The Cedar Project: Racism and its impacts on health and wellbeing among young Indigenous people who use drugs in Prince George and Vancouver, BC.

Racism continues to drive health disparities between Indigenous and non-Indigenous peoples in Canada. This study focuses on racism experienced by young Indigenous people who have used drugs in British Columbia (BC), and predictors of interpersonal racism. Cedar Project is a community-governed cohort study involving young Indigenous people who use drugs in Vancouver and Prince George, BC. This cross-sectional study included data collected between August 2015-October 2016. The Measure of Indigenous Racism Experiences (MIRE) scale was used to assess experiences of interpersonal racism across 9 unique settings on a 5-point Likert scale, collapsing responses into three categories (none/low/high). Multinomial logistic regression models were used to examine associations between key variables and interpersonal racism. Among 321 participants, 79% (n = 255) experienced racism in at least one setting. Thirty two percent (n = 102) experienced high interpersonal racism from police, governmental agencies (child 'welfare', health personnel), and in public settings. Ever having a child apprehended (AOR:2.76, 95%CI:1.14-6.65), probable post-traumatic stress (AOR:2.64; 95%CI:1.08-6.46), trying to quit substances (AOR:3.69; 95%CI:1.04-13.06), leaving emergency room without receiving treatment (AOR:3.05; 95%CI:1.22-7.64), and having a traditional language spoken at home while growing up (AOR:2.86; 95%CI:1.90-6.90) were associated with high interpersonal racism. Among women, experiencing high interpersonal racism was more likely if they lived in Prince George (AOR:3.94; 95%CI:1.07-14.50), ever had a child apprehended (AOR:5.09; 95%CI:1.50-17.30), and had probable post-traumatic stress (AOR:5.21; 95%CI:1.43-18.95). Addressing racism experienced by Indigenous peoples requires immediate structural systemic, and interpersonal anti-racist reforms.

Overcoming the soul wound: Reflecting on experiences and resilience of intergenerational residential school survivors.

BACKGROUND: Between 1883 and 1996, thousands of Indigenous children were apprehended into Canada's Residential School System. Survivors and their descendants have testified to genocidal harms caused across generations. Yet, Indigenous Peoples continue to exist and resist through inherent resilience described by intergenerational survivors in this paper. OBJECTIVE: This article focuses on stories demonstrating the strength, power, and resilience of intergenerational residential school survivors. PARTICIPANTS & SETTING: Cedar Project is an Indigenous-led cohort study that began as a HIV/AIDS response and contributes to healing among young Indigenous people who use drugs in British Columbia, Canada. It is governed by the Cedar Project Partnership, an Indigenous body of Elders, leaders, and health/social services experts. METHODS: We present qualitative research involving in-depth interviews carried out with Cedar participants who have experienced significant and complex adversities including childhood maltreatment and illicit drug use. Woven throughout, Indigenous scholars who are themselves intergenerational (children and grandchildren) of residential school survivors provide first-person reflections on the findings. RESULTS: Analysis focused on narratives of resilience and resistance to stresses of intergenerational traumas across three broad themes: working to break cycles of intergenerational trauma; foundations of resilience and making positive changes and; hopes and dreams. CONCLUSIONS: Findings establish deeper understanding of processes that enable young people to cope with stresses of intergenerational traumas while facing institutional and structural barriers to wellness. Reflections provide context about how intergenerational experiences intersect with challenges that young intergenerational survivors continue to face. We highlight pathways to healing and sources of strength that inform recommendations for wellness.

The Cedar Project - Mobile Phone Use and Acceptability of Mobile Health Among Young Indigenous People Who Have Used Drugs in British Columbia, Canada: Mixed Methods Exploratory Study.

BACKGROUND: Indigenous leaders continue to be concerned about high rates of HIV and barriers to HIV treatment among young Indigenous people involved in substance use. Growing evidence suggests that using mobile phones for health (mHealth) may be a powerful way to support connection with health services, including HIV prevention and treatment. OBJECTIVE: This study examined the patterns of mobile phone ownership and use among young Indigenous people who have used drugs living with or vulnerable to HIV and explored the acceptability of mHealth to support access to health care in this population. METHODS: The Cedar Project is a cohort study involving young Indigenous people who have used drugs in Vancouver and Prince George, British Columbia. This mixed methods exploratory study involved 131 Cedar Project participants enrolled in our WelTel mHealth program. At enrollment, participants completed a questionnaire related to mobile phone use and interest in mHealth. Data were linked to Cedar Project questionnaires and serodata. We present comparative statistics (quantitative) and results of a rapid thematic analysis (qualitative) related to mobile phone patterns and interest in receiving mHealth. RESULTS: Less than half of the participants (59/130; 45.4%) reported owning a phone. Among those with a phone, the majority owned a smartphone (46/59; 78%). Most participants with a phone reported having an unlimited texting plan (39/55; 71%), using the internet on their phone (44/59; 75%), and texting daily (44/55; 80%). A majority reported that using a mobile phone for health would be invaluable (120/130; 92.3%). There were no differences in mHealth acceptance between participants who owned a phone and those who did not (P>.99). All but one participant living with HIV felt using a mobile phone would be helpful for their health, while a small proportion of HIV-negative participants remained unsure (1.9% vs 11.7%; P=.047). In response to open-ended questions asking why using a mobile phone may be helpful for health, participants identified a diverse set of anticipated benefits: (1) connection for emotional, mental, and spiritual support, (2) connection to family, (3) staying in touch and/or being reachable, (4) overcoming current barriers to phone use, (5) convenience, privacy, and safety, and (6) access to health care and emergency services. CONCLUSIONS: We observed high acceptance and interest in using mobile phone technology for health despite low rates of personal mobile phone connectivity among young Indigenous people who have used drugs living with and vulnerable to HIV in British Columbia, Canada. Mobile phones were viewed as a way to support connections and relationships that are seen as critical to health and well-being among young Indigenous people in this study. Findings may be useful for health care providers preparing to scale up mHealth programs to support HIV prevention and treatment in this population.

Evaluation of inhaler technique and achievement and maintenance of mastery of budesonide/formoterol Spiromax® compared with budesonide/formoterol Turbuhaler® in adult patients with asthma: the Easy Low Instruction Over Time (ELIOT) study.

BACKGROUND: Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting ß2-agonists. METHODS: In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. RESULTS: Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05-6.95], p < 0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80-1.98], p = 0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09-0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25-3.54]). CONCLUSIONS: In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler. TRIAL REGISTRATION: EudraCT 2013-004630-14 (registration date 23 January 2014); NCT02570425 .

Real-life effectiveness and safety of salbutamol Steri-Neb™ vs. Ventolin Nebules® for exacerbations in patients with COPD: Historical cohort study.

INTRODUCTION: Ventolin Nebules® (reference product; GlaxoSmithKline) was the first licensed nebulizer solution containing the rapid-onset, short-acting ß2-agonist salbutamol. Salbutamol Steri-Neb™ (comparator; Teva Pharmaceuticals, Inc.) has the same chemical composition as the reference product. This study evaluated whether the effectiveness of the comparator is non-inferior to the reference product alongside concomitant medications during real-life clinical management of COPD exacerbations. Safety in terms of adverse events (AEs) was also examined. METHODS: This matched (1:1) historical cohort study evaluated data from 2 UK primary care databases on patients prescribed the salbutamol comparator or reference. The study included a 1-year baseline period, starting 1 year before the index prescription date, and 1-year outcome period. Cohorts were matched for baseline COPD respiratory medications. The primary outcome was analysis of non-inferiority for the comparator versus reference product for the rate of moderate and severe COPD exacerbations. Non-inferiority was satisfied if the 95% confidence interval (CI) upper limit for mean differences in proportions between treatments was <15%. Secondary outcomes were examined through rate ratios (RR) of severe exacerbations and AEs. RESULTS: After matching, 1191 patients were included in each cohort. Adjusted upper 95% CI for the difference in proportion of patients experiencing moderate or severe exacerbations between comparator and reference groups was 0.032 (3.2%), demonstrating non-inferiority. No significant differences were observed in rates of moderate and severe exacerbations (RR: 1.00; 95% CI: 0.91, 1.10), severe exacerbations (RR: 0.76; 95% CI: 0.49, 1.17), or AEs (RR: 0.98; 95% CI: 0.78, 1.22) after adjusting for baseline confounders. No significant differences across cohorts were observed for rates of any AE or death. CONCLUSION: This matched cohort study of real-life management of COPD patients supports the salbutamol comparator as non-inferior to the reference product, providing an effective treatment alternative for COPD exacerbations. Comparator and reference safety profiles were similar.

The Cedar Project: mortality among young Indigenous people who use drugs in British Columbia.

BACKGROUND: Young Indigenous people, particularly those involved in the child welfare system, those entrenched in substance use and those living with HIV or hepatitis C, are dying prematurely. We report mortality rates among young Indigenous people who use drugs in British Columbia and explore predictors of mortality over time. METHODS: We analyzed data collected every 6 months between 2003 and 2014 by the Cedar Project, a prospective cohort study involving young Indigenous people who use illicit drugs in Vancouver and Prince George, BC. We calculated age-standardized mortality ratios using Indigenous and Canadian reference populations. We identified predictors of mortality using time-dependent Cox proportional hazard regression. RESULTS: Among 610 participants, 40 died between 2003 and 2014, yielding a mortality rate of 670 per 100 000 person-years. Young Indigenous people who used drugs were 12.9 (95% confidence interval [CI] 9.2-17.5) times more likely to die than all Canadians the same age and were 7.8 (95% CI 5.6-10.6) times more likely to die than Indigenous people with Status in BC. Young women and those using drugs by injection were most affected. The leading causes of death were overdose (n = 15 [38%]), illness (n = 11 [28%]) and suicide (n = 5 [12%]). Predictors of mortality included having hepatitis C at baseline (adjusted hazard ratio [HR] 2.76, 95% CI 1.47-5.16), previous attempted suicide (adjusted HR 1.88, 95% CI 1.01-3.50) and recent overdose (adjusted HR 2.85, 95% CI 1.00-8.09). INTERPRETATION: Young Indigenous people using drugs in BC are dying at an alarming rate, particularly young women and those using injection drugs. These deaths likely reflect complex intersections of historical and present-day injustices, substance use and barriers to care.

The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study.

Chronic obstructive pulmonary disease (COPD), a complex progressive disease, is currently the third leading cause of death worldwide. One recommended treatment option is fixed-dose combination therapy of an inhaled corticosteroid (ICS)/long-acting ß-agonist. Clinical trials suggest pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) show similar efficacy and safety profiles in COPD. Real-world observational studies have shown that combination therapy has significantly greater odds of achieving asthma control when delivered via pMDIs. Our aim was to compare effectiveness, in terms of moderate/severe COPD exacerbations and long-acting muscarinic antagonist (LAMA) prescriptions, for COPD patients initiating fluticasone propionate (FP)/salmeterol xinafoate (SAL) via pMDI versus DPI at two doses of FP (500 and 1,000 µg/d) using a real-life, historical matched cohort study. COPD patients with ≥2 years continuous practice data, ≥2 prescriptions for FP/SAL via pMDI/DPI, and no prescription for ICS were selected from the Optimum Patient Care Research Database. Patients were matched 1:1. Rate of moderate/severe COPD exacerbations and odds of LAMA prescription were analyzed using conditional Poisson and logistic regression, respectively. Of 472 patients on 500 µg/d, we observed fewer moderate/severe exacerbations in patients using pMDI (99 [42%]) versus DPI (115 [49%]) (adjusted rate ratio: 0.71; 95% confidence interval: 0.54, 0.93), an important result since the pMDI is not licensed for COPD in the UK, USA, or China. At 1,000 µg/d, we observed lower LAMA prescription for pMDI (adjusted odds ratio: 0.71; 95% confidence interval: 0.55, 0.91), but no difference in exacerbation rates, potentially due to higher dose of ICS overcoming low lung delivery from the DPI.

Real-life effectiveness and safety of the inhalation suspension budesonide comparator vs the originator product for the treatment of patients with asthma: a historical cohort study using a US health claims database.

OBJECTIVE: The objective of this study was to determine whether the effectiveness of budesonide comparator is non-inferior to budesonide reference in the prevention of asthma exacerbations. Asthma-related hospitalizations and safety were also examined. METHODS: This study used a matched, historic cohort design. Data were drawn from the Clinformatics™ Data Mart US claims database and included a 1-year baseline, starting 1 year before the index prescription date, and a 1-year outcome period. Patients received budesonide comparator or reference treatment. The primary outcome was the rate of asthma exacerbations. Non-inferiority for budesonide comparator vs budesonide reference was established if the 95% confidence interval (CI) upper limit of mean difference in proportions between treatments was <15%. Secondary outcomes examined rate of asthma-related hospitalizations and adverse events (AEs). RESULTS: The budesonide comparator and reference-matched cohorts each included 3109 patients. The adjusted upper 95% CI for the difference in proportions of patients experiencing asthma exacerbations was 0.035 (3.5%), demonstrating non-inferiority. Cohorts did not significantly differ in the rate of asthma exacerbations (adjusted rate ratio [RR]=1.04, 95% CI: 0.95-1.14) or rate of asthma-related hospitalizations (adjusted RR=1.10, 95% CI: 0.99-1.24) after adjusting for baseline confounders. No asthma exacerbations occurred during the outcome period in 72.9% of budesonide comparator patients and 71.8% of budesonide reference patients. No asthma-related hospitalizations occurred in 77.9% of patients in the budesonide comparator cohort and 79.0% of patients in the budesonide reference cohort. The most frequent AEs were throat irritation (≤0.4% of patients) and hoarseness/dysphonia (0.02% of patients). AEs did not significantly differ between treatment cohorts. CONCLUSION: In this real-life study, non-inferiority of the budesonide comparator vs reference was met for the primary end point of asthma exacerbation rates. Asthma-related hospitalization and AE rates did not differ between the two treatment cohorts. The budesonide comparator is an effective and safe treatment alternative for asthma exacerbations.

A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma.

BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 µg) or switch to FP/FOR (1000/40 µg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 µg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 µg) (n = 126) was noninferior to FP/SAL (1000/100 µg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 µg) (n = 52) was noninferior to FP/FOR (1000/40 µg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

The Cedar Project WelTel mHealth intervention for HIV prevention in young Indigenous people who use illicit drugs: study protocol for a randomized controlled trial.

BACKGROUND: Despite successes in preventing and treating HIV, Indigenous people in Canada continue to face disproportionately high rates of HIV infection. Programs that support healing from lifetime trauma, support connection to culture, and reduce drug-related harms are critical to preventing HIV among young Indigenous people who use drugs. The Cedar Project WelTel mHealth intervention proposed here is a structured mobile-phone initiative to connect young Indigenous people who use drugs with Cedar Case Managers in a community-based setting. The intervention consists of a package of supports, including a mobile phone and cellular plan, weekly two-way text messaging, and support from Cedar Case Managers. METHODS: The Cedar Project WelTel mHealth study is a multi-site Zelen pre-randomized trial to measure the effect of a two-way supportive text-message intervention to reduce HIV vulnerability among young Indigenous people who use illicit drugs in two Canadian cities. The trial is nested within the Cedar Project, an ongoing cohort study addressing HIV and hepatitis C vulnerability among young Indigenous people who use drugs in Vancouver and Prince George, British Columbia. The Cedar Project Partnership, an independent body of Indigenous Elders, leaders, and health/social service experts, governs all aspects of the study. Two hundred participants will be followed over a 16-month period, with HIV propensity score at 6 months as the primary outcome. Secondary outcomes include HIV propensity at 1 year, HIV risk, resilience, psychological distress, access to drug-related services, and connection to culture measured at 6 months and 1 year. Primary analysis is by intention to treat. DISCUSSION: Culturally safe interventions that address barriers to HIV prevention while supporting the strength of young Indigenous people who use drugs are urgently needed. Despite presenting a tremendous opportunity to connect young, highly transient Indigenous people who use drugs to prevention services, supportive two-way mHealth programs have yet to be tested for HIV prevention in a community-based setting with this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02437123 https://clinicaltrials.gov/show/NCT02437123 (registered 4 May 2015). Protocol version: 24 July 2015.

The Cedar Project: Residential transience and HIV vulnerability among young Aboriginal people who use drugs.

Aboriginal homelessness is considered to be a result of historic dispossession of traditional territories and forced displacement from community structures. Using data collected from 2005-2010 from the Cedar Project, a cohort of young Aboriginal people who use drugs in two Canadian cities, we examined how residential transience shapes HIV vulnerability. At baseline, 48 of 260 participants (18.5%) reported sleeping in six or more places ('highly transient') in the past six months. Generalized linear mixed models identified associations between high transience and sex and drug related HIV vulnerabilities. Transience was independently associated with sex work (AOR:3.52, 95%CI:2.06, 6.05); sexual assault (AOR:2.48, 95%CI:1.26, 4.86); injection drug use (AOR:4.54, 95%CI:2.71, 7.61); daily cocaine injection (AOR:2.16, 95%CI:1.26, 3.72); and public injection (AOR:2.87, 95%CI:1.65, 5.00). After stratification, transience and sexual vulnerability remained significantly associated among women but not men. Ensuring that young Aboriginal people have access to safe spaces to live, work, and inject must include policies addressing residential transience as well as the absence of a roof and walls.

The Cedar Project * : historical trauma and vulnerability to sexual assault among young aboriginal women who use illicit drugs in two Canadian cities.

This study explored trends of sexual assault and associated risk factors within a cohort of young Aboriginal women who used drugs in Vancouver and Prince George, Canada, between 2003 and 2010. Results demonstrated no change in the trend of sexual assault over time; however, odds of sexual assault were significantly higher for women who had at least one parent who attended residential school, had experienced childhood sexual abuse, were involved in sex work, had been offered money to not use condoms, had used injection drugs, had injected cocaine and opiates daily, had binged with injection drugs, and had difficulty accessing clean syringes. Findings highlight the urgency of interventions addressing the complexity of risk and opportunities for healing.

Switching patients from other inhaled corticosteroid devices to the Easyhaler(®): historical, matched-cohort study of real-life asthma patients.

PURPOSE: To investigate the clinical and cost effectiveness of switching real-life asthma patients from other types of inhalers to the Easyhaler(®) (EH) for the administration of inhaled corticosteroids (ICS). PATIENTS AND METHODS: Historical, matched-cohort study of 1,958 asthma patients (children and adults) treated in UK primary-care practices, using data obtained from the Optimum Patient Care Research Database and Clinical Practice Research Datalink. Other inhalers (OH) included pressurized metered-dose inhalers, breath-actuated inhalers, and dry-powder inhalers, delivering beclomethasone, budesonide, fluticasone, or ciclesonide. Patients remaining on OH unchanged (same drug, dosage, and device; n=979) were matched 1:1 with those switched to the EH (beclomethasone or budesonide) at the same or lower ICS dosage (n=979), based on age, sex, year of index patient review/switch, most recent ICS drug, dosage, and device, and the number of severe exacerbations and average daily short-acting ß2 agonist (SABA) dosage in the preceding year. Clinical outcomes and health care costs were compared between groups for 12 months before and after the switch. Co-primary clinical outcomes were: 1) risk domain asthma control (RDAC) - no asthma-related hospitalization, acute oral steroid use, or lower respiratory tract infection (LRTI); 2) exacerbation rate (American Thoracic Society [ATS] definition) - where exacerbation is asthma-related hospitalization or acute oral steroid use; 3) exacerbation rate (clinical definition) - where exacerbation is ATS exacerbation or LRTI; and 4) overall asthma control (OAC) - RDAC plus average salbutamol-equivalent SABA dosage ≤200 µg/day. Non-inferiority (at least equivalence) of EH was tested against OH for the four co-primary outcomes in order (hierarchical approach) by comparing the difference in proportions of patients [EH-OH] achieving asthma control or having no exacerbations in the outcome year, using a limit of 10% difference. RESULTS: Non-inferiority was shown for the EH for all four co-primary outcomes. There were no significant differences between groups for RDAC or exacerbation rates, but EH patients were significantly more likely to achieve OAC (adjusted odds ratio [95% confidence interval]: 1.26 [1.05, 1.52]), as significantly more EH than OH patients had an average SABA dosage of ≤200 µg/day (52% versus 47%, respectively; P<0.001). Mean asthma-related health care costs increased from baseline to outcome years in both groups, but SABA costs increased significantly more in OH than EH patients (mean difference £5.5/patient/year) and consultation costs decreased significantly more in EH than OH patients (mean difference £13.5/patient/year). CONCLUSION: Typical asthma patients may be switched from other ICS devices to the Easyhaler(®) with no reduction in clinical effectiveness or increase in cost.

Quality standards for real-world research. Focus on observational database studies of comparative effectiveness.

Real-world research can use observational or clinical trial designs, in both cases putting emphasis on high external validity, to complement the classical efficacy randomized controlled trials (RCTs) with high internal validity. Real-world research is made necessary by the variety of factors that can play an important a role in modulating effectiveness in real life but are often tightly controlled in RCTs, such as comorbidities and concomitant treatments, adherence, inhalation technique, access to care, strength of doctor-caregiver communication, and socio-economic and other organizational factors. Real-world studies belong to two main categories: pragmatic trials and observational studies, which can be prospective or retrospective. Focusing on comparative database observational studies, the process aimed at ensuring high-quality research can be divided into three parts: preparation of research, analyses and reporting, and discussion of results. Key points include a priori planning of data collection and analyses, identification of appropriate database(s), proper outcomes definition, study registration with commitment to publish, bias minimization through matching and adjustment processes accounting for potential confounders, and sensitivity analyses testing the robustness of results. When these conditions are met, observational database studies can reach a sufficient level of evidence to help create guidelines (i.e., clinical and regulatory decision-making).

The Cedar Project: impacts of policing among young Aboriginal people who use injection and non-injection drugs in British Columbia, Canada.

BACKGROUND: Policing has profound health implications for people who use illicit drugs. Among Aboriginal communities, distrust of police is common, due partly to legacies of colonial policing. In response to the paucity of research among Aboriginal people who use drugs, this paper aims to: (1) Describe the policing experiences of young Aboriginal people who use drugs; (2) Identify policing activities associated with unsafe injection practices; and (3) Elucidate barriers to positive police relations. METHODS: The Cedar Project is a cohort study involving young Aboriginal people in Vancouver and Prince George, British Columbia, who use illicit drugs. This mixed-methods study (N=372) used period prevalence from 2007 to 2010 to describe policing experiences, mixed effects regression models to identify correlates of policing activities, and thematic qualitative analysis to assess attitudes to police relations. RESULTS: Many participants were stopped by police (73%), experienced physical force by police (28%), had drug equipment confiscated (31%), and changed location of drug use because of police (43%). Participants who reported dealing drugs (40%) were significantly more likely to experience police engagement. Among participants in Prince George, 4% reported to have had non-consensual sex with members of the criminal justice system. Policing activity was significantly associated with syringe sharing, rushed injection, and reused syringe. Due to personal experience, practical concerns, and intergenerational legacies of unfair policing practices, most participants did not want a positive relationship with police (57%). Desire for a positive relationship with police was directly associated with being helped by police, and inversely associated with being stopped by police and experiencing physical force by police. CONCLUSION: Policing activities may be impacting the well-being of Aboriginal people who use drugs. Due to focused prosecution of street-level drug dealing, some police may favor enforcement over harm reduction. Positive police engagement and less aggressive policing may enhance perceptions of police among young Aboriginal people who use drugs.

The Cedar Project: risk factors for transition to injection drug use among young, urban Aboriginal people.

BACKGROUND: Studies suggest that Aboriginal people in Canada are over-represented among people using injection drugs. The factors associated with transitioning to the use of injection drugs among young Aboriginal people in Canada are not well understood. METHODS: The Cedar Project is a prospective cohort study (2003-2007) involving young Aboriginal people in Vancouver and Prince George, British Columbia, who use illicit drugs. Participants' venous blood samples were tested for antibodies to HIV and the hepatitis C virus, and drug use was confirmed using saliva screens. The primary outcomes were use of injection drugs at baseline and tranisition to injection drug use in the six months before each follow-up interview. RESULTS: Of 605 participants, 335 (55.4%) reported using injection drugs at baseline. Young people who used injection drugs tended to be older than those who did not, female and in a relationship. Participants who injected drugs were also more likely than those who did not to have been denied shelter because of their drug use, to have been incarcerated, to have a mental illness and to have been involved in sex work. Transition to injection drug use occurred among 39 (14.4%) participants, yielding a crude incidence rate of 19.8% and an incidence density of 11.5 participants per 100 person-years. In unadjusted analysis, transition to injection drug use was associated with being female (odds ratio [OR] 1.98, 95% confidence interval (CI) 1.06-3.72), involved in sex work (OR 3.35, 95% CI 1.75-6.40), having a history of sexually transmitted infection (OR 2.01, 95% CI 1.07-3.78) and using drugs with sex-work clients (OR 2.51, 95% CI 1.19-5.32). In adjusted analysis, transition to injection drug use remained associated with involvement in sex work (adjusted OR 3.94, 95% CI 1.45-10.71). INTERPRETATION: The initiation rate for injection drug use of 11.5 participants per 100 person-years among participants in the Cedar Project is distressing. Young Aboriginal women in our study were twice as likely to inject drugs as men, and participants who injected drugs at baseline were more than twice as likely as those who did not to be involved in sex work.

Presentation of the Goodpasture autoantigen requires proteolytic unlocking steps that destroy prominent T cell epitopes.

The most abundant autoreactive T cells in patients with Goodpasture's disease are specific for peptides in the autoantigen that have high affinity for the disease-associated HLA class II molecule, DR15. How can such T cells escape self-tolerance mechanisms? This study showed that these peptides are highly susceptible to destruction in the earliest stages of antigen processing, and some must be cleaved for antigen digestion to be possible ("unlocking"). Goodpasture autoantigen [collagen alpha3(IV)NC1; approximately 31 kD] that was incubated with B cell lysosomes was cleaved within a few minutes to form approximately 9- and approximately 22-kD fragments, then increasing quantities of smaller peptides. The processing was completely abrogated by pepstatin A, a specific inhibitor of cathepsin D/E, even though lysosomal extracts contain a rich array of proteases. Purified cathepsin D generated the same major alpha3(IV)NC1 fragments as entire lysosomes, suggesting that cathepsin D cleavages are required to initiate alpha3(IV)NC1 processing. The initial unlocking cleavages destroyed two major self-epitopes, and subsequent preferred cleavages destroyed all of the other T cell epitopes that are recognized by most patients' autoreactive T cells. The responses of T cell clones that are specific for a major disease-associated peptide to antigen-pulsed intact antigen-presenting cells were substantially enhanced by pepstatin A treatment. Therefore, cathepsin D activity significantly diminishes presentation of alpha3(IV)NC1 peptides that are recognized by patients' T cells by destroying the peptides in early processing. These observations can explain why the mature T cell repertoire includes reactivity toward these self-peptides and suggests that a key factor in disease initiation is likely to be a shift in antigen processing.

Changes in food intake and body weight associated with basic combat training.

This research project evaluated changes in food selections, food intake, and body weight during 8 weeks of basic combat training (BCT). During the first week of BCT, 139 soldiers from two companies volunteered for participation in the study. In the eighth week of BCT, 92 soldiers were available for retesting. A digital photography method for measuring food selections and food intake was developed for this study. Fruit intake of soldiers was very low at the beginning and end of BCT. Food intake for grains and milk products was low during the first week of BCT but improved by the end of BCT. Average body weight decreased during the 8 weeks of BCT, but heavier soldiers tended to lose weight and thinner soldiers tended to gain weight. These findings suggest that the overall effect of BCT was a trend toward improvement of healthy eating and healthy body weight.