Dynamics of overdose and non-overdose mortality among people living with HIV amidst the illicit drug toxicity crisis in British Columbia.

We sought to characterize overdose and non-overdose mortality among PLWH amidst the illicit drug toxicity crisis in British Columbia, Canada. A population-based analysis of PLWH (age ≥19) in British Columbia accessing healthcare from April 1996 to March 2017 was conducted using data from the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) cohort linkage. Underlying causes of deaths were stratified into overdose and non-overdose causes. We compared (bivariate analysis) health-related characteristics and prescription history between PLWH died of overdose and non-overdose causes between April 2009 and March 2017. Among 9,180 PLWH, we observed 962 deaths (142 [14.7%] overdoses; 820 [85.2%] other causes). Compared to those who died from other causes, those who died of overdose were significantly younger (median age [Q, Q3]: 46 years [42, 52] vs. 54 years [48, 63]); had an indication of chronic pain (35.9% vs. 27.1%) and hepatitis C virus (64.8% vs. 50.4%), but fewer experienced hospitalization in the year before death. PLWH who died were most likely to be prescribed with opioids (>50%) and least likely with opioid agonist therapy (<10%) in a year before death. These findings highlight the syndemic of substance use, HCV, and chronic pain, and how the crisis is unqiuely impacting females and younger people.

Associations between psychosocial factors and antiretroviral therapy outcomes differ by gender and sexual orientation among people living with HIV in British Columbia, Canada.

Little is known about how the co-occurrence of psychosocial factors affect sub-populations of people living with HIV (PLWH). We used cross-sectional data from 999 PLWH, aged ≥19, accessing antiretroviral therapy (ART) in British Columbia, Canada (2007-2010) to examine associations between psychosocial factors and ART-related outcomes separately for trans/cis inclusive women; heterosexual men; and gay, bisexual, and other men who have sex with men (gbMSM). Multivariable logistic regression examined associations between psychosocial factors (0-3): any violence in the past 6 months, depressive symptoms in the past week, and current street drug use (heroin, crack, meth or speedball) with sub-optimal adherence (outcome 1: average annual ART adherence <95% from interview until end of follow-up, death, or December 31st, 2018) and ever viral rebound (outcome 2) adjusting for potential confounders. Of 999 PLWH (264 women, 382 heterosexual men, and 353 gbMSM), women and heterosexual men had significantly higher median counts than gbMSM. Overall, higher counts were associated with sub-optimal adherence (adjusted odds ratio [aOR] = 1.26/1-unit increase, 95%CI = 1.07-1.49). All effect estimates were of a greater magnitude among gbMSM, but not significant for women or heterosexual men, highlighting the need for population (e.g., gender and sexual orientation)-centered care and research.

It's all about connection: Determinants of social support and the influence on HIV treatment interruptions among people living with HIV in British Columbia, Canada.

BACKGROUND: Social support has previously been found to be associated with improved health outcomes of individuals managing chronic illnesses, including amongst people living with HIV (PLWH). For women and people who use injection drugs who continue to experience treatment disparities in comparison to other PLWH, social support may have potential in facilitating better treatment engagement and retention. In this analysis, we examined determinants of social support as measured by the Medical Outcomes Study - Social Support Survey (MOS-SSS) scale, and quantified the relationship between MOS-SSS and HIV treatment interruptions (TIs) among PLWH in British Columbia, Canada. METHODS: Between January 2016 and September 2018, we used purposive sampling to enroll PLWH, 19 years of age or older living in British Columbia into the STOP HIV/AIDS Program Evaluation study. Participants completed a baseline survey at enrolment which included the MOS-SSS scale, where higher MOS-SSS scores indicated greater social support. Multivariable linear regression modeled the association between key explanatory variables and MOS-SSS scores, whereas multivariable logistic regression modeled the association between MOS-SSS scores and experiencing TIs while controlling for confounders. RESULTS: Among 644 PLWH, we found that having a history of injection drug use more than 12 months ago but not within the last 12 months, self-identifying as Indigenous, and sexual activity in the last 12 months were positively associated with MOS-SSS, while being single, divorced, or dating (vs. married), experiences of lifetime violence, and diagnosis of a mental health disorder were inversely associated. In a separate multivariable model adjusted for gender, ethnicity, recent homelessness, sexual activity in the last 12 months, and recent injection drug use, we found that higher MOS-SSS scores, indicating more social support, were associated with a lower likelihood of HIV treatment interruptions (adjusted odds ratio: 0.90 per 10-unit increase, 95% confidence interval: 0.83, 0.99). CONCLUSIONS: Social support may be an important protective factor in ensuring HIV treatment continuity among PLWH. Future research should examine effective means to build social support among communities that have potential to promote increased treatment engagement.

Causal and Associational Language in Observational Health Research: A Systematic Evaluation.

We estimated the degree to which language used in the high-profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched for and screened 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, 3 reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as none (no causal implication) in 13.8%, weak in 34.2%, moderate in 33.2%, and strong in 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was "associate" (45.7%). Reviewers' ratings of linking word roots were highly heterogeneous; over half of reviewers rated "association" as having at least some causal implication. This research undercuts the assumption that avoiding "causal" words leads to clarity of interpretation in medical research.

The impact of lookback windows on the prevalence and incidence of chronic diseases among people living with HIV: an exploration in administrative health data in Canada.

BACKGROUND: We described the impact of different lengths of lookback window (LW), a retrospective time period to observe diagnoses in administrative data, on the prevalence and incidence of eight chronic diseases. METHODS: Our study populations included people living with HIV (N = 5151) and 1:5 age-sex-matched HIV-negative individuals (N = 25,755) in British Columbia, Canada, with complete follow-up between 1996 and 2012. We measured period prevalence and incidence of diseases in 2012 using LWs ranging from 1 to 16 years. Cases were deemed prevalent if identified in 2012 or within a defined LW, and incident if newly identified in 2012 with no previous cases detected within a defined LW. Chronic disease cases were ascertained using published case-finding algorithms applied to population-based provincial administrative health datasets. RESULTS: Overall, using cases identified by the full 16-year LW as the reference, LWs ≥8 years and ≥ 4 years reduced the proportion of misclassified prevalent and incidence cases of most diseases to < 20%, respectively. The impact of LWs varied across diseases and populations. CONCLUSIONS: This study underscored the importance of carefully choosing LWs and demonstrated data-driven approaches that may inform these choices. To improve comparability of prevalence and incidence estimates across different settings, we recommend transparent reporting of the rationale and limitations of chosen LWs.

Tobacco smoking and HIV-related immunologic and virologic response among individuals of the Canadian HIV Observational Cohort (CANOC).

We assessed the relationship between tobacco smoking and immunologic and virologic response among people living with HIV (PLWH) initiating combination antiretroviral therapy (cART) in the Canadian HIV Observational Cohort (CANOC). Positive immunologic and virologic response, respectively, were defined as ≥50 cells/mm3 CD4 count increase (CD4+) and viral suppression ≤50 copies/mL (VL+) within 6 months of cART initiation. Using multinomial regression, we examined the relationship between smoking, immunologic, and virologic response category. Model A adjusted for birth sex, baseline age, enrolling province, and era of cohort entry; models B and C further adjusted for neighbourhood level material deprivation and history of injection drug use (IDU), respectively. Among 4267 individuals (32.7%) with smoking status data, concordant positive (CD4+/VL+) response was achieved by 64.2% never, 66.9% former, and 59.4% current smokers. In the unadjusted analysis, current smoking was significantly associated with concordant negative response (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.40-2.45). Similarly, models A and B showed an increased odds of concordant negative response in current smokers (adjusted OR [aOR] 1.78, 95% CI 1.32-2.39 and 1.74, 95% CI 1.29-2.34, respectively). The association between current smoking and concordant negative response was no longer significant in model C (aOR 1.18, 95%CI 0.85-1.65).

Social Isolation and Mortality Among People Living with HIV in British Columbia, Canada.

Social isolation, a risk factor for poor health within the general population, may be exacerbated by unique challenges faced by people living with HIV (PLHIV). This analysis examines the association between social isolation and all-cause mortality among a cohort of PLHIV experiencing multiple social vulnerabilities. The analytical sample included 936 PLHIV ≥ 19 years, living in British Columbia, Canada, and enrolled in the Longitudinal Investigation into Supportive and Ancillary Health Services (LISA) Study (2007-2010). Participants were classified as Socially Connected (SC), Minimally Isolated (MI) or Socially Isolated (SI) via latent class analysis. Cross-sectional survey data was linked to longitudinal clinical data from a provincial HIV treatment database. Mortality was assessed longitudinally up to and including December 31st, 2017. Through multivariable logistic regression, an association between SI and all-cause mortality was found (adjusted OR: 1.48; 95% CI 1.08, 2.01). These findings emphasize the need to mitigate effects of social isolation among PLHIV.

Correlates of social isolation among people living with HIV in British Columbia, Canada.

Our study aims to define and identify correlates of social isolation among people living with HIV (PLHIV). The Longitudinal Investigation into Supportive and Ancillary health services (LISA) study provided a cross-sectional analytic sample of 996 PLHIV in British Columbia, Canada (sampled between 2007 and 2010). Individuals marginalized by socio-structural inequities were oversampled; sampling bias was addressed through inverse probability of participation weighting. Through latent class analysis, three groups were identified: Socially Connected (SC) (n = 364, 37%), Minimally Isolated (MI) (n = 540, 54%) and Socially Isolated (SI) (n = 92, 9%). Correlates of the SI and MI classes, determined through multivariable multinomial regression using the SC class as a reference, include: recent violence (aOR 1.61, 95%CI 1.28-2.02 [MI vs. SC]; aOR 2.04, 95%CI 1.41-2.96 [SI vs. SC]) and a mental health diagnosis (aOR 1.50, 95% CI 1.31-1.72 [MI vs. SC]; aOR 1.43, 95%CI 1.11-1.83 [SI vs. SC]). Women (aOR 0.47; 95%CI 0.32-0.68 [SI vs. SC]), individuals of Indigenous ancestry (aOR 0.59; 95%CI 0.40-0.87 [SI vs. SC]) and people identifying as gay or lesbian (aOR 0.37; 95%CI 0.26-0.52 [SI vs. SC]) were less likely to experience isolation. These findings highlight the importance of supporting communities fostering connectedness and identifies populations susceptible to isolation.

Assessing the impact of food insecurity on HIV medication adherence in the context of an integrated care programme for people living with HIV in Vancouver, Canada.

OBJECTIVE: Food insecurity, or self-reports of inadequate food access due to limited financial resources, remains prevalent among people living with HIV (PLHIV). We examined the impact of food insecurity on combination antiretroviral therapy (cART) adherence within an integrated care programme that provides services to PLHIV, including two meals per day. DESIGN: Adjusted OR (aOR) were estimated by generalized estimating equations, quantifying the relationship between food insecurity (exposure) and cART adherence (outcome) with multivariable logistic regression. SETTING: We drew on survey data collected between February 2014 and March 2016 from the Dr. Peter Centre Study based in Vancouver, Canada. PARTICIPANTS: The study included 116 PLHIV at baseline, with ninety-nine participants completing a 12-month follow-up interview. The median (quartile 1-quartile 3) age was 46 (39-52) years at baseline and 87 % (n 101) were biologically male at birth. RESULTS: At baseline, 74 % (n 86) of participants were food insecure (≥2 affirmative responses on Health Canada's Household Food Security Survey Module) and 67 % (n 78) were adherent to cART ≥95 % of the time. In the adjusted regression analysis, food insecurity was associated with suboptimal cART adherence (aOR = 0·47, 95 % CI 0·24, 0·93). CONCLUSIONS: While food provision may reduce some health-related harms, there remains a relationship between this prevalent experience and suboptimal cART adherence in this integrated care programme. Future studies that elucidate strategies to mitigate food insecurity and its effects on cART adherence among PLHIV in this setting and in other similar environments are necessary.

Injection drug use, food insecurity, and HIV-HCV co-infection: a longitudinal cohort analysis.

Injection drug use (IDU) and food insecurity (FI) are highly prevalent among individuals living with HIV-hepatitis C virus (HCV) co-infection. We quantified the association between IDU and FI among co-infected individuals using biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). IDU (in the past six months) and IDU frequency (non-weekly/weekly in the past month) were self-reported. FI (in the past six months) and FI severity (marginal FI, moderate FI, and severe FI) were measured using the Household Food Security Survey Module. Generalized estimating equations were used to estimate risk ratios (RR) quantifying the associations between IDU, IDU frequency, and FI with Poisson regression. The associations between IDU, IDU frequency, and FI severity were quantified by relative-risk ratios (RRR) estimated with multinomial regression. At the first time-point in the analytical sample, 54% of participants experienced FI in the past six months, 31% engaged in IDU in the six months preceding the FI measure, and 24% injected drugs in the past month. After adjustment for confounding, IDU in the past six months (RR = 1.15, 95% confidence interval [CI] = 1.04-1.28) as well as non-weekly (RR = 1.15, 95% CI = 1.02-1.29) and weekly IDU (RR = 1.21, 95% CI = 1.07-1.37) in the past month are associated with FI. Weekly IDU in the past month is also strongly associated with severe FI (RRR = 2.68, 95% CI = 1.47-4.91). Our findings indicate that there is an association between IDU and FI, particularly weekly IDU and severe FI. This suggests that reductions in IDU may mitigate FI, especially severe FI, in this vulnerable subset of the HIV-positive population.

Association Between Food Insecurity and HIV Viral Suppression: A Systematic Review and Meta-Analysis.

Although an increasing number of HIV infected people are accessing antiretroviral treatment, many do not achieve complete HIV viral suppression and remain at risk for AIDS and capable of HIV transmission. Food insecurity has been identified as a potential risk factor for poor virologic response, but the association between these factors has been inconsistently documented in the literature. We systematically searched five electronic databases and bibliographies of relevant studies through April 2015 and retrieved 11 studies that met our inclusion criteria, of which nine studies were conducted in North America and the remaining two studies were in Brazil and Uganda respectively. Meta-analyzed results indicated that experiencing food insecurity resulted in 29% lower odds of achieving complete HIV viral suppression (OR = 0.71, 95% CI 0.61-0.82) and this significant inverse association was consistently found regardless of study design, exposure measurement, and confounder adjustment methods. These findings suggest that food insecurity is a potential risk factor for incomplete HIV viral suppression in people living with HIV.

Impact of Food Insecurity on Depressive Symptoms Among HIV-HCV Co-infected People.

Food insecurity (FI) is associated with depressive symptoms among HIV mono-infected people. Our objective was to examine to what extent this association holds among HIV-hepatitis C virus (HCV) co-infected people. We used data from a prospective cohort study of HIV-HCV co-infected people in Canada. FI was measured using the ten-item adult scale of Health Canada's Household Food Security Survey Module and was classified into three categories: food secure, moderate FI, and severe FI. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D-10) and was classified into absence or presence of depressive symptoms. FI, depressive symptoms, and other covariates were updated every 6 months. The association between FI and depressive symptoms was assessed using a stabilized inverse probability weighted marginal structural model. The study sample included 725 HIV-HCV co-infected people with 1973 person-visits over 3 years of follow up. At baseline, 23% of participants experienced moderate food insecurity, 34% experienced severe food insecurity and 52% had depressive symptoms. People experiencing moderate FI had 1.63 times (95% CI 1.44-1.86) the risk of having depressive symptoms and people experiencing severe FI had 2.01 times (95% CI 1.79-2.25) the risk of having depressive symptoms compared to people who were food secure. FI is a risk factor for developing depressive symptoms among HIV-HCV co-infected people. Food supplementation, psychosocial support and counseling may improve patient health outcomes.

Injection Drug Use, Unemployment, and Severe Food Insecurity Among HIV-HCV Co-Infected Individuals: A Mediation Analysis.

Severe food insecurity (FI), which indicates reduced food intake, is common among HIV-hepatitis C virus (HCV) co-infected individuals. Given the importance of unemployment as a proximal risk factor for FI, this mediation analysis examines a potential mechanism through which injection drug use (IDU) is associated with severe FI. We used biannual data from the Canadian Co-infection Cohort (N = 429 with 3 study visits, 2012-2015). IDU in the past 6 months (exposure) and current unemployment (mediator) were self-reported. Severe FI in the following 6 months (outcome) was measured using the Household Food Security Survey Module. An overall association and a controlled direct effect were estimated using marginal structural models. Among participants, 32% engaged in IDU, 78% were unemployed, and 29% experienced severe FI. After adjustment for confounding and addressing censoring through weighting, the overall association (through all potential pathways) between IDU and severe FI was: risk ratio (RR) = 1.69 (95% confidence interval [CI] = 1.15-2.48). The controlled direct effect (the association through all potential pathways except that of unemployment) was: RR = 1.65 (95% CI = 1.08-2.53). We found evidence of an overall association between IDU and severe FI and estimated a controlled direct effect that is suggestive of pathways from IDU to severe FI that are not mediated by unemployment. Specifically, an overall association and a controlled direct effect that are similar in magnitude suggests that the potential impact of IDU on unemployment is not the primary mechanism through which IDU is associated with severe FI. Therefore, while further research is required to understand the mechanisms linking IDU and severe FI, the strong overall association suggests that reductions in IDU may mitigate severe FI in this vulnerable subset of the HIV-positive population.

Food Insecurity in HIV-Hepatitis C Virus Co-infected Individuals in Canada: The Importance of Co-morbidities.

While research has begun addressing food insecurity (FI) in HIV-positive populations, knowledge regarding FI among individuals living with HIV-hepatitis C virus (HCV) co-infection is limited. This exploratory study examines sociodemographic, socioeconomic, behavioral, and clinical factors associated with FI in a cohort of HIV-HCV co-infected individuals in Canada. We analyzed longitudinal data from the Food Security and HIV-HCV Co-infection Study of the Canadian Co-infection Cohort collected between November 2012-June 2014 at 15 health centres. FI was measured using the Household Food Security Survey Module and classified using Health Canada criteria. Generalized estimating equations were used to assess factors associated with FI. Among 525 participants, 59 % experienced FI at their first study visit (baseline). Protective factors associated with FI (p < 0.05) included: enrolment at a Quebec study site (aOR: 0.42, 95 % CI: 0.27, 0.67), employment (aOR: 0.55, 95 % CI: 0.35, 0.87), and average personal monthly income (aOR per $100 CAD increase: 0.98, 95 % CI: 0.97, 0.99). Risk factors for FI included: recent injection drug use (aOR: 1.98, 95 % CI: 1.33, 2.96), trading away food (aOR: 5.23, 95 % CI: 2.53, 10.81), and recent experiences of depressive symptoms (aOR: 2.11, 95 % CI: 1.48, 3.01). FI is common in this co-infected population. Engagement of co-infected individuals in substance use treatments, harm reduction programs, and mental health services may mitigate FI in this vulnerable subset of the HIV-positive population.

Component costs of foodborne illness: a scoping review.

BACKGROUND: Governments require high-quality scientific evidence to prioritize resource allocation and the cost-of-illness (COI) methodology is one technique used to estimate the economic burden of a disease. However, variable cost inventories make it difficult to interpret and compare costs across multiple studies. METHODS: A scoping review was conducted to identify the component costs and the respective data sources used for estimating the cost of foodborne illnesses in a population. This review was accomplished by: (1) identifying the research question and relevant literature, (2) selecting the literature, (3) charting, collating, and summarizing the results. All pertinent data were extracted at the level of detail reported in a study, and the component cost and source data were subsequently grouped into themes. RESULTS: Eighty-four studies were identified that described the cost of foodborne illness in humans. Most studies (80%) were published in the last two decades (1992-2012) in North America and Europe. The 10 most frequently estimated costs were due to illnesses caused by bacterial foodborne pathogens, with non-typhoidal Salmonella spp. being the most commonly studied. Forty studies described both individual (direct and indirect) and societal level costs. The direct individual level component costs most often included were hospital services, physician personnel, and drug costs. The most commonly reported indirect individual level component cost was productivity losses due to sick leave from work. Prior estimates published in the literature were the most commonly used source of component cost data. Data sources were not provided or specifically linked to component costs in several studies. CONCLUSIONS: The results illustrated a highly variable depth and breadth of individual and societal level component costs, and a wide range of data sources being used. This scoping review can be used as evidence that there is a lack of standardization in cost inventories in the cost of foodborne illness literature, and to promote greater transparency and detail of data source reporting. By conforming to a more standardized cost inventory, and by reporting data sources in more detail, there will be an increase in cost of foodborne illness research that can be interpreted and compared in a meaningful way.

Association between component costs, study methodologies, and foodborne illness-related factors with the cost of nontyphoidal Salmonella illness.

Nontyphoidal Salmonella spp. are one of the most common causes of bacterial foodborne illness. Variability in cost inventories and study methodologies limits the possibility of meaningfully interpreting and comparing cost-of-illness (COI) estimates, reducing their usefulness. However, little is known about the relative effect these factors have on a cost-of-illness estimate. This is important for comparing existing estimates and when designing new cost-of-illness studies. Cost-of-illness estimates, identified through a scoping review, were used to investigate the association between descriptive, component cost, methodological, and foodborne illness-related factors such as chronic sequelae and under-reporting with the cost of nontyphoidal Salmonella spp. illness. The standardized cost of nontyphoidal Salmonella spp. illness from 30 estimates reported in 29 studies ranged from $0.01568 to $41.22 United States dollars (USD)/person/year (2012). The mean cost of nontyphoidal Salmonella spp. illness was $10.37 USD/person/year (2012). The following factors were found to be significant in multiple linear regression (p≤0.05): the number of direct component cost categories included in an estimate (0-4, particularly long-term care costs) and chronic sequelae costs (inclusion/exclusion), which had positive associations with the cost of nontyphoidal Salmonella spp. illness. Factors related to study methodology were not significant. Our findings indicated that study methodology may not be as influential as other factors, such as the number of direct component cost categories included in an estimate and costs incurred due to chronic sequelae. Therefore, these may be the most important factors to consider when designing, interpreting, and comparing cost of foodborne illness studies.

Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.