Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis.

Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFκB p65 cascade was performed by Western blot. The secretion of cytokines IL-1ß, IL-6, IL-10 and TNFα was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFκB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1ß, IL-6, IL-10 and TNFα was induced by silica exposure and the induction of IL-1ß, IL-6 and TNFα was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFκB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis.

Cost-effectiveness of a transitional home-based palliative care program for patients with end-stage heart failure.

BACKGROUND: Studies have shown positive clinical outcomes of specialist palliative care for end-stage heart failure patients, but cost-effectiveness evaluation is lacking. AIM: To examine the cost-effectiveness of a transitional home-based palliative care program for patients with end-stage heart failure patients as compared to the customary palliative care service. DESIGN: A cost-effectiveness analysis was conducted alongside a randomized controlled trial (Trial number: NCT02086305). The costs included pre-program training, intervention, and hospital use. Quality of life was measured using SF-6D. SETTING/PARTICIPANTS: The study took place in three hospitals in Hong Kong. The inclusion criteria were meeting clinical indicators for end-stage heart failure patients including clinician-judged last year of life, discharged to home within the service area, and palliative care referral accepted. A total of 84 subjects (study = 43, control = 41) were recruited. RESULTS: When the study group was compared to the control group, the net incremental quality-adjusted life years gain was 0.0012 (28 days)/0.0077 (84 days) and the net incremental costs per case was -HK$7935 (28 days)/-HK$26,084 (84 days). The probability of being cost-effective was 85% (28 days)/100% (84 days) based on the cost-effectiveness thresholds recommended both by National Institute for Health and Clinical Excellence (£20,000/quality-adjusted life years) and World Health Organization (Hong Kong gross domestic product/capita in 2015, HK$328117). CONCLUSION: Results suggest that a transitional home-based palliative care program is more cost-effective than customary palliative care service. Limitations of the study include small sample size, study confined to one city, clinic consultation costs, and societal costs including patient costs and unpaid care-giving costs were not included.

Effects of a transitional palliative care model on patients with end-stage heart failure: a randomised controlled trial.

OBJECTIVE: To examine the effects of home-based transitional palliative care for patients with end-stage heart failure (ESHF) after hospital discharge. METHODS: This was a randomised controlled trial conducted in three hospitals in Hong Kong. The recruited subjects were patients with ESHF who had been discharged home from hospitals and referred for palliative service, and who met the specified inclusion criteria. The interventions consisted of weekly home visits/telephone calls in the first 4 weeks then monthly follow-up, provided by a nurse case manager supported by a multidisciplinary team. The primary outcome measures were any readmission and count of readmissions within 4 and 12 weeks after index discharge, compared using χ(2) tests and Poisson regression, respectively. Secondarily, change in symptoms over time between control and intervention groups were evaluated using generalised estimating equation analyses of data collected using the Edmonton Symptom Assessment Scale (ESAS). RESULTS: The intervention group (n=43) had a significantly lower readmission rate than the control group (n=41) at 12 weeks (intervention 33.6% vs control 61.0% χ(2)=6.8, p=0.009). The mean number (SE) of readmissions for the intervention and control groups was, respectively, 0.42 (0.10) and 1.10 (0.16) and the difference was significant (p=0.001). The relative risk (CI) for 12-week readmissions for the intervention group was 0.55 (0.35 to 0.88). There was no significant difference in readmissions between groups at 4 weeks. However, when compared with the control group, the intervention group experienced significantly higher clinical improvement in depression (45.9% vs 16.1%, p<0.05), dyspnoea (62.2% vs 29.0%, p<0.05) and total ESAS score (73.0% vs 41.4%, p<0.05) at 4 weeks. There were significant differences between groups in changes over time in quality of life (QOL) measured by McGill QOL (p<0.05) and chronic HF (p<0.01) questionnaires. CONCLUSIONS: This study provides evidence of the effectiveness of a postdischarge transitional care palliative programme in reducing readmissions and improving symptom control among patients with ESHF. TRIAL REGISTRATION NUMBER: HKCTR-1562; Results.

Intensive palliative care for patients with hematological cancer dying in hospice: analysis of the level of medical care in the final week of life.

Dying of hematological oncology patients often take place in respective hematology ward or intensive care unit rather than hospice. With the increased attention to quality palliative care for hematology patients, concerns regarding their level of medical care at end-of-life need to be addressed. We conducted a retrospective review of consecutive hematological oncology patients who succumbed in a palliative unit between July 2012 and August 2013. The primary outcome measure was their level of medical care received, including administration of antibiotics, total parenteral nutrition, blood sampling, GCSF injection and blood products transfusion, during their last seven days of life. During the last seven days of life, 85.7 % of patients had blood sampling and 23.8% of patients received G-CSF injection. Total parenteral nutrition was administered in 14.3% of patients. One-third of patients received transfusion of packed cells and nearly half of them received transfusion of platelet concentrates. Almost 90% of patients received antibiotics during their last week of life. Collaboration between hematology and palliative care has resulted in successful transition of hematologic cancer patients into hospice unit in their terminal phase of illness. However, their level of medical care, even approaching last seven days of life, remained intensive. Proper allocation of medical resources and future research regarding optimal end-of-life care for hematology patients are warranted.