, which correlated with upregulation of inflammatory cytokines. In mice bearing xenografted human breast cancers, tumor-derived exosomes were internalized by macrophages in axillary lymph nodes thereby triggering expression of IL-6. Genetic ablation of Toll-like receptor 2 (TLR2) or MyD88, a critical signaling adaptor in the NF-κB pathway, completely abolished the effect of tumor-derived exosomes. In contrast, inhibition of TLR4 or endosomal TLRs (TLR3/7/8/9) failed to abrogate NF-κB activation by exosomes. We further found that palmitoylated proteins present on the surface of tumor-secreted exosomes contributed to NF-κB activation. Thus, our results highlight a novel mechanism used by breast cancer cells to induce pro-inflammatory activity of distant macrophages through circulating exosomal vesicles secreted during cancer progression.