Alcohol Consumption Among Persons Living with HIV: Perceptions, Messages and Interventions-A Qualitative Study at an HIV Treatment Clinic in South Western Uganda.

In Sub-Saharan Africa, efficacy trials of brief interventions to reduce unhealthy drinking among persons living with HIV (PLWH) have yielded mixed results. A better understanding of the perceptions of drinking, especially by PLWH, and how drinking is talked about at HIV treatment clinics in this setting, may guide more optimal designs for future trials. We conducted a qualitative study at an HIV treatment clinic in South Western Uganda to better understand perceptions of drinking, how drinking is talked about, and perceptions of interventions, especially a protocolled screening and brief intervention (SBI) for unhealthy drinking among PLWH. We conducted in-depth interviews with 17 PLWH who engaged in unhealthy drinking and 6 health workers, and one focus group discussion with 3 community advisory-board members. We performed manual preliminary data analysis and computer-assisted detailed thematic analysis to identify emergent themes. Four themes emerged: perceptions of alcohol use in the general population; perceptions of alcohol use in PLWH; interaction between PLWH and health workers about alcohol use; perceptions of interventions for unhealthy drinking including SBI. Unhealthy drinking was seen as a problem in the general population and among those with HIV, where it was negatively perceived. Communication about drinking was done by counselors, but doctors participated in screening for unhealthy alcohol use. Messages about drinking covered reduction and abstinence. Participants expressed positive attitudes towards SBI and preference for person-delivered SBI over technological alternatives. A protocolled SBI for unhealthy alcohol use among PLWH would be well-received but successful implementation may depend on mode of delivery.

A Mixed-Methods Approach to Develop a Combined Model of U.S. College Student Alcohol-Associated Condomless Sex.

Unhealthy alcohol use and sexually transmitted infections (STIs) are significant public health concerns for US college students. Because alcohol use and condomless sex often co-occur in this population, alcohol-associated condomless sex has been identified as a behavioral intervention target. Existing theoretical frameworks have not garnered sufficient empirical support to serve as the foundation for interventions. The primary goal of the current study was to use a mixed-methods approach to develop a model of college student alcohol-associated condomless sex that combines elements from well-established health behavior theories. In Aim 1, multilevel modeling was used to predict condomless vaginal sex in a sample of heterosexual college student drinkers (N = 53). Aim 2 consisted of in-depth interviews (n = 18) to gather perceptions about the role of alcohol in sexual activity and identify supplemental constructs omitted from theories in Aim 1. The multilevel model explained a significant proportion of variance in condomless vaginal sex at the between- and within-person level. Themes derived from the in-depth interviews identified complementary elements of condom use decision-making. Findings from both aims were synthesized to construct a combined model of alcohol-associated condomless sex. This model can be further refined and ultimately serve as the foundation of an alcohol-STI prevention-intervention.

Mental health, coping, and protective factors in mothers of children with 22q11.2 deletion syndrome.

Compared to the large body of maternal mental health research for other pediatric disorders, we know far less about the experience of mothers of children with 22q11DS. This study investigates the coping methods, protective factors, and mental health of this population. These findings might lead to better support for 22q11DS maternal mental health. An international sample of 71 mothers (M = 40.5 years) of children with 22q11DS (M = 9.2 years) was recruited and completed an online survey assessing maternal mental health (symptoms of depression, anxiety, traumatic stress, general stress, and alcohol consumption), coping methods, and mental health protective factors (social support, dyadic adjustment, parenting competence). Maternal ratings of child mental health symptoms were also obtained. Mothers' self-report revealed a high percentage who screened positive for elevated levels of general stress (69%), hazardous alcohol consumption (30.9%), traumatic stress (33.8%), anxiety (26.8%), and depression (26.8%). After controlling for demographic variables and child mental health symptoms, maternal self-reported maladaptive coping methods were positively associated with maternal symptoms of depression, anxiety, stress, and traumatic stress. Reducing maladaptive coping methods may be a promising intervention for improving mental health in mothers of children with 22q11DS.

Feasibility of remote self-collection of dried blood spots, hair, and nails among people with HIV with hazardous alcohol use.

BACKGROUND: The use of biomarkers in behavioral HIV research can help to address limitations of self-reported data. The COVID-19 pandemic forced many researchers to transition from standard in-person data collection to remote data collection. We present data on the feasibility of remote self-collection of dried blood spots (DBS), hair, and nails for the objective assessment of alcohol use, antiretroviral therapy adherence, and stress in a sample of people with HIV (PWH) who are hazardous drinkers. METHODS: Standardized operating procedures for remote self-collection of DBS, hair, and nails were developed for an ongoing pilot study of a transdiagnostic alcohol intervention for PWH. Prior to each study appointment, participants were mailed a kit containing materials for self-collection, instructions, a video link demonstrating the collection process, and a prepaid envelope for returning samples. RESULTS: A total of 133 remote study visits were completed. For DBS and nail collection at baseline, 87.5% and 83.3% of samples, respectively, were received by the research laboratory, of which 100% of samples were processed. Although hair samples were intended to be analyzed, most of the samples (77.7%) were insufficient or the scalp end of the hair was not marked. We, therefore, decided that hair collection was not feasible in the framework of this study. CONCLUSION: An increase in remote self-collection of biospecimens may significantly advance the field of HIV-related research, permitting the collection of specimens without resource-intensive laboratory personnel and facilities. Further research is needed on the factors that impeded participants' ability to complete remote biospecimen collection.

Sexual Assault, Mental Health, and Alcohol Use in College Women: The Role of Resilience and Campus Belonging.

Understanding the mental health outcomes of sexual assault among college women is a public health priority. Although research has identified risk factors for the development of mental health problems following an assault, few studies have utilized a strengths-based approach to identify personal and social resources that may mediate the sexual assault-mental health link. Prior studies allude to the role of resilience and perceived campus belonging in explaining the relationship between sexual assault and mental health. This study represents the first application of the stress process model using a large sample of college women to examine (a) the association between sexual assault and mental health (i.e., psychological distress, suicidality, self-harm) and alcohol use problems and (b) the role of resilience and perceived campus belonging as partial mediators of these associations. Data were collected as part of the Spring 2021 American College Health Association National College Health Assessment (ACHA-NCHA; n = 31,328, Mean age = 20.26, SD = 1.64, 58.8% White), a cross-sectional, online survey that samples college students from 143 self-selected United States colleges. To test our primary hypothesis, a structural regression model was conducted, which included a latent sexual assault predictor, manifest resilience and campus belonging mediators, a latent mental health outcome, and a manifest alcohol use problems outcome. Mental health and alcohol use problems were positively associated with sexual assault and negatively associated with resilience and campus belonging. Resilience partially mediated the association between sexual assault and mental health. Campus belonging partially mediated the association between sexual assault, mental health, and alcohol use problems. This model explained 23.2% of the variance in mental health and 5.9% of the variance in alcohol use. Resilience and campus belonging may represent modifiable factors that can be targeted in trauma-focused interventions in efforts to improve victimized college women's mental health.

Effect of two counseling interventions on self-reported alcohol consumption, alcohol biomarker phosphatidylethanol (PEth), and viral suppression among persons living with HIV (PWH) with unhealthy alcohol use in Uganda: A randomized controlled trial.

PURPOSE: To test the efficacy of two interventions to reduce alcohol use and increase viral suppression compared to a control in persons with HIV (PWH). METHODS: In a three-arm (1:1:1) randomized controlled trial (N = 269), we compared in-person counselling (45-70 minutes, two sessions over three months) with interim monthly booster phone calls (live call arm) or twice-weekly automated booster sessions (technology arm) to a brief advice control arm. We enrolled PWH self-reporting unhealthy alcohol use (Alcohol Use Disorders Identification Test - Consumption, prior three months, women ≥3, men ≥4). Primary outcomes were number of self-reported drinking days (NDD) in the prior 21 and biomarker phosphatidylethanol (PEth) at six and nine months and viral suppression (<40 copies/mL) at nine months; we adjusted for sex and baseline outcomes. RESULTS: At baseline, mean 21-day NDDs were 9.4 (95 % CI: 9.1-9.8), mean PEth was 407.8 ng/mL (95 % CI: 340.7-474.8), and 89.2 % were virally suppressed. At follow-up, there were significant reductions in mean NDDs for the live call versus control arm (3.5, 95 % CI:2.1-4.9, p < 0.001) and for the technology versus control arm (3.6, 95 % CI: 2.2-5.1, p < 0.001). The mean PEth differences compared to the control arm were not significant, i.e. 36.4 ng/mL (95 % CI: -117.5 to 190.3, p = 0.643) for the live call and -30.9 ng/mL (95 % CI: -194.8 to 132.9, p = 0.711) for the technology arm. Nine-month viral suppression compared to the control was similar in the live call and in the technology arm. CONCLUSION: Intervention effects were found on self-reported NDD but not PEth or viral suppression, suggesting no treatment effect. (NCT #03928418).

Moderation of Risks to Sexual Health by Substance Use in College Students With ADHD.

Objective: Poor sexual health is a public health concern for college students and individuals with attention-deficit/hyperactivity disorder (ADHD), yet limited information is available on the sexual health of college students with ADHD. Here, the sexual health of college students with and without ADHD was described and moderators of risk to sexual health were identified.Methods: A secondary data analysis of the National College Health Assessment III (Fall 2019, Spring 2020, and Fall 2020 administrations) was conducted using a sample of sexually active undergraduate students (N = 36,236). Logistic regressions were used to compare sexual behaviors and health outcomes of college students with and without self-reported ADHD and test for interactions between ADHD and substance use-related moderators of risk to sexual health (ie, alcohol use, binge drinking, and cannabis use).Results: Compared to non-ADHD peers, college students with ADHD reported more past-year sexual partners (adjusted odds ratio [aOR] = 1.27; P < .01), lower rates of condom use (aOR = 0.77; P < .001), and higher rates of condomless sex while drinking (aOR = 1.52; P < .001). College students with ADHD reported more sexually transmitted infection diagnoses (aOR = 1.29; P < .01), a greater number of unplanned pregnancies (aOR = 1.72; P < .001), and more emergency contraception use (aOR = 1.19; P < .001). Alcohol use, binge drinking, and cannabis use moderated the relationship between ADHD and sexual health.Conclusions: College students with ADHD represent a vulnerable population for poor sexual health and are differentially impacted by substance use. Indicated sexual health prevention strategies and treatment for college students with ADHD are warranted.

Daily Associations Between Alcohol Consumption and Antiretroviral Therapy (ART) Adherence Among HIV-Positive Men Who Have Sex With Men.

Alcohol consumption is one of the strongest predictors of suboptimal adherence to antiretroviral therapy (ART), however, there is little research that has investigated both within- and between-person associations of alcohol consumption and ART adherence at the event-level. In this secondary data-analysis, (N = 22) HIV-positive MSM prospectively reported daily alcohol consumption and ART adherence for 42-days. Multilevel models demonstrated (1) days in which participants reported consuming any alcohol was associated with 2.48 increased odds of ART non-adherence, compared to days in which participants reported no alcohol consumption, and (2) there was a non-significant trend indicating days in which participants reported consuming greater than their own average levels of alcohol was associated with increased odds of ART non-adherence. Findings highlight the importance of combining intervention efforts that address alcohol consumption and suboptimal ART adherence, and indicate a need for future research to investigate the mechanisms by which alcohol influences ART adherence.

Development of a Telephone-Delivered Acceptance and Commitment Therapy Intervention for People Living with HIV who are Hazardous Drinkers.

Alcohol use among people living with HIV (PWH) has been increasingly recognized as an important component of HIV care. Transdiagnostic treatments, such as Acceptance and Commitment Therapy (ACT), that target core processes common to multiple mental health and substance-related problems, may be ideal in HIV treatment settings where psychological and behavioral health comorbidities are high. In advance of a randomized clinical trial (RCT), the overall objective of this study was to systematically adapt an ACT-based intervention originally developed for smoking cessation, into an ACT intervention for PWH who drink at hazardous levels. Consistent with the ADAPT-ITT model, the adaptation progressed systematically in several phases, which included structured team meetings, three focus group discussions with PWH (N = 13), and in-depth interviews with HIV providers (N = 10), and development of standardized operating procedures for interventionist training, supervision, and eventual RCT implementation. The procedures described here offer a template for transparent reporting on early phase behavioral RCTs.

A conceptual model of alcohol use and adherence to antiretroviral therapy: systematic review and theoretical implications for mechanisms of action.

Alcohol consumption is one of the most prevalent correlates of antiretroviral therapy (ART) adherence, yet causal processes underlying this association remain largely unexplored. The goal of this systematic review was to develop a conceptual model that describes the causal effect of alcohol consumption on ART nonadherence. We reviewed 230 studies that examined the association between alcohol consumption and ART adherence with three primary aims: (1) to replicate and extend previous reviews of the literature, (2) to summarize and critique study designs capable of answering questions about temporal overlap and (3) to summarize potential mechanisms of action. A model of alcohol-associated ART nonadherence was proposed to guide future work, integrating general theories of ART adherence and theory on the psychological and behavioral effects of alcohol intoxication. The conceptual model describes two mechanistic processes-prospective memory impairment and interactive toxicity beliefs/avoidance behaviors-involved in alcohol-associated intentional and unintentional nonadherence, respectively. This model can be used to guide future research on the causal processes involved in the frequently observed correlation between alcohol consumption and adherence.

Substance use, sexual behavior, and general well-being of U.S. college students during the COVID-19 pandemic: A brief report.

This study gathered preliminary data on the impact of the U.S. response to the COVID-19 pandemic on the substance use, sexual behavior, and general well-being of U.S. college students. Participants from colleges across the U.S. (N = 212; 50.5% female; M age = 22.09) completed an online survey between May 20th and July 5th, 2020 about COVID-19-related behavior change. Most students reported a decrease in quality of life (71.7%), an increase in levels of anxiety (63.7%), and problems with basic resource needs (53.8%). Reports of alcohol consumption increased for 26.9% of students and 15.1% reported an increase in cannabis use. Most students (57.5%) reported a decrease in sexual activity, yet access to, and use of, condoms generally remained unchanged. As universities resume residential instruction, existing prevention and intervention services will need to be adapted to address the mental and behavioral health needs of college students during the era of COVID-19.

The Association Between Financial Resources Strain and Self-Reported Antiretroviral Therapy (ART) Adherence among HIV-Positive Men Who Have Sex with Men.

The purpose of this study was to assess the relationship between financial resources strain and self-reported ART adherence among men who have sex with men (MSM) who are living with HIV. Secondary data analyses were conducted with a sample of HIV-positive MSM (N = 77) who participated in a daily diary study on substance use and sexual behavior. Logistic regression was used to model the odds of self-reported ART adherence associated with financial resources strain. The adjusted model revealed a significant association between financial resources strain and self-reported ART adherence such that financially strained participants were 78.4% less likely to have "excellent" self-reported adherence ability compared with non-financially strained participants (aOR = .216, 95% CI [.063, .749], p = .016). Financial resources strain may negatively influence ART adherence. Future research should consider objectively measuring ART adherence. Health care providers might consider assessing patients' financial situation to identify those at-risk for nonadherence.

Parent mental health and family functioning following diagnosis of CHD: a research agenda and recommendations from the Cardiac Neurodevelopmental Outcome Collaborative.

Diagnosis of CHD substantially affects parent mental health and family functioning, thereby influencing child neurodevelopmental and psychosocial outcomes. Recognition of the need to proactively support parent mental health and family functioning following cardiac diagnosis to promote psychosocial adaptation has increased substantially over recent years. However, significant gaps in knowledge remain and families continue to report critical unmet psychosocial needs. The Parent Mental Health and Family Functioning Working Group of the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute to identify significant knowledge gaps related to parent mental health and family functioning, as well as critical questions that must be answered to further knowledge, policy, care, and outcomes. Conceptually driven investigations are needed to identify parent mental health and family functioning factors with the strongest influence on child outcomes, to obtain a deeper understanding of the biomarkers associated with these factors, and to better understand how parent mental health and family functioning influence child outcomes over time. Investigations are also needed to develop, test, and implement sustainable models of mental health screening and assessment, as well as effective interventions to optimise parent mental health and family functioning to promote psychosocial adaptation. The critical questions and investigations outlined in this paper provide a roadmap for future research to close gaps in knowledge, improve care, and promote positive outcomes for families of children with CHD.

Framed Messages to Increase Condom Use Frequency Among Individuals Taking Daily Antiretroviral Medication for Pre-exposure Prophylaxis.

PrEP delivery and routine care provide a unique opportunity to promote sexually transmitted infection (STI) prevention by both increasing STI testing frequency and creating a space for affirmative and effective safer sex counseling. This study was a feasibility and acceptability pilot of an adapted framed message intervention to increase condom use frequency with PrEP. In the formative phase, two focus groups with PrEP users (N = 7) provided feedback on a provisional loss-framed message intervention and identified potential study barriers. In the pilot trial, the adapted loss-framed message intervention was compared to a gain-framed message intervention and enhanced skills condition in a sample of PrEP users (N = 29). In terms of intervention feasibility, 58% of approached PrEP users completed the eligibility screen; 79% of those eligible enrolled in the study and 66% of enrolled participants completed the three-month follow-up. In terms of intervention acceptability, participants found the informational messages, regardless of assignment, to be moderately interesting (M = 6.24, SD = 2.97) and useful (M = 7.07, SD = 3.00), and very easy to understand (M = 9.50, SD = 0.97) on Likert-type scales ranging from 1 to 10. In terms of intervention effects, there was a small effect of the gain-framed intervention (b = .58, SE = .93, CI = -1.33, 2.48, Cohen's d = .26) on HIV/STI risk transmission. There was a small-medium effect of both the loss- (b = 2.00, SE = .90, CI = .15, 3.85, Cohen's d = 1.46) and gain-framed (b = 2.24, SE = .93, CI = .34, 4.15, Cohen's d = 1.65) interventions on condom use motivation. Finally, there was a medium-large effect of both the loss- (b = .97, SE = 1.33, CI = -1.88, 3.82, Cohen's d = .54) and gain-framed intervention (b = 1.97, SE = 1.33, CI = -.88, 4.82, Cohen's d = .87) on condom use frequency. Further refinement and testing, in a larger -scale trial with higher ecological validity than this initial pilot intervention, is warranted.

Cultural Adaptation of an Intervention to Reduce Hazardous Alcohol Use Among People Living with HIV in Southwestern Uganda.

Hazardous drinking by persons living with HIV (PLHIV) is a well-established determinant of sub-optimal HIV care and treatment outcomes. Despite this, to date, few interventions have sought to reduce hazardous drinking among PLHIV in sub-Saharan Africa (SSA). We describe an iterative cultural adaptation of an evidence-based multi-session alcohol reduction intervention for PLHIV in southwestern Uganda. The adaptation process included identifying core, theoretically informed, intervention elements, and conducting focus group discussions and cognitive interviews with community members, HIV clinic staff and patients to modify key intervention characteristics for cultural relevance and saliency. Adaptation of evidence-based alcohol reduction interventions can be strengthened by the inclusion of the target population and key stakeholders in shaping the content, while retaining fidelity to core intervention elements.

Assessing the interaction between depressive symptoms and alcohol use prior to antiretroviral therapy on viral suppression among people living with HIV in Rural Uganda.

Although there is evidence of individual associations between depressive symptoms and hazardous alcohol use with suboptimal antiretroviral therapy (ART) adherence among people living with HIV (PLWH), few studies have established how the two risk factors may interact to predict viral suppression. We conducted secondary data analyses with two cohorts of Ugandan PLWH (N = 657) to investigate the hypothesized interaction between depressive symptoms (Center for Epidemiological Studies Depression Scale) and hazardous alcohol use (Alcohol Use Disorder Identification Test -Consumption and/or Phosphatidylethanol biomarker) prior to ART initiation with viral suppression (<550 copies/ml). We were unable to detect an interaction between depressive symptoms and hazardous alcohol use prior to ART initiation with viral suppression in the first two years (M = 19.9 months) after ART initiation (p = 0.75). There was also no evidence of a main effect association for depressive symptoms (Adjusted Odds Ratio [AOR] = 0.88, 95% Confidence Interval [CI]: 0.50, 1.55) or hazardous alcohol use (AOR = 1.37, 95% CI: 0.80, 2.33). PLWH with depressive symptoms and/or hazardous alcohol use appear to exhibit similar levels of viral suppression as others in care; further work is needed to determine effects on HIV testing and treatment engagement.

Acceptance and Commitment Therapy (ACT) for HIV-infected Hazardous Drinkers: A Qualitative Study of Acceptability.

Alcohol use is a significant problem in HIV care, and clinical trials of alcohol interventions for people living with HIV infection (PLWH) have produced mixed results. The purpose of this qualitative study was to collect preliminary data on the practical feasibility and acceptability of Acceptance and Commitment Therapy (ACT) as a treatment for PLWH who are hazardous drinkers. A total of 25 PLWH participated in individual interviews. Four major themes emerged from the thematic analysis: (I) Perceived Appropriateness for PLWH and People who use Alcohol and/or other Substances, (II) General Satisfaction and Dissatisfaction, (III) Positive and Negative Effects on Participants and (IV) Facilitators and Barriers to Implementing ACT Intervention Strategies.

Social Desirability Bias Impacts Self-Reported Alcohol Use Among Persons With HIV in Uganda.

BACKGROUND: Self-report is widely used to assess alcohol use in research and clinical practice, but may be subject to social desirability bias. We aimed to determine if social desirability impacts self-reported alcohol use. METHODS: Among 751 human immunodeficiency virus (HIV)-infected patients from a clinic in southwestern Uganda, we measured social desirability using the Marlowe-Crowne Social Desirability Scale (SDS) Short Form C, self-reported alcohol use (prior 3 months) Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), and phosphatidylethanol (PEth), a biomarker of prior 3 weeks' drinking. We conducted multiple regression analyses to assess the relationship between SDS score (low, medium, and high levels) and (i) any self-reported recent alcohol use, among those who were PEth-positive (≥8 ng/ml), and (ii) continuous AUDIT-C score, among those reporting any recent alcohol use. We controlled for PEth level, age, gender, education, economic assets, marital status, religion, spirituality/religiosity, social support, and study cohort. RESULTS: Of 751 participants, 59% were women; the median age was 31 years (interquartile range [IQR]: 26 to 39). Median SDS score was 9 (IQR: 4 to 10). Two-thirds (62%) self-reported any recent alcohol use; median AUDIT-C was 1 (IQR: 0 to 4). Among those who were PEth-positive (57%), 13% reported no recent alcohol use. Those with the highest SDS tertile had decreased odds of reporting any recent alcohol use compared to the lowest tertile, but the association did not reach statistical significance in multivariable analyses (adjusted odds ratio 0.55 [95% confidence interval (CI): 0.25, 1.23]). Among participants self-reporting recent alcohol use, SDS level was negatively associated with AUDIT-C scores (adjusted ß: -0.70 [95% CI: -1.19, -0.21] for medium vs. low SDS and -1.42 [95% CI: -2.05, -0.78] for high vs. low SDS). CONCLUSIONS: While use of objective measures (e.g., alcohol biomarkers) is desirable for measuring alcohol use, SDS scores may be used to adjust self-reported drinking levels by participants' level of social desirability in HIV research studies.

Alcohol use and relationship quality among South African couples.

OBJECTIVE: The HIV literature has largely ignored the importance of alcohol use in the quality of intimate relationships in sub-Saharan Africa (SSA), despite evidence of alcohol's role in relational behaviors that increase risk for HIV infection and other harms. The present study explored the association of alcohol use with relationship functioning among heterosexual couples from rural South Africa. METHOD: Dyadic analyses were conducted with 443 sexually active, heterosexual, South African couples (886 individuals) to examine the association between male partners' alcohol use (abstinent, nonhazardous, and hazardous), and male and female partners' reports of relationship intimacy, trust, mutually constructive communication, demand/withdraw communication, and satisfaction. Five structural equation models were fit using male partner alcohol use as a predictor of male and female reports of relationship quality. RESULTS: Women with a hazardous-drinking male partner (compared to an abstainer) reported significantly higher levels of intimacy (p <.05) and significantly more demand/withdraw communication (p <.001); men who were hazardous drinkers reported significantly less trust in their relationship compared to men who were abstainers (p < .01). CONCLUSIONS: Hazardous alcohol use among South African couples is positively correlated with women's relationship intimacy and maladaptive communication patterns, yet negatively correlated with men's perceived trust.

Correction to: Association of Depressive Symptoms with Lapses in Antiretroviral Medication Adherence Among People Living with HIV: A Test of an Indirect Pathway.

The original version of this article unfortunately contained a mistake in Fig. 1. The figure was incorrectly presented with the results of an additional path model for forgotten antiretroviral therapy (ART) doses that was dropped from the primary analyses.