Reducing Immunogenicity by Design: Approaches to Minimize Immunogenicity of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) have transformed therapeutic strategies for various diseases. Their high specificity to target antigens makes them ideal therapeutic agents for certain diseases. However, a challenge to their application in clinical practice is their potential risk to induce unwanted immune response, termed immunogenicity. This challenge drives the continued efforts to deimmunize these protein therapeutics while maintaining their pharmacokinetic properties and therapeutic efficacy. Because mAbs hold a central position in therapeutic strategies against an array of diseases, the importance of conducting comprehensive immunogenicity risk assessment during the drug development process cannot be overstated. Such assessment necessitates the employment of in silico, in vitro, and in vivo strategies to evaluate the immunogenicity risk of mAbs. Understanding the intricacies of the mechanisms that drive mAb immunogenicity is crucial to improving their therapeutic efficacy and safety and developing the most effective strategies to determine and mitigate their immunogenic risk. This review highlights recent advances in immunogenicity prediction strategies, with a focus on protein engineering strategies used throughout development to reduce immunogenicity.

Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation.

For Plasmodium falciparum, the most widespread and virulent malaria parasite that infects humans, persistence depends on continuous asexual replication in red blood cells, while transmission to their mosquito vector requires asexual blood-stage parasites to differentiate into non-replicating gametocytes. This decision is controlled by stochastic derepression of a heterochromatin-silenced locus encoding AP2-G, the master transcription factor of sexual differentiation. The frequency of ap2-g derepression was shown to be responsive to extracellular phospholipid precursors but the mechanism linking these metabolites to epigenetic regulation of ap2-g was unknown. Through a combination of molecular genetics, metabolomics and chromatin profiling, we show that this response is mediated by metabolic competition for the methyl donor S-adenosylmethionine between histone methyltransferases and phosphoethanolamine methyltransferase, a critical enzyme in the parasite's pathway for de novo phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of SAM for de novo phosphatidylcholine synthesis impairs maintenance of the histone methylation responsible for silencing ap2-g, increasing the frequency of derepression and sexual differentiation. This provides a key mechanistic link that explains how LysoPC and choline availability can alter the chromatin status of the ap2-g locus controlling sexual differentiation.

Patient Engagement in a Multimodal Digital Phenotyping Study of Opioid Use Disorder.

BACKGROUND: Multiple digital data sources can capture moment-to-moment information to advance a robust understanding of opioid use disorder (OUD) behavior, ultimately creating a digital phenotype for each patient. This information can lead to individualized interventions to improve treatment for OUD. OBJECTIVE: The aim is to examine patient engagement with multiple digital phenotyping methods among patients receiving buprenorphine medication for OUD. METHODS: The study enrolled 65 patients receiving buprenorphine for OUD between June 2020 and January 2021 from 4 addiction medicine programs in an integrated health care delivery system in Northern California. Ecological momentary assessment (EMA), sensor data, and social media data were collected by smartphone, smartwatch, and social media platforms over a 12-week period. Primary engagement outcomes were meeting measures of minimum phone carry (≥8 hours per day) and watch wear (≥18 hours per day) criteria, EMA response rates, social media consent rate, and data sparsity. Descriptive analyses, bivariate, and trend tests were performed. RESULTS: The participants' average age was 37 years, 47% of them were female, and 71% of them were White. On average, participants met phone carrying criteria on 94% of study days, met watch wearing criteria on 74% of days, and wore the watch to sleep on 77% of days. The mean EMA response rate was 70%, declining from 83% to 56% from week 1 to week 12. Among participants with social media accounts, 88% of them consented to providing data; of them, 55% of Facebook, 54% of Instagram, and 57% of Twitter participants provided data. The amount of social media data available varied widely across participants. No differences by age, sex, race, or ethnicity were observed for any outcomes. CONCLUSIONS: To our knowledge, this is the first study to capture these 3 digital data sources in this clinical population. Our findings demonstrate that patients receiving buprenorphine treatment for OUD had generally high engagement with multiple digital phenotyping data sources, but this was more limited for the social media data. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.3389/fpsyt.2022.871916.

The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching.

The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var, and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P. falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.

A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency.

Eukaryotes have canonical pathways for responding to amino acid (AA) availability. Under AA-limiting conditions, the TOR complex is repressed, whereas the sensor kinase GCN2 is activated. While these pathways have been highly conserved throughout evolution, malaria parasites are a rare exception. Despite auxotrophic for most AA, Plasmodium does not have either a TOR complex nor the GCN2-downstream transcription factors. While Ile starvation has been shown to trigger eIF2α phosphorylation and a hibernation-like response, the overall mechanisms mediating detection and response to AA fluctuation in the absence of such pathways has remained elusive. Here we show that Plasmodium parasites rely on an efficient sensing pathway to respond to AA fluctuations. A phenotypic screen of kinase knockout mutant parasites identified nek4, eIK1 and eIK2-the last two clustering with the eukaryotic eIF2α kinases-as critical for Plasmodium to sense and respond to distinct AA-limiting conditions. Such AA-sensing pathway is temporally regulated at distinct life cycle stages, allowing parasites to actively fine-tune replication and development in response to AA availability. Collectively, our data disclose a set of heterogeneous responses to AA depletion in malaria parasites, mediated by a complex mechanism that is critical for modulating parasite growth and survival.

Genome-wide profiling of histone modifications in Plasmodium falciparum using CUT&RUN.

We recently adapted a CUT&RUN protocol for genome-wide profiling of chromatin modifications in the human malaria parasite Plasmodium Using the step-by-step protocol described below, we were able to generate high-quality profiles of multiple histone modifications using only a small fraction of the cells required for ChIP-seq. Using antibodies against two commonly profiled histone modifications, H3K4me3 and H3K9me3, we show here that CUT&RUN profiling is highly reproducible and closely recapitulates previously published ChIP-seq-based abundance profiles of histone marks. Finally, we show that CUT&RUN requires substantially lower sequencing coverage for accurate profiling compared with ChIP-seq.

Technology-Based Interventions in Substance Use Treatment to Promote Health Equity Among People Who Identify as African American/Black, Hispanic/Latinx, and American Indian/Alaskan Native: Protocol for a Scoping Review.

BACKGROUND: Technology-based interventions (TBIs; ie, web-based and mobile interventions) have the potential to promote health equity in substance use treatment (SUTx) for underrepresented groups (people who identify as African American/Black, Hispanic/Latinx, and American Indian/Alaskan Native) by removing barriers and increasing access to culturally relevant effective treatments. However, technologies (emergent and more long-standing) may have unintended consequences that could perpetuate health care disparities among people who identify as a member of one of the underrepresented groups. Health care research, and SUTx research specifically, is infrequently conducted with people who identify with these groups as the main focus. Therefore, an improved understanding of the literature at the intersection of SUTx, TBIs, and underrepresented groups is warranted to avoid exacerbating inequities and to promote health equity. OBJECTIVE: This study aims to explore peer-reviewed literature (January 2000-March 2021) that includes people who identify as a member of one of the underrepresented groups in SUTx research using TBIs. We further seek to explore whether this subset of research is race/ethnicity conscious (does the research consider members of underrepresented groups beyond their inclusion as study participants in the introduction, methods, results, or discussion). METHODS: Five electronic databases (MEDLINE, Scopus, Cochrane Library, CINAHL, and PsycInfo) were searched to identify SUTx research using TBIs, and studies were screened for eligibility at the title/abstract and full-text levels. Studies were included if their sample comprised of people who identify as a member of one of the underrepresented groups at 50% or more when combined. RESULTS: Title/abstract and full-text reviews were completed in 2021. These efforts netted a sample of 185 studies that appear to meet inclusionary criteria. Due to the uniqueness of tobacco relative to other substances in the SUTx space, as well as the large number of studies netted, we plan to separately publish a scoping review on tobacco-focused studies that meet all other criteria. Filtering for tobacco-focused studies (n=31) netted a final full-text sample for a main scoping review of 154 studies. The tobacco-focused scoping review manuscript is expected to be submitted for peer review in Spring 2022. The main scoping review data extraction and data validation to confirm the accuracy and consistency of data extraction across records was completed in March 2022. We expect to publish the main scoping review findings by the end of 2022. CONCLUSIONS: Research is needed to increase our understanding of the range and nature of TBIs being used in SUTx research studies with members of underrepresented groups. The planned scoping review will highlight research at this intersection to promote health equity. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34508.

The Feasibility and Utility of Harnessing Digital Health to Understand Clinical Trajectories in Medication Treatment for Opioid Use Disorder: D-TECT Study Design and Methodological Considerations.

Introduction: Across the U.S., the prevalence of opioid use disorder (OUD) and the rates of opioid overdoses have risen precipitously in recent years. Several effective medications for OUD (MOUD) exist and have been shown to be life-saving. A large volume of research has identified a confluence of factors that predict attrition and continued substance use during substance use disorder treatment. However, much of this literature has examined a small set of potential moderators or mediators of outcomes in MOUD treatment and may lead to over-simplified accounts of treatment non-adherence. Digital health methodologies offer great promise for capturing intensive, longitudinal ecologically-valid data from individuals in MOUD treatment to extend our understanding of factors that impact treatment engagement and outcomes. Methods: This paper describes the protocol (including the study design and methodological considerations) from a novel study supported by the National Drug Abuse Treatment Clinical Trials Network at the National Institute on Drug Abuse (NIDA). This study (D-TECT) primarily seeks to evaluate the feasibility of collecting ecological momentary assessment (EMA), smartphone and smartwatch sensor data, and social media data among patients in outpatient MOUD treatment. It secondarily seeks to examine the utility of EMA, digital sensing, and social media data (separately and compared to one another) in predicting MOUD treatment retention, opioid use events, and medication adherence [as captured in electronic health records (EHR) and EMA data]. To our knowledge, this is the first project to include all three sources of digitally derived data (EMA, digital sensing, and social media) in understanding the clinical trajectories of patients in MOUD treatment. These multiple data streams will allow us to understand the relative and combined utility of collecting digital data from these diverse data sources. The inclusion of EHR data allows us to focus on the utility of digital health data in predicting objectively measured clinical outcomes. Discussion: Results may be useful in elucidating novel relations between digital data sources and OUD treatment outcomes. It may also inform approaches to enhancing outcomes measurement in clinical trials by allowing for the assessment of dynamic interactions between individuals' daily lives and their MOUD treatment response. Clinical Trial Registration: Identifier: NCT04535583.

The application of digital health to the assessment and treatment of substance use disorders: The past, current, and future role of the National Drug Abuse Treatment Clinical Trials Network.

The application of digital technologies to better assess, understand, and treat substance use disorders (SUDs) is a particularly promising and vibrant area of scientific research. The National Drug Abuse Treatment Clinical Trials Network (CTN), launched in 1999 by the U.S. National Institute on Drug Abuse, has supported a growing line of research that leverages digital technologies to glean new insights into SUDs and provide science-based therapeutic tools to a diverse array of persons with SUDs. This manuscript provides an overview of the breadth and impact of research conducted in the realm of digital health within the CTN. This work has included the CTN's efforts to systematically embed digital screeners for SUDs into general medical settings to impact care models across the nation. This work has also included a pivotal multi-site clinical trial conducted on the CTN platform, whose data led to the very first "prescription digital therapeutic" authorized by the U.S. Food and Drug Administration (FDA) for the treatment of SUDs. Further CTN research includes the study of telehealth to increase capacity for science-based SUD treatment in rural and under-resourced communities. In addition, the CTN has supported an assessment of the feasibility of detecting cocaine-taking behavior via smartwatch sensing. And, the CTN has supported the conduct of clinical trials entirely online (including the recruitment of national and hard-to-reach/under-served participant samples online, with remote intervention delivery and data collection). Further, the CTN is supporting innovative work focused on the use of digital health technologies and data analytics to identify digital biomarkers and understand the clinical trajectories of individuals receiving medications for opioid use disorder (OUD). This manuscript concludes by outlining the many potential future opportunities to leverage the unique national CTN research network to scale-up the science on digital health to examine optimal strategies to increase the reach of science-based SUD service delivery models both within and outside of healthcare.

Generation of Transmission-Competent Human Malaria Parasites with Chromosomally-Integrated Fluorescent Reporters.

Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.

Barriers to antiretroviral therapy initiation for HIV-positive children aged 2-18 months in Swaziland.

Although early antiretroviral therapy (ART) reduces HIV-related mortality in children by up to 75%, almost half of HIV-positive children younger than 1 year old in Swaziland do not initiate ART. This study was conducted to identify barriers to early ART initiation among HIV-positive infants. This was a case-control study among HIV-positive infants, aged 2 to 18 months, who either did not initiate ART (cases), or initiated ART (controls), during 18 months after testing. Multivariable logistic regression showed that infants who visited the clinic every month, or every 2 months, were 5.78 and 6.20 times more likely to initiate ART than those who visited less often (OR 5.78, 95% CI 1.82-18.33 and OR 6.20, 95% CI 1.30-29.60 respectively). Children who lived ≤30 and 31-60 minutes from the nearest clinic were 84% and 79% less likely respectively to initiate ART (OR 0.16, 95% CI 0.03-0.78 and OR 0.21, 95% CI 0.04-0.98) compared with those who lived more than 60 minutes away. Children who received immunisation after 6 months were 22.59 times more likely to initiate ART (OR 22.59, 95% CI 7.00-21.72) than those who did not. Infants of caregivers who had excellent or good relationships with their healthcare provider were 4.32 times more likely to initiate ART (OR 4.32, 95% CI 1.01-18.59) than those of caregivers who had average or poor relationships with healthcare providers. The significant predictors of ART initiation identified in this study should be regarded as priority areas for intervention among HIV-positive women in Swaziland.

Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites.

Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes. Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite and ends, 48 hours later, with a schizont releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes. Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600), the master regulator of sexual development, from an epigenetically silenced state during asexual replication. AP2-G expression during this 'commitment cycle' prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism. To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1-30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling. Here we use highly parallel, single-cell RNA sequencing of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G+ mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histone-modifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.

A qualitative analysis of the barriers to antiretroviral therapy initiation among children 2 to 18 months of age in Swaziland.

HIV/AIDS remains one of the leading causes of death among children under 5 years old in Swaziland. Although studies have shown that early initiation of infants and children diagnosed with HIV on antiretroviral therapy (ART) significantly reduces mortality, many children do not initiate ART until the later stages of disease. This study was designed to collect qualitative data from mothers and caregivers of HIV-positive children to identify the barriers to ART initiation. Focus group discussion (FGD) sessions were conducted in siSwati between July and September 2014 among caregivers of aged children 2-18 months in Swaziland who did or did not initiate ART between January 2011 and December 2012 after HIV DNA PCR-positive diagnosis of the infants. Denial, guilt, lack of knowledge, tuberculosis (TB)/HIV co-infection, HIV-related stigma, lack of money, and distance to clinics were reported by the participants as barriers to ART initiation. The findings further revealed that non-initiation on ART was not linked to a negative perception of the treatment. Findings suggest a need to improve sensitivity among healthcare workers as well as education and counselling services that will facilitate the ART initiation process.

A qualitative analysis of the barriers to antiretroviral therapy initiation among children 2 to 18 months of age in Swaziland

HIV/AIDS remains one of the leading causes of death among children under 5 years old in Swaziland. Although studies have shown that early initiation of infants and children diagnosed with HIV on antiretroviral therapy (ART) significantly reduces mortality, many children do not initiate ART until the later stages of disease. This study was designed to collect qualitative data from mothers and caregivers of HIV-positive children to identify the barriers to ART initiation. Focus group discussion (FGD) sessions were conducted in siSwati between July and September 2014 among caregivers of aged children 2­18 months in Swaziland who did or did not initiate ART between January 2011 and December 2012 after HIV DNA PCR-positive diagnosis of the infants. Denial, guilt, lack of knowledge, tuberculosis (TB)/HIV co-infection, HIV-related stigma, lack of money, and distance to clinics were reported by the participants as barriers to ART initiation. The findings further revealed that non-initiation on ART was not linked to a negative perception of the treatment. Findings suggest a need to improve sensitivity among healthcare workers as well as education and counselling services that will facilitate the ART initiation process

The influence of family and social problems on treatment outcomes of persons with co-occurring substance use disorders and PTSD.

OBJECTIVE: Family and social problems may contribute to negative recovery outcomes in patients with co-occurring substance use and psychiatric disorders, yet few studies have empirically examined this relationship. This study investigates the impact of family and social problems on treatment outcomes among patients with co-occurring substance use and posttraumatic stress disorder (PTSD). METHOD: A secondary analysis was conducted using data collected from a randomized controlled trial of an integrated therapy for patients with co-occurring substance use and PTSD. Substance use, psychiatric symptoms, and social problems were assessed. Longitudinal outcomes were analyzed using generalized estimating equations (GEE) and multiple linear regression. RESULTS: At baseline, increased family and social problems were associated with more severe substance use and psychiatric symptoms. Over time, all participants had comparable decreases in substance use and psychiatric problem severity. However, changes in family and social problem severity were predictive of PTSD symptom severity, alcohol use, and psychiatric severity at follow-up. CONCLUSIONS: For patients with co-occurring substance use and PTSD, family and social problem severity is associated with substance use and psychiatric problem severity at baseline and over time. Targeted treatment for social and family problems may be optimal.

Using a Learning Collaborative Strategy With Office-based Practices to Increase Access and Improve Quality of Care for Patients With Opioid Use Disorders.

OBJECTIVES: Rapidly escalating rates of heroin and prescription opioid use have been widely observed in rural areas across the United States. Although US Food and Drug Administration-approved medications for opioid use disorders exist, they are not routinely accessible to patients. One medication, buprenorphine, can be prescribed by waivered physicians in office-based practice settings, but practice patterns vary widely. This study explored the use of a learning collaborative method to improve the provision of buprenorphine in the state of Vermont. METHODS: We initiated a learning collaborative with 4 cohorts of physician practices (28 total practices). The learning collaborative consisted of a series of 4 face-to-face and 5 teleconference sessions over 9 months. Practices collected and reported on 8 quality-improvement data measures, which included the number of patients prescribed buprenorphine, and the percent of unstable patients seen weekly. Changes from baseline to 8 months were examined using a p-chart and logistic regression methodology. RESULTS: Physician engagement in the learning collaborative was favorable across all 4 cohorts (85.7%). On 6 of the 7 quality-improvement measures, there were improvements from baseline to 8 months. On 4 measures, these improvements were statistically significant (P < 0.001). Importantly, practice variation decreased over time on all measures. The number of patients receiving medication increased only slightly (3.4%). CONCLUSIONS: Results support the effectiveness of a learning collaborative approach to engage physicians, modestly improve patient access, and significantly reduce practice variation. The strategy is potentially generalizable to other systems and regions struggling with this important public health problem.

The impact of addiction medications on treatment outcomes for persons with co-occurring PTSD and opioid use disorders.

BACKGROUND AND OBJECTIVES: Previous research has been inconclusive about whether adding psychosocial treatment to medication assisted treatment (MAT) improves outcomes for patients with co-occurring psychiatric and opioid use disorders. This study evaluated the impact of MAT and psychosocial therapies on treatment outcomes for patients with co-occurring opioid use disorders and PTSD. METHODS: Patients meeting criteria for PTSD and substance use disorders were randomly assigned to one of three treatment conditions: Standard Care (SC) alone, Integrated Cognitive Behavioral Therapy (ICBT) plus SC, or Individual Addiction Counseling (IAC) plus SC. Substance use and psychiatric symptoms were assessed at baseline and 6 months. Only patients with opioid use disorders were included in the present analyses (n = 126). Two-way ANOVAS and logistic regression analyses were used to examine associations between treatment conditions and MAT, for substance use and psychiatric outcomes. RESULTS: MAT patients receiving ICBT had significantly decreased odds of a positive urine drug screen, compared to non-MAT patients receiving SC alone (OR = .07, 95% CI = .01, .81, p = .03). For PTSD symptoms, a significant MAT by psychosocial treatment condition interaction demonstrated that MAT patients had comparable declines in PTSD symptoms regardless of psychosocial treatment type (F(2, 88) = 4.74, p = .011). Non-MAT patients in ICBT had significantly larger reductions in PTSD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: For patients with co-occurring opioid use disorders and PTSD, MAT plus ICBT is associated with more significant improvement in substance use. For non-MAT patients, ICBT is most beneficial for PTSD symptoms.

Adherence and competence in two manual-guided therapies for co-occurring substance use and posttraumatic stress disorders: clinician factors and patient outcomes.

BACKGROUND: The challenges of implementing and sustaining evidence-based therapies into routine practice have been well-documented. OBJECTIVES: This study examines the relationship among clinician factors, quality of therapy delivery, and patient outcomes. METHODS: Within a randomized controlled trial, 121 patients with current co-occurring substance use and posttraumatic stress disorders were allocated to receive either manualized Integrated Cognitive Behavioral Therapy (ICBT) or Individual Addiction Counseling (IAC). Twenty-two clinicians from seven addiction treatment programs were trained and supervised to deliver both therapies. Clinician characteristics were assessed at baseline; clinician adherence and competence were assessed over the course of delivering both therapies; and patient outcomes were measured at baseline and 6-month follow-up. RESULTS: Although ICBT was delivered at acceptable levels, clinicians were significantly more adherent to IAC (p < 0.05). At session 1, clinical female gender (p < 0.05) and lower education level (p < 0.05) were predictive of increased clinician adherence and competence across both therapies. Adherence and competence at session 1 in either therapy were significantly predictive of positive patient outcomes. ICBT adherence (p < 0.05) and competence (p < 0.01) were predictive of PTSD symptom reduction, whereas IAC adherence (p < 0.01) and competence (p < 0.01) were associated with decreased drug problem severity. CONCLUSIONS: The differential impact of adherence and competence for both therapy types is consistent with their purported primary target: ICBT for PTSD and IAC for substance use. These findings also suggest the benefits of considering clinician factors when implementing manual-guided therapies. Future research should focus on diverse clinician samples, randomization of clinicians to therapy type, and prospective designs to evaluate models of supervision and quality monitoring.

A randomized controlled trial of treatments for co-occurring substance use disorders and post-traumatic stress disorder.

BACKGROUND AND AIMS: Post-traumatic stress disorder (PTSD) is common among people with substance use disorders, and the comorbidity is associated with negative outcomes. We report on a randomized controlled trial comparing the effect of integrated cognitive-behavioral therapy (ICBT) plus standard care, individual addiction counseling plus standard care and standard care alone on substance use and PTSD symptoms. DESIGN: Three-group, multi-site randomized controlled trial. SETTING: Seven addiction treatment programs in Vermont and New Hampshire, USA. PARTICIPANTS/CASES: Recruitment took place between December 2010 and January 2013. In this single-blind study, 221 participants were randomized to one of three conditions: ICBT plus standard care (SC) (n = 73), individual addiction counseling (IAC) plus SC (n = 75) or SC only (n = 73). One hundred and seventy-two patients were assessed at 6-month follow-up (58 ICBT; 61 IAC; 53 SC). Intervention and comparators: ICBT is a manual-guided therapy focused on PTSD and substance use symptom reduction with three main components: patient education, mindful relaxation and flexible thinking. IAC is a manual-guided therapy focused exclusively on substance use and recovery with modules organized in a stage-based approach: treatment initiation, early abstinence, maintaining abstinence and recovery. SC are intensive out-patient program services that include 9-12 hours of face-to-face contact per week over 2-4 days of group and individual therapies plus medication management. MEASUREMENTS: Primary outcomes were PTSD severity and substance use severity at 6 months. Secondary outcomes were therapy retention. FINDINGS: PTSD symptoms reduced in all conditions with no difference between them. In analyses of covariance, ICBT produced more favorable outcomes on toxicology than IAC or SC [comparison with IAC, parameter estimate: 1.10; confidence interval (CI) = 0.17-2.04; comparison with SC, parameter estimate: 1.13; CI = 0.18-2.08] and had a greater reduction in reported drug use than SC (parameter estimate: -9.92; CI = -18.14 to -1.70). ICBT patients had better therapy continuation versus IAC (P<0.001). There were no unexpected or study-related adverse events. CONCLUSIONS: Integrated cognitive behavioral therapy may improve drug-related outcomes in post-traumatic stress disorder sufferers with substance use disorder more than drug-focused counseling, but probably not by reducing post-traumatic stress disorder symptoms to a greater extent.

The Prevalence of Posttraumatic Stress Disorder Symptoms among Addiction Treatment Patients with Cocaine Use Disorders.

Co-occurring cocaine use and posttraumatic stress disorders are prevalent and associated with negative treatment, health and societal consequences. This study examined the relationships among PTSD symptoms, gender, and cocaine use problems. Within a cross-sectional design, we gathered archival point prevalence data on new admissions (n = 573) to three addiction treatment agencies. Demographic, substance use, and PTSD symptom information were collected across the three agencies. Logistic regression analyses revealed that patients with cocaine use disorders had a two-fold increased odds for a probable PTSD diagnosis, compared to patients without a cocaine use disorder (OR = 2.19, 95% CI = 1.49-3.22, p < 0.001). Among females with cocaine use disorder, multinomial regression yielded a significant increase in the risk of moderate (RRR = 2.12, 95% CI = 1.10-4.10, p < 0.05) and severe (RRR = 2.87, 95% CI = 1.33-6.21, p < 0.01) PTSD symptoms. Males with cocaine use disorders had a two-fold increase in the risk of moderate PTSD symptoms (RRR = 2.13, 95% CI = 1.23-3.68, p < 0.01), but had no increased risk of developing severe PTSD symptoms (RRR = 1.93, 95% CI = 0.85-4.39, p = 0.117). Cocaine use appears to impact the risk of PTSD symptoms, especially in females. Future research should explore the generalizability of these findings to more racially and ethnically diverse samples, as well as among persons with this comorbidity who are not engaged in treatment services.