Multidimensional Family Therapy for Justice-Involved Young Adults with Substance Use Disorders.

The present study explored the acceptability, feasibility, fidelity, and outcomes of a young adult adaptation of multidimensional family therapy (MDFT), an evidence-based family treatment originally developed for adolescents. Participants included 22 individuals between the ages of 19 to 25 who were enrolled in a criminal drug court program. MDFT was found to be feasible and was delivered with strong fidelity to young adults and their families. Participants reported high satisfaction with MDFT, and 95% completed treatment. Analyses revealed statistically significant decreases in substance use on all indicators from baseline to the 6-month follow-up. Significant improvements were also noted in vocational functioning, including a 73% increase in full-time employment from baseline to 6-month follow-up. Criminal justice outcomes included a significant decrease in legal risk, and 86% of study participants had no rearrests from baseline through the 18-month follow-up period. The article concludes with recommendations for implementing family-based interventions with young adults, as well as future research directions in this important area.

Antibody Response to SARS-CoV-2 Infection and Vaccination in COVID-19-naïve and Experienced Individuals.

Understanding the magnitude of responses to vaccination during the ongoing SARS-CoV-2 pandemic is essential for ultimate mitigation of the disease. Here, we describe a cohort of 102 subjects (70 COVID-19-naïve, 32 COVID-19-experienced) who received two doses of one of the mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)). We document that a single exposure to antigen via infection or vaccination induces a variable antibody response which is affected by age, gender, race, and co-morbidities. In response to a second antigen dose, both COVID-19-naïve and experienced subjects exhibited elevated levels of anti-spike and SARS-CoV-2 neutralizing activity; however, COVID-19-experienced individuals achieved higher antibody levels and neutralization activity as a group. The COVID-19-experienced subjects exhibited no significant increase in antibody or neutralization titer in response to the second vaccine dose (i.e., third antigen exposure). Finally, we found that COVID-19-naïve individuals who received the Moderna vaccine exhibited a more robust boost response to the second vaccine dose (p = 0.004) as compared to the response to Pfizer-BioNTech. Ongoing studies with this cohort will continue to contribute to our understanding of the range and durability of responses to SARS-CoV-2 mRNA vaccines.

Breakthrough Infections with Multiple Lineages of SARS-CoV-2 Variants Reveals Continued Risk of Severe Disease in Immunosuppressed Patients.

The pandemic of COVID-19 caused by SARS-CoV-2 infection continues to spread around the world. Vaccines that elicit protective immunity have reduced infection and mortality, however new viral variants are arising that may evade vaccine-induced immunity or cause disease in individuals who are unable to develop robust vaccine-induced responses. Investigating the role of viral variants in causing severe disease, evading vaccine-elicited immunity, and infecting vulnerable individuals is important for developing strategies to control the pandemic. Here, we report fourteen breakthrough infections of SARS-CoV-2 in vaccinated individuals with symptoms ranging from asymptomatic/mild (6/14) to severe disease (8/14). High viral loads with a median Ct value of 19.6 were detected in the nasopharyngeal specimens from subjects regardless of disease severity. Sequence analysis revealed four distinct virus lineages, including alpha and gamma variants of concern. Immunosuppressed individuals were more likely to be hospitalized after infection (p = 0.047), however no specific variant was associated with severe disease. Our results highlight the high viral load that can occur in asymptomatic breakthrough infections and the vulnerability of immunosuppressed individuals to post-vaccination infections by diverse variants of SARS-CoV-2.

Multidimensional Family Therapy as a community-based alternative to residential treatment for adolescents with substance use and co-occurring mental health disorders.

This randomized clinical trial (RCT) compared Multidimensional Family Therapy (MDFT) with residential treatment (RT) for adolescents with co-occurring substance use and mental health disorders on substance use, delinquency, and mental health symptoms. Using an intent-to-treat design, 113 adolescents who had been referred for residential treatment were randomly assigned to either RT or MDFT in the home/community. The sample was primarily male (75%) and Hispanic (68%) with an average age of 15.4 years. Seventy-one percent of youth had at least one previous residential treatment placement. Participants were assessed at baseline and at 2, 4, 12 and 18 months post-baseline. During the early phase of treatment (baseline to 2 months), youth in both treatments showed significant reductions in substance use [substance use problems (d = 1.10), frequency of use (d = 1.36)], delinquent behaviors (d = 0.18) and externalizing symptoms (d = 0.77), and youth receiving MDFT reported significantly greater reductions in internalizing symptoms than youth receiving RT (d = 0.42). In phase 2, from 2 to 18 months after baseline, youth in MDFT maintained their early treatment decreases in substance use problems (d = 0.51), frequency of use (d = 0.24), and delinquent behaviors (d = 0.42) more effectively than youth in RT. During this period, there were no significant treatment differences in maintenance of gains for externalizing and internalizing symptoms. Results suggest that Multidimensional Family Therapy is a promising alternative to residential treatment for youth with substance use and co-occurring disorders. The results, if supported through replication, are important because they challenge the prevailing assumption that adolescents who meet criteria for residential treatment cannot be adequately managed in a non-residential setting.

Family-Based HIV and Sexually Transmitted Infection Risk Reduction for Drug-Involved Young Offenders: 42-Month Outcomes.

This study tested a family-based human immunodeficiency virus (HIV)/sexually transmitted infection (STI) prevention approach integrated within an empirically supported treatment for drug-involved young offenders, Multidimensional Family Therapy (MDFT). A randomized, controlled, two-site community-based trial was conducted with 154 youth and their parents. Drug-involved adolescents were recruited in detention, randomly assigned to either MDFT or Enhanced Services as Usual (ESAU), and assessed at intake, 3, 6, 9, 18, 24, 36, and 42-month follow-ups. Youth in both conditions received structured HIV/STI prevention in detention and those in MDFT also received family-based HIV/STI prevention as part of ongoing treatment following detention release. Youth in both conditions and sites significantly reduced rates of unprotected sex acts and STI incidence from intake to 9 months. They remained below baseline levels of STI incidence (10%) over the 42-month follow-up period. At Site A, adolescents who were sexually active at intake and received MDFT showed greater reduction in overall frequency of sexual acts and number of unprotected sexual acts than youth in ESAU between intake and 9-month follow-ups. These intervention differences were evident through the 42-month follow-up. Intervention effects were not found for STI incidence or unprotected sex acts at Site B. Intensive group-based and family intervention in detention and following release may reduce sexual risk among substance-involved young offenders, and a family-based approach may enhance effects among those at highest risk. Site differences in intervention effects, study limitations, clinical implications, and future research directions are discussed.

Membrane anchoring of Epstein-Barr virus gp42 inhibits fusion with B cells even with increased flexibility allowed by engineered spacers.

UNLABELLED: We recently described the architecture of the Epstein-Barr virus (EBV) fusion-triggering complex consisting of the EBV B cell receptor human leukocyte antigen (HLA) class II and the EBV-encoded proteins gp42 and gH/gL. The architecture of this structure positioned the main body of gp42, comprising the C-type lectin domain (CTLD), away from the membrane and distant from where the membrane-bound form of gp42 might be tethered. gp42 is a type II membrane glycoprotein, with functional gp42 formed by cleavage near the gp42 amino-terminal transmembrane domain. This cleavage results in an approximately 50-amino-acid unstructured region that is responsible for binding gH/gL with nanomolar affinity. Our previous studies had shown that membrane-bound gp42 is not functional in B cell fusion. To investigate whether we could restore gp42 function by extending it from the membrane, we introduced one, two, and four structured immunoglobulin-like domains from muscle protein titin into a membrane-bound form of gp42 and tested function in binding to gHgL and HLA class II and function in fusion. We hypothesized that cleavage of gp42 generates a soluble functional form that relieves steric hindrance imposed on gHgL by membrane-bound gp42. All of the linker mutants had a dominant-negative effect on gp42 function, indicating that gp42 fusion function could not be restored simply by the addition of one to four titin domains. IMPORTANCE: Epstein-Barr virus (EBV) is associated with numerous diseases from benign mononucleosis to Burkitt's and Hodgkin's lymphoma, nasopharyngeal and gastric carcinoma, and lymphoproliferative disorders in patients with immune dysfunction resulting from immune suppression. Among the glycoproteins important for fusion, gp42, along with gH/gL, determines EBV tropism between epithelial and B cells. The function of gp42 is dependent on N-terminal cleavage, since membrane-bound gp42 cannot mediate fusion. We further investigated whether insertion of a linker into membrane-bound gp42 would relieve steric hindrance imposed on membrane-bound gp42 and restore fusion function. However, adding one, two, or four structured immunoglobulin-like domains to membrane gp42 did not restore fusion activity, indicating that the architecture and membrane orientation of the B cell fusion-triggering complex of EBV may be easily perturbed and that gp42 cleavage is essential for B cell fusion.

A randomized clinical trial of family therapy in juvenile drug court.

The objective of this article is to examine the effectiveness of 2 theoretically different treatments delivered in juvenile drug court--family therapy represented by multidimensional family therapy (MDFT) and group-based treatment represented by adolescent group therapy (AGT)--on offending and substance use. Intent-to-treat sample included 112 youth enrolled in juvenile drug court (primarily male [88%], and Hispanic [59%] or African American [35%]), average age 16.1 years, randomly assigned to either family therapy (n = 55) or group therapy (n = 57). Participants were assessed at baseline and 6, 12, 18 and 24 months following baseline. During the drug court phase, youth in both treatments showed significant reduction in delinquency (average d = .51), externalizing symptoms (average d = 2.32), rearrests (average d = 1.22), and substance use (average d = 4.42). During the 24-month follow-up, family therapy evidenced greater maintenance of treatment gains than group-based treatment for externalizing symptoms (d = 0.39), commission of serious crimes (d = .38), and felony arrests (d = .96). There was no significant difference between the treatments with respect to substance use or misdemeanor arrests. The results suggest that family therapy enhances juvenile drug court outcomes beyond what can be achieved with a nonfamily based treatment, especially with respect to what is arguably the primary objective of juvenile drug courts: reducing criminal behavior and rearrests. More research is needed on the effectiveness of juvenile drug courts generally and on whether treatment type and family involvement influence outcomes. TRIAL REGISTRY NAME: Clinical Trials.gov, Identified NCT01668303.

Assembly and architecture of the EBV B cell entry triggering complex.

Epstein-Barr Virus (EBV) is an enveloped double-stranded DNA virus of the gammaherpesvirinae sub-family that predominantly infects humans through epithelial cells and B cells. Three EBV glycoproteins, gH, gL and gp42, form a complex that targets EBV infection of B cells. Human leukocyte antigen (HLA) class II molecules expressed on B cells serve as the receptor for gp42, triggering membrane fusion and virus entry. The mechanistic role of gHgL in herpesvirus entry has been largely unresolved, but it is thought to regulate the activation of the virally-encoded gB protein, which acts as the primary fusogen. Here we study the assembly and function of the reconstituted B cell entry complex comprised of gHgL, gp42 and HLA class II. The structure from negative-stain electron microscopy provides a detailed snapshot of an intermediate state in EBV entry and highlights the potential for the triggering complex to bring the two membrane bilayers into proximity. Furthermore, gHgL interacts with a previously identified, functionally important hydrophobic pocket on gp42, defining the overall architecture of the complex and playing a critical role in membrane fusion activation. We propose a macroscopic model of the initiating events in EBV B cell fusion centered on the formation of the triggering complex in the context of both viral and host membranes. This model suggests how the triggering complex may bridge the two membrane bilayers, orienting critical regions of the N- and C- terminal ends of gHgL to promote the activation of gB and efficient membrane fusion.

Implementation fidelity of Multidimensional Family Therapy in an international trial.

Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of the treatment as prescribed in treatment manuals and protocols, is also essential to the successful implementation of effective programs into new practice settings. Although infrequently studied in the drug abuse field, stronger implementation fidelity has been linked to better outcomes in practice but appears to be more difficult to achieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment (INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of Multidimensional Family Therapy (MDFT) in comparison to individual psychotherapy (IP) in Brussels, Berlin, Paris, The Hague, and Geneva with 450 adolescents with a cannabis use disorder and their parents. This study reports on the implementation fidelity of MDFT across these five Western European sites in terms of treatment adherence, dose and program differentiation, and discusses possible implications for international implementation efforts.

A soluble form of Epstein-Barr virus gH/gL inhibits EBV-induced membrane fusion and does not function in fusion.

We investigated whether soluble EBV gH/gL (sgH/gL) functions in fusion and made a series of truncations of gH/gL domains based on the gH/gL crystal structure. We found sgH/gL failed to mediate cell-cell fusion both when co-expressed with the other entry glycoproteins and when added exogenously to fusion assays. Interestingly, sgH/gL inhibited cell-cell fusion in a dose dependent manner when co-expressed. sgH/gL from HSV was unable to inhibit EBV fusion, suggesting the inhibition was specific to EBV gH/gL. sgH/gL stably binds gp42, but not gB nor gH/gL. The domain mutants, DI/gL, DI-II/gL and DI-II-III/gL were unable to bind gp42. Instead, DI-II/gL, DI-II-III/gL and sgH/gL but not DI/gL decreased the expression of gp42, resulting in decreased overall fusion. Overall, our results suggest that domain IV may be required for proper folding and the transmembrane domain and cytoplasmic tail of EBV gH/gL are required for the most efficient fusion.

Family therapy for drug abuse: review and updates 2003-2010.

Just 15 years ago, Liddle and Dakof (Journal of Marital and Family Therapy, 1995; 21, 511) concluded, based on the available evidence, that family therapy represented a "promising, but not definitive" approach for the treatment of drug problems among adolescents and adults. Seven years later, Rowe and Liddle (2003) review described considerable progress in this specialty with encouraging findings on adolescent-focused models based on rigorous methodology, as well as advances with adult-focused family-based treatments. The current review brings the field up to date with highlights from research conducted in the intervening 7 years, cross-cutting issues, recommendations for new research, and practice implications of these findings. Adolescent-focused family-based models that attend to the ecology of the teen and family show the most consistent and strongest findings in recent studies. Adult-focused models based on behavioral and systems theories of change also show strong effects with drug abusers and their families. The overarching conclusion is that family-based models are not only a viable treatment alternative for the treatment of drug abuse, but are now consistently recognized among the most effective approaches for treating both adults and adolescents with drug problems.

The KGD motif of Epstein-Barr virus gH/gL is bifunctional, orchestrating infection of B cells and epithelial cells.

Epstein-Barr virus (EBV), a member of the herpesvirus family, is the causative agent of common human infections and specific malignancies. EBV entry into target cells, including B cells and epithelial cells, requires the interaction of multiple virus-encoded glycoproteins. Glycoproteins H and L (gH/gL) cooperate with glycoprotein B (gB) to mediate fusion of the viral envelope with target cell membranes. Both the gH/gL complex and gB are required for fusion, whereas glycoprotein 42 (gp42) acts as a tropism switch and is required for B cell infection and inhibits epithelial cell infection. Our previous studies identified a prominent KGD motif located on the surface of gH/gL. In the current study, we found that this motif serves as a bifunctional domain on the surface of gH/gL that directs EBV fusion of B cells and epithelial cells. Mutation of the KGD motif to AAA decreased fusion with both epithelial and B cells and reduced the binding of gH/gL to epithelial cells and to gp42. We also demonstrate that deletion of amino acids 62 to 66 of gp42 selectively reduces binding to wild-type gH/gL, but not the KGD mutant, suggesting that the KGD motif of gH/gL interacts with the N-terminal amino acids 62 to 66 of gp42.

Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42).

The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self-association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLA class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods.

Family and individual factors associated with substance involvement and PTS symptoms among adolescents in greater New Orleans after Hurricane Katrina.

OBJECTIVE: This study examined the influence of hurricane impact as well as family and individual risk factors on posttraumatic stress (PTS) symptoms and substance involvement among clinically referred adolescents affected by Hurricane Katrina. METHOD: A total of 80 adolescents (87% male; 13-17 years old; mean age = 15.6 years; 38% minorities) and their parents were interviewed at the adolescent's intake into substance abuse treatment, 16 to 46 months postdisaster. Independent measures included hurricane impact variables (initial loss/disruption and perceived life threat); demographic and predisaster variables (family income, gender, predisaster adolescent substance use, predisaster trauma exposure, and parental substance abuse); postdisaster family factors (parental psychopathology, family cohesion, and parental monitoring); and postdisaster adolescent delinquency. RESULTS: Hierarchical multivariate regression analyses showed that adolescent substance involvement was associated with higher family income, lower parental monitoring (adolescent report), and more adolescent delinquency. Adolescent-reported PTS symptoms were associated with greater hurricane-related initial loss/disruption, lower family cohesion (adolescent report), and more adolescent delinquency, whereas parent-reported adolescent PTS symptoms were associated with greater parental psychopathology, lower parental monitoring (adolescent report), and lower family cohesion (parent report). CONCLUSIONS: The results suggest that hurricane impact was related only to adolescent-reported PTS. However, certain postdisaster family and individual risk factors (low family cohesion and parental monitoring, more adolescent delinquency) were associated both with adolescent substance involvement and with PTS symptoms. Identification of these factors suggests directions for future research as well as potential target areas for screening and intervention with substance-abusing adolescents after disasters.

Multidimensional family therapy: addressing co-occurring substance abuse and other problems among adolescents with comprehensive family-based treatment.

Adolescent substance abuse rarely occurs without other psychiatric and developmental problems, but it is often treated and researched as if it can be isolated from comorbid conditions. Few comprehensive interventions are available that effectively address the range of co-occurring problems associated with adolescent substance abuse. This article reviews the clinical interventions and research evidence supporting the use of Multidimensional Family Therapy (MDFT) for adolescents with substance abuse and co-occurring problems. MDFT is uniquely suited to address adolescent substance abuse and related disorders given its comprehensive interventions that systematically target the multiple interacting risk factors underlying many developmental disruptions of adolescence.

Multidimensional family therapy HIV/STD risk-reduction intervention: an integrative family-based model for drug-involved juvenile offenders.

Drug and juvenile justice involved youths show remarkably high rates of human immunodeficiency virus (HIV)/sexually transmitted disease (STD) risk behaviors. However, existing interventions aimed at reducing adolescent HIV risk behavior have rarely targeted these vulnerable young adolescents, and many approaches focus on individual-level change without attention to family or contextual influences. We describe a new, family-based HIV/ STD prevention model that embeds HIV/STD focused multifamily groups within an adolescent drug abuse and delinquency evidence-based treatment, Multidimensional Family Therapy (MDFT). The approach has been evaluated in a multisite randomized clinical trial with juvenile justice involved youths in the National Institute on Drug Abuse Criminal Justice Drug Abuse Treatment Studies (www.cjdats.org). Preliminary baseline to 6-month outcomes are promising. We describe research on family risk and protective factors for adolescent problem behaviors, and offer a rationale for family-based approaches to reduce HIV/STD risk in this population. We describe the development and implementation of the Multidimensional Family Therapy HIV/STD risk-reduction intervention (MDFT-HIV/ STD) in terms of using multifamily groups and their integration in standard MDFT and also offers a clinical vignette. The potential significance of this empirically based intervention development work is high; MDFT-HIV/STD is the first model to address largely unmet HIV/STD prevention and sexual health needs of substance abusing juvenile offenders within the context of a family-oriented evidence-based intervention.

Multidimensional family therapy for young adolescent substance abuse: twelve-month outcomes of a randomized controlled trial.

Research has established the dangers of early onset substance use for young adolescents and its links to a host of developmental problems. Because critical developmental detours can begin or be exacerbated during early adolescence, specialized interventions that target known risk and protective factors in this period are needed. This controlled trial (n = 83) provided an experimental test comparing multidimensional family therapy (MDFT) and a peer group intervention with young teens. Participants were clinically referred, were of low income, and were mostly ethnic minority adolescents (average age = 13.73 years). Treatments were manual guided, lasted 4 months, and were delivered by community agency therapists. Adolescents and parents were assessed at intake, at 6-weeks post-intake, at discharge, and at 6 and 12 months following treatment intake. Latent growth curve modeling analyses demonstrated the superior effectiveness of MDFT over the 12-month follow-up in reducing substance use (effect size: substance use frequency, d = 0.77; substance use problems, d = 0.74), delinquency (d = 0.31), and internalized distress (d = 0.54), and in reducing risk in family, peer, and school domains (d = 0.27, 0.67, and 0.35, respectively) among young adolescents.

When the levee breaks: treating adolescents and families in the aftermath of hurricane katrina.

Hurricane Katrina brought to the surface serious questions about the capacity of the public health system to respond to community-wide disaster. The storm and its aftermath severed developmentally protective family and community ties; thus its consequences are expected to be particularly acute for vulnerable adolescents. Research confirms that teens are at risk for a range of negative outcomes under conditions of life stress and family disorganization. Specifically, the multiple interacting risk factors for substance abuse in adolescence may be compounded when families and communities have experienced a major trauma. Further, existing service structures and treatments for working with young disaster victims may not address their risk for co-occurring substance abuse and traumatic stress reactions because they tend to be individually or peer group focused, and fail to consider the multi-systemic aspects of disaster recovery. This article proposes an innovative family-based intervention for young disaster victims, based on an empirically supported model for adolescent substance abuse, Multidimensional Family Therapy (MDFT; Liddle, 2002). Outcomes and mechanisms of the model's effects are being investigated in a randomized clinical trial with clinically referred substance-abusing teens in a New Orleans area community impacted by Hurricane Katrina.

Predicting HIV/STD risk level and substance use disorders among incarcerated adolescents.

Incarcerated adolescents are among the most vulnerable groups for STD infection, and substance abuse is prevalent in over half of this population. Substance abuse and HIV/STD-associated risk behaviors are closely linked among juvenile justice-involved youth, but it is unclear whether common antecedents explain these different problems. The current study examined predictors of HIV/STD risk level and substance use disorders, and investigated whether family variables added unique predictive variance for these problems among incarcerated youth. The sample included 154 substance-involved youth ages 13 to 17 recruited in detention facilities in Miami and Tampa, FL and was primarily male (82%) and African-American (58%). Using a comprehensive assessment strategy with data obtained from youth report, parent report, and laboratory confirmed STD testing, the results show that delinquency is a consistent predictor of both HIV/STD risk level and substance use disorders, and also that substance use directly predicts HIV/STD risk level among incarcerated adolescents. Consistent with previous research, family conflict is an important predictor of substance use disorders even after controlling for other factors. The results suggest the need for integrated family-based interventions addressing delinquency, substance abuse, and HIV/STD-associated risk factors with juvenile justice-involved adolescents.

Acculturation and drug use among dually diagnosed Hispanic adolescents.

With drug abuse among Hispanic youth on the rise, examining cultural factors such as acculturation may provide insight into understanding and addressing this problem. This study examined the relationship between acculturation and severity of drug use among a sample of severely impaired Hispanic adolescents referred for residential substance abuse treatment. As recent studies with clinical samples have found, it was hypothesized that lower levels of acculturation would be associated with higher levels of substance use. Results indicated that youth born outside the United States reported greater frequency of drug use at intake into treatment than those born in the United States, supporting the hypothesis.