A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day -1. All patients received T-cell-replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

Malnutrition and clinical outcomes post alloSCT.

BACKGROUND: Malnutrition has been linked with higher risk of poor outcomes post-allogeneic stem cell transplantation (alloSCT); however, few studies have used a validated nutrition assessment tool such as the Patient Generated Subjective Global Assessment (i.e., PG-SGA) to measure nutritional status and investigate associations with long-term clinical outcomes. The present study aimed to assess the incidence of malnutrition prior to alloSCT and determine whether there was an association between nutritional status pre-transplant and post-transplant clinical outcomes including acute kidney injury, graft-versus-host disease, intensive care admission, need for haemodialysis and survival. METHODS: A retrospective analysis of 362 patients (213 males:149 females, mean ± SD age = 47.8 ± 14.1 years) who underwent alloSCT from 2008 to 2013 was conducted. Data on clinical outcomes were obtained for 5 years post-transplant. RESULTS: Fifteen percent (n = 56) of patients were identified as malnourished pre-admission. Malnutrition was associated with longer hospital stay (p = 0.007), increased requirement for haemodialysis (p = 0.016) and increased admissions to the intensive care unit (p = 0.003). There was no association between malnutrition and acute kidney injury, graft-versus-host disease or survival. Following multivariate analyses, malnutrition remained significantly associated with increased admission rates to the intensive care unit (odds ratio = 3.8, 95% confidence interval = 1.3-10.5, p = 0.011) and increased length of hospital stay > 30 days (odds ratio = 3.6. 95% confidence interval = 1.8-7.4, p ≤ 0.001). CONCLUSIONS: These findings add importance to the need for nutrition screening and assessment to be routinely undertaken for patients prior to alloSCT and throughout hospitalisation to provide early nutrition intervention for the prevention of malnutrition, poor clinical outcomes and increased healthcare costs.

Navajo Nation Stores Show Resilience During COVID-19 Pandemic.

On April 8, 2020, the Navajo Nation issued an administrative order limiting business operations. Facing high coronavirus disease 2019 (COVID-19) rates and limited food infrastructure, a survey was conducted among Navajo Nation store managers to assess: (1) COVID-19 adaptations; (2) challenges; (3) changes in customer volume and purchasing; and (4) suggestions for additional support. Purposive sampling identified 29 stores in Navajo communities. Representatives from 20 stores (19 store managers/owners, 1 other; 7 grocery, and 13 convenience/other stores) were interviewed by phone or in-person to reach saturation (new information threshold < 5%). Responses were coded using frequencies and inductive thematic analysis. All 20 stores implemented COVID-19 guidelines (Centers for Disease Control and Prevention [CDC]/Navajo Nation) and most received orientation/support from local chapters, community organizations, or health centers. Stores implemented staff policies (50%, handwashing, vaccinations, protective personal equipment (PPE), sick leave, temperature checks), environmental changes (50%, hand sanitizer, checkout dividers), customer protocols (40%, limit customers, mask requirements, closed restrooms), and deep cleaning (40%). Most stores (65%) reported challenges including stress/anxiety, changing guidelines, supply chain and customer compliance; 30% reported infection or loss of staff. Weekday customer volume was slightly higher vs. pre-COVID, but weekend lower. Stores reported consistent or more healthy food purchases (50%), more nonfood essentials (20%), or shelf-stable foods (10%). Desired support included further orientation (30%), leadership support (20%), overtime/time to learn guidelines (20%), and signage/handouts (15%). Despite a high COVID-19 burden and limited food store infrastructure, Navajo Nation stores adapted by implementing staff, environmental and customer policies. Local support, staffing, and small store offerings were key factors in healthy food access.

Implementation of Indigenous Food Tax Policies in Stores on Navajo Nation.

In 2014, the Navajo Nation Healthy Diné Nation Act (HDNA) was enacted and permanently approved in 2020; HDNA places a 2% surtax on unhealthy foods and beverages, while other 2014 legislation exempted healthy food items from the 6% regular sales tax. Little is known about Navajo Nation store manager/owner perspectives toward the HDNA and how best to support stores to implement the legislation. Purposive sampling was used to ensure a balanced sample of correct HDNA implementers, incorrect HDNA implementers, and stores which made healthy store changes over the past 6 years. Three community-based interviewers collected surveys by phone or in-person. Frequency of closed-ended questions was quantified, and open-ended responses were coded using thematic analysis. Of 29 identified sample stores, 20 were interviewed to reach saturation. Eleven of 20 stores made changes improving their healthy food environments. Barriers included lack of equipment (6/20) and low consumer demand (5/20). Facilitators included consumer awareness and increased produce supply options (5/20). Sixteen of 20 stores supported HDNA continuation. Facilitators to HDNA implementation included orientation and informational materials (6/20) and promotion of tax-free items (5/20). Barriers included confusion about the tax (6/20) and tax exemption (5/20). Suggestions for support included printed materials (6/20) and store training (5/20). HDNA benefits included greater awareness of healthy choices among staff (7/20) and customer-community members (2/20). Most managers and owners expressed receiving support for healthy store changes and HDNA, but also identified a need for added resources and support. Findings inform legislative action to promote timely and appropriate uptake of HDNA, and support equitable, healthy food systems.

Bacterial Contact-Dependent Inhibition Protein Binds near the Open Lateral Gate in BamA Prior to Toxin Translocation.

Contact-dependent inhibition (CDI) is a mechanism of interbacterial competition in Gram-negative bacteria. The critical component of CDI systems is a large protein named CdiA; it forms a filament on the bacterial cell surface and contains a toxin domain at its C-terminal end. Upon binding to a receptor protein on the surface of a neighboring cell, CdiA delivers the toxin domain through the outer membrane of the neighboring bacterium. The mechanism of that delivery process is poorly understood. We have characterized how CdiA from E. coli EC93 binds to its receptor, BamA, to understand how this binding event might initiate the process of toxin delivery. BamA is an essential protein that assembles ß-barrel proteins into the outer membranes of all Gram-negative bacteria; this assembly process depends on BamA's unique ability to open laterally in the lipid bilayer through a gate in its own membrane-embedded ß-barrel. Through site-specific photo-cross-linking and mutational analysis, we demonstrate that the BamA-CdiA interaction depends on a small number of non-conserved amino acids on the extracellular surface of BamA, but the protein interface extends over a region near BamA's lateral gate. We further demonstrate that BamA's lateral gate can open without disrupting the interaction with CdiA. CdiA thus appears to initially engage BamA in a manner that could allow it to utilize BamA's lateral gate in subsequent steps in the toxin translocation process.

Community-based outreach associated with increased health utilization among Navajo individuals living with diabetes: a matched cohort study.

BACKGROUND: Navajo community members face high rates of diabetes mellitus and other chronic diseases. The Navajo Community Health Representative Outreach Program collaborated with healthcare providers and academic partners to implement structured and coordinated outreach to patients living with diabetes. The intervention, called Community Outreach and Patient Empowerment or COPE, provides home-based health coaching and community-clinic linkages to promote self-management and engagement in healthcare services among patients living with diabetes. The purpose of this study was to evaluate how outreach by Navajo Community Health Representatives ("COPE Program") affected utilization of health care services among patients living with diabetes. METHODS: De-identified data from 2010 to 2014 were abstracted from electronic health records at participating health facilities. In this observational cohort study, 173 cases were matched to 2880 controls. Healthcare utilization was measured as the number of times per quarter services were accessed by the patient. Changes in utilization over 4 years were modeled using a difference-in-differences approach, comparing the trajectory of COPE patients' utilization before versus after enrollment with that of the control group. The model was estimated using generalized linear mixed models for count outcomes, controlling for clustering at the patient level and the service unit level. RESULTS: COPE enrollees showed a 2.5% per patient per quarter (pppq) greater increase in total utilization (p = 0.001) of healthcare services than non-COPE enrollees; a 3.2% greater increase in primary care visits (p = 0.024); a 6.3% greater increase in utilization of counseling and behavioral health services (p = 0.013); and a 9.0% greater increase in pharmacy visits (p <  0.001). We found no statistically significant differences in utilization trends of inpatient, emergency room, specialty outpatient, dental, laboratory, radiology, or community encounter services among COPE participants versus control. CONCLUSIONS: A structured intervention consisting of Community Health Representative outreach and coordination with clinic-based providers was associated with a modest increase in health care utilization, including primary care and counseling services, among Navajo patients living with diabetes. Community health workers may provide an important linkage to enable patients to access and engage in clinic-based health care. TRIAL REGISTRATION: NCT03326206, registered 10/31/2017, retrospectively registered.

Qualitative evaluation of a community health representative program on patient experiences in Navajo Nation.

BACKGROUND: Community Health Representatives (CHRs) overcome health disparities in Native communities by delivering home care, health education, and community health promotion. The Navajo CHR Program partners with the non-profit Community Outreach and Patient Empowerment (COPE), to provide home-based outreach to Navajo clients living with diabetes. COPE has created an intervention (COPE intervention) focusing on multiple levels of improved care including trainings for CHRs on Motivational Interviewing and providing CHRs with culturally-appropriate education materials. The objective of this research is to understand the participant perspective of the CHR-COPE collaborative outreach through exploring patient-reported outcomes (PROs) of clients who consent to receiving the COPE intervention (COPE clients) using a qualitative methods evaluation. METHODS: Seven COPE clients were selected to participate in semi-structured interviews one year after finishing COPE to explore their perspective and experiences. Qualitative interviews were recorded, transcribed, and coded to identify themes. RESULTS: Clients revealed that health education delivered by CHRs facilitated lifestyle changes by helping them understand key health indicators and setting achievable goals through the use of accessible material and encouragement. Clients felt comfortable with CHRs who respected traditional practices and made regular visits. Clients also appreciated when CHRs educated their family members, who in turn were better able to support the client in their health management. Finally, CHRs who implemented the COPE intervention helped patients who were unable to regularly see a primary care doctor for critical care and support in their disease management. CONCLUSION: The COPE-CHR collaboration facilitated trusting client-CHR relationships and allowed clients to better understand their diagnoses. Further investment in materials that respect traditional practices and aim to educate clients' families may foster these relationships and improve health outcomes. TRIAL REGISTRATION: clinicaltrials.gov: NCT03326206. Registered 9/26/2017 (retrospectively registered).

Community Outreach for Navajo People Living with Diabetes: Who Benefits Most?

INTRODUCTION: The Community Outreach and Patient Empowerment (COPE) intervention provides integrated outreach through community health representatives (CHRs) to people living with diabetes in Navajo Nation. The aim of this study was to identify groups for whom the intervention had the greatest effect on glycated hemoglobin A1c (HbA1c). METHODS: We analyzed de-identified data extracted from routine health records dated from December 1, 2010, through August 31, 2014, to compare net change in HbA1c among COPE patients and non-COPE patients. We used linear mixed models to assess whether the intervention was modified by age, sex, preferred language, having a primary care provider, baseline HbA1c, or having a mental health condition. RESULTS: Age, having a primary care provider, and baseline HbA1c significantly modified HbA1c levels. Among patients aged 64 or younger, COPE participation was associated with a net decrease in HbA1c of 0.77%; among patients aged 65 or older, the net decrease was 0.49% (P = .03). COPE participation was associated with a steeper decrease in HbA1c among patients without a primary care physician (net decrease, 0.99%) than among patients with a primary care provider (net decrease, 0.57%) (P = .03). COPE patients with a baseline HbA1c >9% had a net decrease of 0.70%, while those with a baseline HbA1c ≤9% had a net decrease of 0.34% (P = .01). We found no significant differences based on sex, preferred language, or having a mental health condition. CONCLUSION: Findings suggest that the COPE intervention was robust and equitable, benefiting all groups living with diabetes in Navajo Nation, but conferring the greatest benefit on the most vulnerable.

Integrating community health representatives with health care systems: clinical outcomes among individuals with diabetes in Navajo Nation.

BACKGROUND: We studied the impact of Community Outreach and Patient Empowerment (COPE) intervention to support Community Health Representatives (CHR) on the clinical outcomes of patients living with diabetes in the Navajo Nation extending into the States of Arizona, Utah, and New Mexico. The COPE intervention integrated CHRs into healthcare teams by providing a structured approach to referrals and home visits. METHODS: We abstracted routine clinical data from the Indian Health Service's information system on individuals with diabetes mellitus seen at participating clinical sites from 2010 to 2014. We matched 173 COPE participants to 2880 patients with similar demographic and clinical characteristics who had not participated in COPE. We compared the changes in clinical outcomes between the two groups using linear mixed models. RESULTS: Over the four years of the study, COPE patients had greater improvements in glycosylated hemoglobin (- 0.56%) than non-COPE participants (+ 0.07%) for a difference in differences of 0.63% (95% confidence interval (CI): 0.50, 0.76). Low-density lipoprotein fell more steeply in the COPE group (- 10.58 mg/dl) compared to the non-COPE group (- 3.18 mg/dl) for a difference in differences of 7.40 mg/dl (95%CI: 2.00, 12.80). Systolic blood pressure increased slightly more among COPE (2.06 mmHg) than non-COPE patients (0.61 mmHg). We noted no significant change for body mass index in either group. CONCLUSION: Structured outreach by Community Health Representatives as part of an integrated care team was associated with improved glycemic and lipid levels in the target Navajo population. TRIAL REGISTRATION: Trial registration: NCT03326206. Registered 31 October 2017 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT03326206.

Correction to: Glycemic control and healthcare utilization following pregnancy among women with pre-existing diabetes in Navajo Nation.

In the original publication of this article [1] an author's name needs to be revised from Katrina Nelson to Adrianne Katrina Nelson.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Glycemic control and healthcare utilization following pregnancy among women with pre-existing diabetes in Navajo Nation.

BACKGROUND: Native American communities experience greater burden of diabetes than the general population, including high rates of Type 2 diabetes among women of childbearing age. Diabetes in pregnancy is associated with risks to both the mother and offspring, and glycemic control surrounding the pregnancy period is of vital importance. METHODS: A retrospective chart review was conducted at a major Navajo Area Indian Health Service (IHS) hospital, tracking women with pre-existing diabetes who became pregnant between 2010 and 2012. Logistic regression was performed to find patient-level predictors of our desired primary outcome-having hemoglobin A1c (HbA1c) consistently < 8% within 2 years after pregnancy. Descriptive statistics were generated for other outcomes, including glycemic control and seeking timely IHS care. RESULTS: One hundred twenty-two pregnancies and 114 individuals were identified in the dataset. Baseline HbA1c was the only covariate which predicted our primary outcome (OR = 1.821, 95% CI = 1.184-2.801). Examining glycemic control among pregnancies with complete HbA1c data (n = 59), 59% were controlled before, 85% during, and 34% after pregnancy. While nearly all women received care in the immediate postpartum period, only 49% of women visited a primary care provider and 71% had HbA1c testing in the 2 years after pregnancy. CONCLUSIONS: This is the first analysis of outcomes among women with diabetes in pregnancy in Navajo Nation, the largest reservation and tribal health system in the United States. Our findings demonstrate the positive impact of specialized prenatal care in achieving glycemic control during pregnancy, while highlighting the challenges in maintaining glycemic control and continuity of healthcare after pregnancy.

A randomized trial of olanzapine versus palonosetron versus infused ondansetron for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients undergoing hematopoietic stem cell transplantation.

PURPOSE: The primary aim of this study was to compare the effectiveness of olanzapine, palonosetron and ondansetron infusion (standard of care) for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients undergoing hematopoietic stem cell transplantation (HSCT). METHOD: It was a randomized open-label prospective study. Sixty-two patients were randomized to receive either ondansetron 32-mg infusion over 24 h, or olanzapine wafer 10 mg once daily in addition to ondansetron 8 mg IV three times a day or a single dose of palonosetron 0.25 mg IV instead of ondansetron. All groups were allowed rescue antiemetics. The primary endpoint was a composite outcome of no emesis, no use of rescue medication, and nausea score reduction of ≥50 %. The secondary endpoint was nausea score reduction of ≥50 %. Both endpoints were measured at 24 and 48 h after initiation of the study treatment. Statistical analysis was conducted using a double-sided Fisher's exact test. RESULT: The primary endpoint was achieved in 6, 45, and 18 %, and 6, 64, and 18 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. The secondary outcome was observed in 17, 60, and 62 %, and 35, 71, and 43 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. Serious adverse drug reactions were not reported in any arms. Time to engraftment was not significantly different between the arms. CONCLUSIONS: Olanzapine was an effective treatment of breakthrough CINV. A single dose of palonosetron significantly reduced nausea up to 24 h.

Use of brentuximab vedotin as salvage therapy pre-allogeneic stem cell transplantation in relapsed/refractory CD30 positive lympho-proliferative disorders: a single centre experience.

BACKGROUND: The role of brentuximab peri-allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined. AIM: To assess the outcome of use of brentuximab as a bridge to allogeneic stem cell transplantation (SCT) in patient with relapsed/refractory CD30+ classic Hodgkin lymphoma cHL and anaplastic large cell lymphoma (ALCL). METHODS: Outcomes of consecutive patients with relapsed/refractory cHL/ALCL treated with brentuximab as a bridge to SCT were determined by retrospective review of individual medical records. Survival analysis was measured from start of brentuximab treatment. RESULTS: A total of 12 patients (10 cHL, 2 ALCL) had received brentuximab as a planned bridge to allogeneic SCT. Median age was 27 years (range 20-54 years); median prior lines of therapy was 4 (range 3-6) and all except one patient had undergone prior autologous SCT (92%). Patients received at median of 3 brentuximab doses pre-allogeneic SCT (range 1-4), with an overall response rate of 66.7%. At a median follow up of 30 months (range 6-52 months), 2 years progression free survival and overall survival post-allogeneic SCT is 58 and 92% respectively. Incidence of non-relapse mortality, grade 3-4 acute graft versus host disease and extensive stage chronic graft versus host disease is 8, 17 and 18% respectively. Of five patients who subsequently relapsed post-SCT, four remain alive with disease control post manipulation of immune-suppression. CONCLUSION: Our experience suggests that brentuximab use pre-allogeneic SCT is not associated with any significant post-transplant toxicity, and is associated with a rapid response in a majority of patients with relapsed/refractory CD30 positive lymphomas. Brentuximab may thus provide a non-toxic bridge to allogeneic SCT for patients with relapsed/refractory CD30 positive cHL or ALCL.

Strengthening the role of Community Health Representatives in the Navajo Nation.

BACKGROUND: Strengthening Community Health Worker systems has been recognized to improve access to chronic disease prevention and management efforts in low-resource communities. The Community Outreach and Patient Empowerment (COPE) Program is a Native non-profit organization with formal partnerships with both the Navajo Nation Community Health Representative (CHR) Program and the clinical facilities serving the Navajo Nation. COPE works to better integrate CHRs into the local health care system through training, strengthening care coordination, and a standardized culturally appropriate suite of health promotion materials for CHRs to deliver to high-risk individuals in their homes. METHODS: The objective of this mixed methods, cross sectional evaluation of a longitudinal cohort study was to explore how the COPE Program has effected CHR teams over the past 6 years. COPE staff surveyed CHRs in concurrent years (2014 and 2015) about their perceptions of and experience working with COPE, including potential effects COPE may have had on communication among patients, CHRs, and hospital-based providers. COPE staff also conducted focus groups with all eight Navajo Nation CHR teams. RESULTS: CHRs and other stakeholders who viewed our results agree that COPE has improved clinic-community linkages, primarily through strengthened collaborations between Public Health Nurses and CHRs, and access to the Electronic Health Records. CHRs perceived that COPE's programmatic support has strengthened their validity and reputation with providers and clients, and has enhanced their ability to positively effect health outcomes among their clients. CHRs report an improved ability to deliver health coaching to their clients. Survey results show that 80. 2% of CHRs feel strongly positive that COPE trainings are useful, while 44.6% of CHRs felt that communication and teamwork had improved because of COPE. CONCLUSIONS: These findings suggest that CHRs have experienced positive benefits from COPE through training. COPE may provide a useful programmatic model on how best to support other Community Health Workers through strengthening clinic-community linkages, standardizing competencies and training support, and structuring home-based interventions for high-risk individuals.

Cultural elements underlying the community health representative - client relationship on Navajo Nation.

BACKGROUND: Navajo Nation Community Health Representatives (CHR) are trained community health workers (CHWs) who provide crucial services for patients and families. The success of the CHRs' interventions depends on the interactions between the CHRs and their clients. This research investigates the culturally specific factors that build and sustain the CHR-client interaction. METHODS: In-depth interviews were conducted with 16 CHRs on Navajo Nation. Interviews were transcribed and coded according to relevant themes. Code summaries were organized into a narrative using grounded theory techniques. RESULTS: The analysis revealed four findings critical to the development of a CHR-client relationship. Trust is essential to this relationship and provides a basis for providing quality services to the client. The ability to build and maintain trust is defined by tradition and culture. CHRs must be respectful of the diverse traditional and social practices. Lastly, the passing of clients brings together the CHR, the client's family, and the community. CONCLUSION: Understanding the cultural elements of the CHR-client relationship will inform the work of community partners, clinical providers, and other indigenous communities working to strengthen CHR programs and obtain positive health outcomes among marginalized communities.

Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.

BACKGROUND: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. METHODS: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. FINDINGS: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. FUNDING: National Health and Medical Research Council and Queensland Health.

A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 µg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.