Universal substance use care for adolescents with chronic medical conditions: a protocol to examine equitable implementation determinants and strategies for SBIRT at a pediatric hospital.

BACKGROUND: Adolescents with chronic medical conditions (CMC) use alcohol and marijuana at levels equal to or even greater than their peers without CMC and are more likely to initiate substance use at 14 years or younger. Approximately 33% of adolescents with CMC binge drink alcohol and 20% use marijuana. When using substances, adolescents with CMC are at elevated risk for problem use and adverse consequences given their medical conditions. Although there has recently been progress integrating substance use services into adult hospitals, there has been almost no implementation of standardized substance use services into pediatric hospitals for adolescents with CMC. Screening, Brief Intervention, and Referral to Treatment (SBIRT) for adolescents is an evidence-based, public health approach to promote the early detection and intervention of risky alcohol use in high-risk youth. This paper describes a study protocol combining two leading implementation science frameworks, the Consolidated Framework for Implementation Research (CFIR) and the Health Equity Implementation framework (HEIF), to engage pediatric hospital partners (hospital staff and clinicians, patients with CMC, and caregivers) to identify and specify contextual determinants of SBIRT implementation, which can be used to derive implementation strategies to optimize SBIRT adoption, reach, and fidelity. METHOD: This study will use semi-structured interviews and focus groups with pediatric hospital partners (e.g., hospital staff and clinicians, adolescent patients, and caregivers) to identify SBIRT implementation determinants, using semi-structured interview and focus group guides that integrate CFIR and HEIF dimensions. DISCUSSION: Understanding implementation determinants is one of the first steps in the implementation science process. The use of two determinant frameworks highlighting a comprehensive set of determinants including health equity and justice will enable identification of barriers and facilitators that will then map on to strategies that address these factors. This study will serve as an essential precursor to further work evaluating the feasibility of and the degree of engagement with SBIRT among this vulnerable pediatric population.

Implementing Screening, Brief Interventions, and Referral to Treatment at Pediatric Trauma Centers: A Step Wedge Cluster Randomized Trial.

BACKGROUND: Pediatric trauma centers have had challenges meeting the American College of Surgeons criteria for screening and intervening for alcohol with adolescent trauma patients. The study objective was to conduct an implementation trial to evaluate the effectiveness of the Science to Service Laboratory (SSL) implementation strategy in improving alcohol and other drugs (AOD) screening, brief intervention, and referral to treatment (SBIRT) delivery at pediatric trauma centers. METHODS: Using a stepped wedge cross-over cluster randomized design, 10 US pediatric trauma centers received the SSL implementation strategy to deliver SBIRT with admitted adolescent (12-17 years old) trauma patients. The strategy adapted three core SSL elements: didactic training, performance feedback, and facilitation. The main outcome measured was SBIRT reach. Data were collected from each center's electronic health record (EHR) during pre- and post-implementation wedges (2018-2022). RESULTS: EHR data from 8461 adolescent patients were extracted. Aggregated across all sites, the reach of screening with a validated AOD screening tool increased significantly from 25.2% (95% CI: 23.9, 26.5%) of adolescents during pre-implementation to 47.7% (95% CI: 46.3%, 49.2%) post-implementation. There was variability of change across centers. Brief interventions continued to be delivered at high levels to identified adolescents. Referral to primary care providers for further AOD discussion or referral to specialty service for adolescents with high risk use did not improve post-implementation and remained low. CONCLUSIONS: The SSL implementation strategy can be successfully utilized by pediatric trauma centers to improve AOD screening, but challenges exist in connecting adolescents for continuation of AOD discussions after discharge. LEVEL OF EVIDENCE: Level II, Therapeutic.

Standard Versus Family-Based Screening, Brief Intervention, and Referral to Treatment for Adolescent Substance Use in Primary Care: Protocol for a Multisite Randomized Effectiveness Trial.

BACKGROUND: Screening, brief intervention, and referral to treatment for adolescents (SBIRT-A) is widely recommended to promote detection and early intervention for alcohol and other drug (AOD) use in pediatric primary care. Existing SBIRT-A procedures rely almost exclusively on adolescents alone, despite the recognition of caregivers as critical protective factors in adolescent development and AOD use. Moreover, controlled SBIRT-A studies conducted in primary care have yielded inconsistent findings about implementation feasibility and effects on AOD outcomes and overall developmental functioning. There is urgent need to investigate the value of systematically incorporating caregivers in SBIRT-A procedures. OBJECTIVE: This randomized effectiveness trial will advance research and scope on SBIRT-A in primary care by conducting a head-to-head test of 2 conceptually grounded, evidence-informed approaches: a standard adolescent-only approach (SBIRT-A-Standard) versus a more expansive family-based approach (SBIRT-A-Family). The SBIRT-A-Family approach enhances the procedures of the SBIRT-A-Standard approach by screening for AOD risk with both adolescents and caregivers; leveraging multidomain, multireporter AOD risk and protection data to inform case identification and risk categorization; and directly involving caregivers in brief intervention and referral to treatment activities. METHODS: The study will include 2300 adolescents (aged 12-17 y) and their caregivers attending 1 of 3 hospital-affiliated pediatric settings serving diverse patient populations in major urban areas. Study recruitment, screening, randomization, and all SBIRT-A activities will occur during a single pediatric visit. SBIRT-A procedures will be delivered digitally on handheld tablets using patient-facing and provider-facing programming. Primary outcomes (AOD use, co-occurring behavior problems, and parent-adolescent communication about AOD use) and secondary outcomes (adolescent quality of life, adolescent risk factors, and therapy attendance) will be assessed at screening and initial assessment and 3-, 6-, 9-, and 12-month follow-ups. The study is well powered to conduct all planned main and moderator (age, sex, race, ethnicity, and youth AOD risk status) analyses. RESULTS: This study will be conducted over a 5-year period. Provider training was initiated in year 1 (December 2023). Participant recruitment and follow-up data collection began in year 2 (March 2024). We expect the results from this study to be published in early 2027. CONCLUSIONS: SBIRT-A is widely endorsed but currently underused in pediatric primary care settings, and questions remain about optimal approaches and overall effectiveness. In particular, referral to treatment procedures in primary care remains virtually untested among youth. In addition, whereas research strongly supports involving families in interventions for adolescent AOD, SBIRT-A effectiveness trial testing approaches that actively engage family members in primary care are absent. This trial is designed to help fill these research gaps to inform the critical health decision of whether and how to include caregivers in SBIRT-A activities conducted in pediatric primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05964010; https://www.clinicaltrials.gov/study/NCT05964010. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/54486.

Dual fluorescence reporter mice for Ccl3 transcription, translation, and intercellular communication.

Chemokines guide immune cells during their response against pathogens and tumors. Various techniques exist to determine chemokine production, but none to identify cells that directly sense chemokines in vivo. We have generated CCL3-EASER (ErAse, SEnd, Receive) mice that simultaneously report for Ccl3 transcription and translation, allow identifying Ccl3-sensing cells, and permit inducible deletion of Ccl3-producing cells. We infected these mice with murine cytomegalovirus (mCMV), where Ccl3 and NK cells are critical defense mediators. We found that NK cells transcribed Ccl3 already in homeostasis, but Ccl3 translation required type I interferon signaling in infected organs during early infection. NK cells were both the principal Ccl3 producers and sensors of Ccl3, indicating auto/paracrine communication that amplified NK cell response, and this was essential for the early defense against mCMV. CCL3-EASER mice represent the prototype of a new class of dual fluorescence reporter mice for analyzing cellular communication via chemokines, which may be applied also to other chemokines and disease models.

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells.

Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as "latency". During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a "window of risk" between therapeutic hemato-ablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM increase in numbers over time in the latently infected host, a phenomenon known as 'memory inflation' (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which relies almost entirely on superior proliferative potential of TCM.

Intervention for marijuana using, court-involved non-incarcerated youth.

INTRODUCTION: Justice-involved youth (JIY) are at elevated risk for substance use and for substance use-related harm compared to non-JIY. Marijuana use is of significant concern in this population, as it is tied to reoffending. Motivational enhancement therapy (MET) and electronic interventions show promise in reducing youth substance use; the degree to which these findings extend to JIY requires additional research attention. Thus, the purpose of this study was to test the preliminary feasibility and effectiveness of a combined brief electronic parenting intervention plus a brief MET-based electronic intervention for JIY adolescents, followed by feedback and development of a change plan with a court worker, on marijuana use. METHODS: Participants were 83 parent-youth dyads recruited from a diversionary family court program who screened positive for past-year marijuana use. At baseline and 3- and 6-month follow-ups, youth self-reported on their substance use, parental monitoring, peer substance use, and dyads completed a discussion task querying parental monitoring, limit setting, and substance use. The study randomized dyads to psychoeducation or the experimental intervention condition post-baseline. The MET-based intervention involved the self-administered e-TOKE (an electronic, marijuana-specific assessment and feedback tool) and a brief follow-up meeting with court staff counselors to review feedback and create a marijuana use change plan. Caregivers completed a computer program aimed at improving parenting and communication with their adolescents. The study administered feasibility and acceptability measures for both conditions. RESULTS: Feasibility of study procedures was demonstrated through recruitment and retention (∼75 % success). Acceptability ratings from youth, parents, and court staff were high and positive. While levels of parental monitoring, as assessed by an observational task, improved over the course of the study, the intervention did not result in a significant change in any of the outcomes tested. CONCLUSIONS: Despite high acceptability and feasibility ratings for the use of an electronic plus in-person MET intervention, reduction of marijuana and other substances was limited for most youth. This suggests that a more intensive intervention, such as stepped care, may be necessary for JIY who are not specifically referred for court proceedings due to marijuana use or those with already well-established use patterns.

Implementing Chronic Care Model Treatments for Cigarette Dependence in Community Mental Health Clinics.

Objective: Tobacco use is rarely addressed in community mental healthcare settings, despite its high prevalence among people with serious mental illness. The aim of the current study was to gather stakeholder feedback regarding the feasibility of chronic care management strategies for tobacco dependence in community mental health centers (CMHCs). Chronic care strategies evaluated included the 5 As (Ask about tobacco use, Advise users of tobacco to quit, Assess interest in cessation, Assist with cessation, and Arrange for follow-up) and proactive telephone outreach (reaching out to all users of tobacco to offer connection to tobacco cessation treatment). Methods: Using a semi-structured interview guide informed by the Practical Robust Implementation and Sustainability Model, we conducted individual semi-structured interviews with providers, leaders, and clients across two CMHCs. Our objectives were to capture their attitudes toward smoking cessation treatment, two chronic care model interventions (i.e., proactive outreach, the 5 As), and to determine the infrastructure needed to implement such interventions in their CMHCs. Thematic analysis was conducted by two independent coders to uncover pertinent themes. Results: Participants (n = 20) included nine providers, six leaders, and five clients. Thematic analysis revealed three major themes: (1) characteristics of recipients, (2) characteristics of the intervention, and (3) infrastructure needed for implementation and sustainability. Providers, leaders, and clients all reported that tobacco cessation treatment was rarely provided in CMHCs and expressed an interest in such treatments becoming more available. The 5 As and proactive outreach were viewed as feasible and acceptable to deliver and receive. Providers, leaders, and clients wanted support to connect clients with smoking cessation treatment. Providers and leaders requested a range of implementation supports, including didactic trainings, decision aids, performance feedback, and coaching on evidence-based tobacco cessation treatments for people with serious mental illness. Clients requested tobacco cessation resources, such as a cessation counseling provided at the CMHC and prescriptions for cessation medication. Conclusions: CMHC providers, leaders, and clients are interested in making tobacco cessation services more widely accessible and available. The feedback gathered in this study can be used to inform the delivery and implementation of guideline-adherent tobacco dependence care in CMHCs.

Variability in opioid pain medication prescribing for adolescent trauma patients in a sample of US pediatric trauma centers.

Objectives: The primary objective of this study was to examine opioid prescription frequency and identify differences across a national cohort of pediatric trauma centers in rates of prescribing opioids to injured adolescents at discharge. Methods: This was a retrospective observational study using electronic health records of injured adolescents (12-17 years) admitted to one of 10 pediatric trauma centers. Results: Of the 1345 electronic health records abstracted, 720 (53.5%, 95% CI 50.8 to 56.2) patients received opioid prescriptions at discharge with variability across sites (28.6%-72%). There was no association between patient factors and frequency of prescribing opioids. Center's trauma volume was significantly positively correlated with a higher rate of opioid prescribing at discharge (r=0.92, p=0.001). There was no significant difference between the frequency of opioid prescriptions at discharge among alcohol and other drugs (AOD)-positive patients (53.8%) compared with AOD-negative patients (53.5%). Conclusions: Across a sample of 10 pediatric trauma centers, just over half of adolescent trauma patients received an opioid prescription at discharge. Prescribing rates were similar for adolescent patients screening positive for AOD use and those screening negative. The only factor associated with a higher frequency of prescribing was trauma center volume. Consensus and dissemination of outpatient pain management best practices for adolescent trauma patients is warranted. Level of evidence: III-prognostic. Trial registration number: NCT03297060.

Mast Cells Meet Cytomegalovirus: A New Example of Protective Mast Cell Involvement in an Infectious Disease.

Cytomegaloviruses (CMVs) belong to the ß-subfamily of herpesviruses. Their host-to-host transmission involves the airways. As primary infection of an immunocompetent host causes only mild feverish symptoms, human CMV (hCMV) is usually not considered in routine differential diagnostics of common airway infections. Medical relevance results from unrestricted tissue infection in an immunocompromised host. One risk group of concern are patients who receive hematopoietic cell transplantation (HCT) for immune reconstitution following hematoablative therapy of hematopoietic malignancies. In HCT patients, interstitial pneumonia is a frequent cause of death from hCMV strains that have developed resistance against antiviral drugs. Prevention of CMV pneumonia requires efficient reconstitution of antiviral CD8 T cells that infiltrate lung tissue. A role for mast cells (MC) in the immune control of lung infection by a CMV was discovered only recently in a mouse model. MC were shown to be susceptible for productive infection and to secrete the chemokine CCL-5, which recruits antiviral CD8 T cells to the lungs and thereby improves the immune control of pulmonary infection. Here, we review recent data on the mechanism of MC-CMV interaction, a field of science that is new for CMV virologists as well as for immunologists who have specialized in MC.

Predictors and moderators of response to brief interventions among adolescents with risky alcohol and marijuana use.

Background:Brief interventions have shown promise in reducing adolescent alcohol and marijuana use. This manuscript presents a secondary analysis of a randomized trial that compared a brief parent motivational intervention (Family Check Up; FCU) to brief psychoeducation (PE) condition and found no effect of treatment condition on either binge drinking or marijuana use days. The current analyses explored whether the response to treatment may have varied as a function of six empirically-based baseline moderators and predictors: biological sex, age, race/ethnicity, mental health problems, parent-adolescent communication, and peer deviance. Methods: Data from the parent trial randomizing 102 parents to either the FCU (n = 51) or PE (n = 51) interventions were re-analyzed across four time points (baseline, 3-, 6-, and 12-months). Moderators and predictors were tested via a series of hierarchical linear models. Results: Parent-adolescent communication and peer deviance emerged as significant predictors of adolescent treatment response. Specifically, low-levels of parent-adolescent communication or peer deviance were associated with worse treatment response (i.e., significant increases in binge drinking days and marijuana use days) in the PE condition, but not in the FCU condition. Non-Hispanic Whites and girls had worse treatment response, regardless of treatment condition. Conclusions: The FCU condition appeared to mitigate risks of poor parent-adolescent communication and affiliation with deviant peers better than the PE condition. Clinical recommendations for decision-making around assignment to brief interventions are discussed.

Therapeutic Vaccination of Hematopoietic Cell Transplantation Recipients Improves Protective CD8 T-Cell Immunotherapy of Cytomegalovirus Infection.

Reactivation of latent cytomegalovirus (CMV) endangers the therapeutic success of hematopoietic cell transplantation (HCT) in tumor patients due to cytopathogenic virus spread that leads to organ manifestations of CMV disease, to interstitial pneumonia in particular. In cases of virus variants that are refractory to standard antiviral pharmacotherapy, immunotherapy by adoptive cell transfer (ACT) of virus-specific CD8+ T cells is the last resort to bridge the "protection gap" between hematoablative conditioning for HCT and endogenous reconstitution of antiviral immunity. We have used the well-established mouse model of CD8+ T-cell immunotherapy by ACT in a setting of experimental HCT and murine CMV (mCMV) infection to pursue the concept of improving the efficacy of ACT by therapeutic vaccination (TherVac) post-HCT. TherVac aims at restimulation and expansion of limited numbers of transferred antiviral CD8+ T cells within the recipient. Syngeneic HCT was performed with C57BL/6 mice as donors and recipients. Recipients were infected with recombinant mCMV (mCMV-SIINFEKL) that expresses antigenic peptide SIINFEKL presented to CD8+ T cells by the MHC class-I molecule Kb. ACT was performed with transgenic OT-I CD8+ T cells expressing a T-cell receptor specific for SIINFEKL-Kb. Recombinant human CMV dense bodies (DB-SIINFEKL), engineered to contain SIINFEKL within tegument protein pUL83/pp65, served for vaccination. DBs were chosen as they represent non-infectious, enveloped, and thus fusion-competent subviral particles capable of activating dendritic cells and delivering antigens directly into the cytosol for processing and presentation in the MHC class-I pathway. One set of our experiments documents the power of vaccination with DBs in protecting the immunocompetent host against a challenge infection. A further set of experiments revealed a significant improvement of antiviral control in HCT recipients by combining ACT with TherVac. In both settings, the benefit from vaccination with DBs proved to be strictly epitope-specific. The capacity to protect was lost when DBs included the peptide sequence SIINFEKA lacking immunogenicity and antigenicity due to C-terminal residue point mutation L8A, which prevents efficient proteasomal peptide processing and binding to Kb. Our preclinical research data thus provide an argument for using pre-emptive TherVac to enhance antiviral protection by ACT in HCT recipients with diagnosed CMV reactivation.

Advancing a cascading train-the-trainer model of frontline HIV service providers in South Africa: protocol of an implementation trial.

BACKGROUND: South Africa is marked by high rates of both HIV and alcohol use, and there is a detrimental synergistic relationship between these two epidemics. The Institute of Medicine recommends integrated care for alcohol use treatment and HIV, but implementation of integrated services remains a challenge in South Africa. This protocol describes a study designed to evaluate trainer, provider-, and patient encounter-level outcomes relating to the national rollout of a cascade train-the-trainer model of task-sharing to build capacity of the HIV workforce to deliver Screening, Brief Intervention, and Referral to Treatment (SBIRT) to address risky alcohol use. METHODS: This 5 year protocol consists of two phases. First, we will finalize development of a robust SBIRT train-the-trainer model, which will include an SBIRT Trainer Manual, Provider Resource Guide, fidelity observational coding system, case vignettes, and a curriculum for ongoing consultation sessions. Materials will be designed to build the capacity of novice trainers to train lay workers to deliver SBIRT with fidelity. Second, we will recruit 24-36 trainers and 900 providers in order to evaluate the effects of the SBIRT train-the-trainer model on trainer- (e.g., fidelity, knowledge), provider- (e.g., SBIRT attitudes, confidence, acceptability), and patient encounter- (e.g., proportion receiving screening, brief intervention, referral to treatment) level variables. Data on patient encounters will be tracked by providers on programmed tablets or scannable paper forms in real-time. Providers will report on SBIRT delivery on an ongoing basis over a 6-months period. Additionally, we will test the hypothesis that trainer-level factors will account for a substantial proportion of variability in provider-level factors which will, in turn, account for a substantial proportion of variability in patient encounter-level outcomes. DISCUSSION: This protocol will allow us to take advantage of a unique national training initiative to gather comprehensive data on multi-level factors associated with the implementation of SBIRT in HIV service settings. In the long-term, this research can help to advance the implementation of integrated alcohol-HIV services, providing lessons that can extend to other low-and-middle income countries confronting dual epidemics.

Screening Adolescent Trauma Patients for Substance Use at 10 Pediatric Trauma Centers.

BACKGROUND: The American College of Surgeons Committee on Trauma recommends universal alcohol screening be part of the evaluation of admitted trauma patients. Yet, suboptimal screening rates have been reported for admitted adult and adolescent trauma patients. This lack of screening, in turn, has limited the ability of trauma services to provide patients with brief interventions during their hospital admission and subsequent referrals to treatment after discharge. The primary aim of this study was to examine current rates of alcohol and other drug screening with admitted injured adolescents across a national cohort of 10 pediatric trauma centers. METHODS: This retrospective observational study was nested within a larger adolescent screening, brief intervention, and referral to treatment implementation study (Clinicaltrials.gov NCT03297060). Ten pediatric trauma centers participated in a retrospective chart review of a random sample of adolescent trauma patients presenting for care between March 1, 2018, and November 30, 2018. RESULTS: Three hundred charts were abstracted across the 10 participating trauma centers (n = 30 per site). Screening rates varied substantially across centers from five (16.7%) to 28 (93.3%) of the 30 extracted charts. The most frequent screening type documented was blood alcohol concentration (BAC) (N = 80, 35.2% of all screens), followed by the CRAFFT (N = 79, 26.3%), and then the urine drug screen (UDS) (N = 77, 25.6%). The BAC test identified 11 patients as positive for recent alcohol use. The CRAFFT identified 11 positive patients. CONCLUSIONS: Alcohol and drug screening is underutilized for adolescents admitted to pediatric trauma centers. More research is warranted on how best to utilize the teachable moment of the pediatric trauma visit to ensure comprehensive screening of adolescent alcohol or other drug (AOD) use.

Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation.

Hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstituting the co-ablated immune system is a therapeutic option to cure aggressive forms of hematopoietic malignancies. In cases of family donors or unrelated donors, immunogenetic mismatches in major histocompatibility complex (MHC) and/or minor histocompatibility (minor-H) loci are unavoidable and bear a risk of graft-vs.-host reaction and disease (GvHR/D). Transient immunodeficiency inherent to the HCT protocol favors a productive reactivation of latent cytomegalovirus (CMV) that can result in multiple-organ CMV disease. In addition, there exists evidence from a mouse model of MHC class-I-mismatched GvH-HCT to propose that mismatches interfere with an efficient reconstitution of antiviral immunity. Here we used a mouse model of MHC-matched HCT with C57BL/6 donors and MHC-congenic BALB.B recipients that only differ in polymorphic autosomal background genes, including minor-H loci coding for minor-H antigens (minor-HAg). Minor-HAg mismatch is found to promote lethal CMV disease in absence of a detectable GvH response to an immunodominant minor-HAg, the H60 locus-encoded antigenic peptide LYL8. Lethality of infection correlates with inefficient reconstitution of viral epitope-specific CD8+ T cells. Notably, lethality is prevented and control of cytopathogenic infection is restored when viral antigen presentation is enhanced by deletion of immune evasion genes from the infecting virus. We hypothesize that any kind of mismatch in GvH-HCT can induce "non-cognate transplantation tolerance" that dampens not only a mismatch-specific GvH response, which is beneficial, but adversely affects also responses to mismatch-unrelated antigens, such as CMV antigens in the specific case, with the consequence of lethal CMV disease.

A Targeted LC-MS Strategy for Low-Abundant HLA Class-I-Presented Peptide Detection Identifies Novel Human Papillomavirus T-Cell Epitopes.

For rational design of therapeutic vaccines, detailed knowledge about target epitopes that are endogenously processed and truly presented on infected or transformed cells is essential. Many potential target epitopes (viral or mutation-derived), are presented at low abundance. Therefore, direct detection of these peptides remains a challenge. This study presents a method for the isolation and LC-MS3 -based targeted detection of low-abundant human leukocyte antigen (HLA) class-I-presented peptides from transformed cells. Human papillomavirus (HPV) was used as a model system, as the HPV oncoproteins E6 and E7 are attractive therapeutic vaccination targets and expressed in all transformed cells, but present at low abundance due to viral immune evasion mechanisms. The presented approach included preselection of target antigen-derived peptides by in silico predictions and in vitro binding assays. The peptide purification process was tailored to minimize contaminants after immunoprecipitation of HLA-peptide complexes, while keeping high isolation yields of low-abundant target peptides. The subsequent targeted LC-MS3 detection allowed for increased sensitivity, which resulted in successful detection of the known HLA-A2-restricted epitope E711-19 and ten additional E7-derived peptides on the surface of HPV16-transformed cells. T-cell reactivity was shown for all the 11 detected peptides in ELISpot assays, which shows that detection by our approach has high predictive value for immunogenicity. The presented strategy is suitable for validating even low-abundant candidate epitopes to be true immunotherapy targets.

Implementing Alcohol Misuse SBIRT in a National Cohort of Pediatric Trauma Centers-a type III hybrid effectiveness-implementation trial.

BACKGROUND: The American College of Surgeons mandates universal screening for alcohol misuse and delivery of an intervention for those screening positive as a requirement for certification as a level 1 trauma center. Though this requirement has been mandated for over a decade, its implementation has been challenging. Our research team completed an implementation study supporting seven pediatric trauma centers' compliance with the requirement by developing and implementing an institutional alcohol Screening, Brief Intervention and Referral to Treatment (SBIRT) policy for adolescent trauma patients. A mixed-methods approach indicated that SBIRT adoption rates increased at all sites; however, providers' fidelity to the SBIRT intervention was variable, and providers reported a number of barriers to SBIRT implementation. The goal of this study is to conduct a fully powered type III hybrid effectiveness-implementation trial to test the effectiveness of a comprehensive implementation strategy in increasing the implementation of SBIRT for alcohol and other drug use (AOD) in pediatric trauma centers. METHODS: Our implementation strategy is based on the Science to Service Laboratory (SSL), an approach developed by the SAMHSA-funded Addiction Technology Transfer Centers that consists of three core elements (i.e., didactic training + performance feedback + leadership coaching). Utilizing a stepped wedge design, a national cohort of 10 pediatric trauma centers will receive the SSL implementation strategy. At six distinct time points, each of the 10 sites will provide data from 30 electronic medical records (n = 1800 in total). A subset of adolescents will also report on fidelity of intervention delivery and linkage to care (i.e., continued AOD discussion and/or treatment with a primary care provider) 1 month after hospital discharge. In addition, nurses, social workers, and leaders will report on organizational readiness for implementation at four distinct time points. DISCUSSION: This protocol proposes a unique opportunity to examine whether a comprehensive implementation strategy can improve the fidelity of SBIRT delivery across a national cohort of pediatric trauma centers. With injured adolescents, this could optimize the detection and intervention of AOD use and improve adolescent health. TRIAL REGISTRATION: Clinicaltrials.gov NCT03297060 .

SBIRT-A: Adapting SBIRT to Maximize Developmental Fit for Adolescents in Primary Care.

The Screening, Brief Intervention and Referral to Treatment (SBIRT) model is widely recommended as part of routine visits in pediatric primary care despite a dearth of evidence on its effectiveness, feasibility, and developmental appropriateness for adolescents in this setting. The purpose of this article is to explicate ways that SBIRT may be tailored to better serve adolescents in primary care under a set of recommended adaptations that we refer to collectively as SBIRT-A or Screening, Brief Intervention, and Referral to Treatment for Adolescents. Each component of the SBIRT-A framework incorporates recommendations to optimize developmental fit with adolescents based on extant empirical research, developmental theory, and well-documented barriers to service delivery in primary care. Commonalities across proposed adaptations include reliance upon proactive methods to identify and engage youth; innovation in service delivery aimed at improving the consistency and reach of interventions; and a family-focused approach to engagement, assessment, and intervention. Specific recommendations include taking advantage of every clinical encounter with the family to screen, involving caregivers in assessments and brief interventions, leveraging technology to administer brief interventions and booster sessions, and patient- and family-centered procedures for treatment referral and engagement. The adaptations proposed in this article have the potential to enhance the detection of adolescents with SU problems in primary care, the consistency of intervention provision, and engagement of this typically recalcitrant population into appropriate treatment.

Visceral leishmaniasis with associated immune dysregulation leading to lymphoma.

OBJECTIVE: We describe an atypical presentation of visceral leishmaniasis (VL) complicated by Epstein-Barr virus (EBV)-lymphoproliferative disorder and angioimmunoblastic T-cell lymphoma in a U.S. Government contractor recently deployed to Iraq and Afghanistan. METHODS: We performed a search of PubMed (1966-2012) using the terms visceral, leishmaniasis, operation, iraqi, freedom, desert, storm, EBV, lymphoproliferative, angioimmunoblastic, and lymphoma. The purpose of the search was two-fold: to find reported cases of VL during U.S. military operations and to ascertain if lymphoproliferative disorder (specifically, because of EBV) was ever described as a sequelae of VL. RESULTS: Case series of VL acquired in the Middle East between 1990 and 2012 showed that while fever, abdominal pain, and hepatosplenomegaly were common signs and symptoms of VL, diffuse lymphadenopathy (our patient's presentation) was rare. Moreover, VL in and of itself lends to profound immune dysregulation, leading to a myriad of complications to include EBV-lymphoproliferative diseases. CONCLUSIONS: Diffuse lymphadenopathy because of VL is a very atypical presentation for infection acquired in the Middle East. Clinicians must be mindful of the extreme immune dysfunction that occurs as a result of this potentially fatal infection and the associated complications to include EBV-related lymphoproliferative disorders and lymphoma.

Psychological, peer, and family influences on smoking among an adolescent psychiatric sample.

Although much is known about adolescent cigarette use and initiation in community samples, less is known about these factors among adolescents in clinic-referred populations or those with severe psychopathology. Data were collected from 106 adolescents aged 12 to 15 years (M = 13.6, SD = 0.74) recruited from a psychiatric inpatient facility. Hierarchical logistic regressions assessed the relationship among psychological, peer, and family environment factors and smoking at baseline and 18 months posthospitalization. Conduct problem symptoms, friends' cigarette use, and friends' marijuana use were associated with greater odds of lifetime and current smoking at baseline but not at follow-up. After accounting for the significant effect of baseline use, greater family conflict predicted decreased odds of having initiated smoking at the 18-month follow-up. The period following inpatient psychiatric hospitalization may represent an important window for smoking cessation and prevention efforts targeting peer and family factors, especially for youth with externalizing problems.

An analysis of health behavior theories applied to breast-screening behavior for relevance with American Indian women.

This article reviews studies of the efficacy of breast-screening interventions and their related theories that have had a positive effect in influencing women to use mammography and assesses the potential of various behavioral models for use with American Indian women. The study involved a search of literature in nursing and other health fields. Both community and practice-based interventions have incorporated elements of various theoretical models. Because of its adaptability, the modified health behavior model appears most relevant for designing interventions to encourage mammography use among American Indian women.