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Abstract Background Depression is often a chronic relapsing condition, with relapse rates of 50-80% in those who have been depressed before. This is particularly problematic for those who become suicidal when depressed since habitual recurrence of suicidal thoughts increases likelihood of further acute suicidal episodes. Therefore the question how to prevent relapse is of particular urgency in this group. Methods/Design This trial compares Mindfulness-Based Cognitive Therapy (MBCT), a novel form of treatment combining mindfulness meditation and cognitive therapy for depression, with both Cognitive Psycho-Education (CPE), an equally plausible cognitive treatment but without meditation, and treatment as usual (TAU). It will test whether MBCT reduces the risk of relapse in recurrently depressed patients and the incidence of suicidal symptoms in those with a history of suicidality who do relapse. It recruits participants, screens them by telephone for main inclusion and exclusion criteria and, if they are eligible, invites them to a pre-treatment session to assess eligibility in more detail. This trial allocates eligible participants at random between MBCT and TAU, CPE and TAU, and TAU alone in a ratio of 2:2:1, stratified by presence of suicidal ideation or behaviour and current anti-depressant use. We aim to recruit sufficient participants to allow for retention of 300 following attrition. We deliver both active treatments in groups meeting for two hours every week for eight weeks. We shall estimate effects on rates of relapse and suicidal symptoms over 12 months following treatment and assess clinical status immediately after treatment, and three, six, nine and twelve months thereafter. Discussion This will be the first trial of MBCT to investigate whether MCBT is effective in preventing relapse to depression when compared with a control psychological treatment of equal plausibility; and to explore the use of MBCT for the most severe recurrent depression - that in people who become suicidal when depressed. Trial Registration Current Controlled Trials: ISRCTN97185214.

Introduction: Regulatory CD8 T cells (CD8 Treg) are responsible for the selective killing of self-reactive and pathogenic CD4 T cells. In autoimmune disease, CD8 Treg may accumulate in the peripheral blood but fail to control the expansion of pathogenic CD4 T cells that subsequently cause tissue destruction. This CD8 Treg dysfunction is due in part to the expression of inhibitory killer immunoglobulin-like receptors (KIR; KIR2DL isoforms [KIR2DL1, KIR2DL2, and KIR2DL3]); these molecules serve as autoimmune checkpoints and limit CD8 Treg activation., Methods: Here we describe the pre-clinical characterization of MTX-101, a bispecific antibody targeting inhibitory KIR and CD8. Using human peripheral blood mononuculear cells (PBMC) derived from healthy donors and autoimmune patients, humanized mouse models, and human derived tissue organoids, we evaluated the molecular mechanisms and functional effects of MTX-101., Results: By binding to KIR, MTX-101 inhibited KIR signaling that can restore CD8 Treg ability to eliminate pathogenic CD4 T cells. MTX-101 bound and activated CD8 Treg in human peripheral blood mononuclear cells (PBMC), resulting in increased CD8 Treg cytolytic capacity, activation, and prevalence. Enhancing CD8 Treg function with MTX-101 reduced pathogenic CD4 T cell expansion and inflammation, without increasing pro-inflammatory cytokines or activating immune cells that express either target alone. MTX-101 reduced antigen induced epithelial cell death in disease affected tissues, including in tissue biopsies from individuals with autoimmune disease (i.e., celiac disease, Crohn's disease). The effects of MTX-101 were specific to autoreactive CD4 T cells and did not suppress responses to viral and bacterial antigens. In a human PBMC engrafted Graft versus Host Disease (GvHD) mouse model of acute inflammation, MTX-101 bound CD8 Treg and delayed onset of disease. MTX-101 induced dose dependent binding, increased prevalence and cytolytic capacity of CD8 Treg, as well as increased CD4 T cell death. MTX-101 selectively bound CD8 Treg without unwanted immune cell activation or increase of pro-inflammatory serum cytokines and exhibited an antibody-like half-life in pharmacokinetic and exploratory tolerability studies performed using IL-15 transgenic humanized mice with engrafted human lymphocytes, including CD8 Treg at physiologic ratios., Conclusion: Collectively, these data support the development of MTX-101 for the treatment of autoimmune diseases., Competing Interests: The authors were employed by Mozart Therapeutics and declare that the study was funded by Mozart Therapeutics. Mozart Therapeutics was involved in the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication., (Copyright © 2024 Gardell, Maurer, Childs, Pham, Meengs, Julien, Tan, Boster, Quach, Therriault, Hermansky, Patton, Bowser, Chen, Morgan, Gilbertson, Bogatzki, Encarnacion, McMahan, Crane and Swiderek.)

Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (αIL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized αIL-10 antibody. The efficacy of αIL-10 GEMs was assessed in human gastrointestinal tumor slice culture models developed from resected specimens of pancreatic ductal adenocarcinoma primary tumors and colorectal cancer liver metastases. LV transduction led to sustained production of BT-063 by αIL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but αIL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an ~5-fold higher rate of tumor cell apoptosis than control., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: There is a growing recognition of the importance of changes in drinking prior to the first treatment session (i.e., pretreatment change). A major limitation of past studies of pretreatment change is the reliance on retrospective reporting on drinking rates between the baseline assessment and the first treatment session collected at the end of treatment. The present study sought to extend previous findings by examining 12-month treatment outcomes and correlates of pretreatment changes in drinking measured weekly during treatment., Methods: Data from a randomized behavioral clinical trial examining the effect of therapeutic alliance feedback on drinking outcomes were analyzed (n = 165). All participants received cognitive behavioral therapy for alcohol dependence, completed pre and posttreatment assessments, and provided weekly measures of drinking during treatment., Results: Results indicated that approximately half of the sample reduced their heavy drinking days by 70% or more and number of drinking days by 50% or more prior to beginning treatment. Further, individuals who reported greater consideration of how their problematic drinking affected their social environment displayed greater changes in drinking days prior to treatment. Changes in heavy drinking days were also related to relationship status, such that individuals who were single/never married were less likely to change prior to treatment than those who were married/cohabitating or separated/divorced., Conclusion: These confirm the importance of pretreatment change in the study of treatment outcomes, and suggest that interpersonal processes, including the appraisal of drinking behavior in a social context, may play an important role in pretreatment changes in drinking., (© 2023 Research Society on Alcohol.)

Intimate partner violence (IPV) is a prominent public health problem in the United States, with significant health impacts that are often severe and persistent. Healthcare systems have been called upon to improve both the systematic identification and treatment of IPV largely by adopting secondary and tertiary prevention efforts. Research to date demonstrates both benefits and challenges with the current strategies employed. In this paper, we summarize current knowledge about the healthcare system's response to IPV and evaluate the strengths, limitations, and opportunities. We offer recommendations to broaden the continuum of healthcare resources to address IPV, which include a population health approach to primary prevention.

Previous research suggests that reactive and proactive aggression likely have distinct underlying mechanisms that uniquely contribute to the perpetration of each as a result of faulty cognitive and emotional processes. Still, very little work has examined the association of the functions of relational aggression with emotion dysregulation and hostile attribution biases. In addition, it is important to examine relational aggression in its pure and co-occurring functions given that past work finds reactive and proactive aggression to occur both jointly and distinctly. Thus, the current study employed a bifactor model to distinguish between pure reactive, pure proactive, and co-occurring relational aggression in emerging adulthood (N = 647, M age  = 19.92, SD = 2.83), a developmental time period for which relational aggression is particularly prominent. To further address gaps in the relational aggression literature, indirect pathway models revealed that relational hostile attribution biases emerged as a concurrent indirect path in the relationship between emotion dysregulation and pure reactive relational aggression. Furthermore, emotion dysregulation was directly positively associated with both pure functions as well as co-occurring relational aggression, and hostile attribution biases for relational provocations were directly associated with both pure functions of relational aggression, though the association was negative for pure proactive and positive for pure reactive relational aggression. Findings highlight the potential influence of emotion dysregulation and attributing hostile intent to social situations on engaging in the different functions of relational aggression., (© 2022 Wiley Periodicals LLC.)

This study explores differences in characteristics and relationship treatment preferences across different levels of intimate partner violence (IPV) among Veterans Affairs (VA) primary care patients. In Fall 2019, we sent a mail-in survey assessing relationship healthcare needs to N = 299 Veterans randomly sampled from 20 northeastern VA primary care clinics (oversampling female and younger Veterans). We compared those reporting past year use or experience of physical/sexual aggression, threats/coercion, or injury (Severe IPV; 21%), to those only reporting yelling and screaming (Verbal Conflict; 51%), and denying any IPV (No IPV; 28%). Participants across groups desired 2-6 sessions of face-to-face support for couples' health and communication. No IPV participants were older and had preferred treatment in primary care. The Verbal Conflict and Severe IPV groups were both flagged by IPV screens and had similar interest in couple treatment and relationship evaluation. The Severe IPV group had higher rates of harms (e.g., depression, alcohol use disorder, relationship dissatisfaction, fear of partner) and higher interest in addressing safety outside of VA. Exploratory analyses suggested differences based on use vs. experience of Severe IPV. Findings highlight ways integrated primary care teams can differentiate services to address dissatisfaction and conflict while facilitating referrals for Severe IPV.

Background: Human immune cells, including monocyte-derived macrophages, can be engineered to deliver proinflammatory cytokines, bispecific antibodies, and chimeric antigen receptors to support immune responses in different disease settings. When gene expression is regulated by constitutively active promoters, lentiviral payload gene expression is unregulated, and can result in potentially toxic quantities of proteins. Regulated delivery of lentivirally encoded proteins may allow localized or conditional therapeutic protein expression to support safe delivery of adoptively transferred, genetically modified cells with reduced capacity for systemic toxicities., Methods: In this study, we engineered human macrophages to express genes regulated by hypoxia responsive elements included in the lentiviral promoter region to drive conditional lentiviral gene expression only under hypoxic conditions. We tested transduced macrophages cultured in hypoxic conditions for the transient induced expression of reporter genes and the secreted cytokine, interleukin-12. Expression of hypoxia-regulated genes was investigated both transcriptionally and translationally, and in the presence of human tumor cells in a slice culture system. Finally, hypoxia-regulated gene expression was evaluated in a subcutaneous humanized-mouse cancer model., Results: Engineered macrophages were shown to conditionally and tranisently express lentivirally encoded gene protein products, including IL-12 in hypoxic conditions in vitro. On return to normoxic conditions, lentiviral payload expression returned to basal levels. Reporter genes under the control of hypoxia response elements were upregulated under hypoxic conditions in the presence of human colorectal carcinoma cells and in the hypoxic xenograft model of glioblastoma, suggesting utility for systemic engineered cell delivery capable of localized gene delivery in cancer., Conclusions: Macrophages engineered to express hypoxia-regulated payloads have the potential to be administered systemically and conditionally express proteins in tissues with hypoxic conditions. In contrast to immune cells that function or survive poorly in hypoxic conditions, macrophages maintain a proinflammatory phenotype that may support continued gene and protein expression when regulated by conditional hypoxia responsive elements and naturally traffic to hypoxic microenvironments, making them ideal vehicles for therapeutic payloads to hypoxic tissues, such as solid tumors. With the ability to fine-tune delivery of potent proteins in response to endogenous microenvironments, macrophage-based cellular therapies may therefore be designed for different disease settings., Competing Interests: Competing interests: CAC is an inventor on a patent US20170087185A1, Genetic engineering of macrophages for immunotherapy. CAC receives research support and is on the scientific advisory board for BlueRock Therapeutics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune-suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand-tagged polymeric prodrugs, termed "drugamers." The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide-3-kinase inhibitor, PI-103. The extended release of PI-103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein-drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron-tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene-activating small molecule prodrugs., (© 2021 Wiley-VCH GmbH.)

Cross-sectional survey, prospective, and experimental data have been evaluated to better understand the role of alcohol as a contributing cause of intimate partner aggression. Laboratory-based alcohol administration studies provide controlled data regarding causality, but the use of this methodology lacks ecological validity and has been hampered by rigorous procedural and financial demands. Online crowdsourcing is an emerging pseudoexperimental methodology with low costs, rapid data collection, access to diverse populations, greater ecological validity, and the potential to facilitate prolific research to supplement the chronic scarcity of experimental data. The current rapid review first summarizes prior methodological approaches to investigating the proximal influence of alcohol on partner aggression, then reviews prior crowdsourcing research in the disparate areas of alcohol and partner aggression, then describes aggression paradigms that may be readily adapted to online administration. We conclude by introducing recommendations for future quasi-experimental research investigating alcohol-related partner aggression research using the online crowdsourcing methodology. Initial evidence suggests that online crowdsourcing may yield appropriate samples and that existing paradigms may be adapted to rapidly, efficiently, and ethically supplement experimental alcohol-related partner aggression research.

Alcohol consumption is common in married/cohabiting couples, and many studies have attempted to understand its effects on their behavior patterns. Traditionally, those evaluations have been done through questionnaires and self-reports. While these approaches have unique contributions, they cannot track instantaneous behavioral changes, such as when a person shows disagreement, and are subjective to personal bias. Hence, we developed a computation model to automatically and objectively quantify instantaneous non-verbal disagreement expressed by head shakings and the corresponding following behavior. We conducted a preliminary analysis based on data from a randomized controlled experiment, where married/cohabiting couples discussed conflicts in different alcohol consumption conditions. Results showed that participants demonstrated different behavioral patterns in expressing moderate and strong disagreement. In addition, alcohol influenced males' head-shaking magnitude and females' following behavior more than their partners'. The proposed method is general and can be extended to investigate other behavioral cues.

Purpose: Past studies demonstrated the efficacy of integrated cognitive-behavioral therapy (CBT) for substance use disorder (SUD) and intimate partner violence (IPV) as well as high rates of depressive symptoms in this population. However, little is known about how depressive symptoms impact treatment outcomes. We hypothesized that integrated CBT, but not standard drug counseling (DC), would buffer the negative effects of depressive symptoms on treatment response., Design/methodology/approach: A secondary analysis of a randomized trial compared men assigned to 12 weeks of integrated CBT for SUD and IPV ( n =29) to those in DC ( n =34)., Findings: Most (60%) of the sample reported any depressive symptoms. Controlling for baseline IPV, reporting any depressive symptoms was associated with more positive cocaine screens during treatment. Among men with depressive symptoms, integrated CBT but not DC was associated with fewer positive cocaine screens. Controlling for baseline alcohol variables, integrated CBT and depressive symptoms were each associated with less aggression outside of intimate relationships (e.g., family, strangers) during treatment. For men without depressive symptoms, integrated CBT was associated with less non-IPV aggression compared to DC. Effects were not significant for other substances, IPV, or at follow-up., Originality: Although integrated CBT's efficacy for improving SUD and IPV has been established, moderators of treatment response have not been investigated., Practical Implications: Integrated CBT buffered depressive symptoms' impact on cocaine use, yet only improved non-IPV aggression in men without depressive symptoms., Research Limitations/implications: This study found some evidence for differential response to CBT by depressive symptoms on cocaine and aggression at end of treatment, which did not persist three months later. Future studies should explore mechanisms of integrated CBT for SUD and IPV, including mood regulation, on depressive symptoms in real-world samples.

Background: Prior research has demonstrated that various substances of abuse play a contributing role to acts of physical and verbal aggression. It is less clear if and to what extent substance use is associated with an increased risk in perpetrating cyber aggression, an emerging form of aggressive behavior that occurs through digital communication., Methods: A comprehensive review of the literature resulted in 15 studies and 18 unique samples from which effect size estimates were calculated., Results: Analyses resulted in a moderate, significant mean observed correlation indicating that individuals who engaged in substance use were more likely than those who did not to perpetrate cyber aggression (r = 0.24, k = 18, 95% CI = 0.20, 0.28). Comparing data across types of substances revealed that alcohol use represents a stronger risk factor for cyber aggression than nicotine, cannabis, or other illicit drugs. Results also suggest a stronger relationship between substance use and cyber aggression among older than younger samples and in the context of intimate partner rather than peer aggression. Comparable estimates of substance-related cyber aggression emerged across types of cyber aggression and perpetrator gender., Conclusions: Further research is required to increase confidence in estimates used in moderation analyses. As with traditional aggression, alcohol use appears to represent a risk factor for cyber aggression, though it is unclear if the disinhibitory properties of alcohol are the mechanism of action for substance-related cyber aggression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Sexual health is an important, yet often overlooked, aspect of overall health. Veterans may be particularly at risk for sexual dysfunction. The objectives of this study were to assess the prevalence and correlates of sexual dysfunction and examine preferences among veterans for discussing sexual problems., Methods: In this cross-sectional study, we mailed 1500 surveys to a random sample of primary care patients from 3 Veterans Affairs medical centers; 313 were returned (21% response rate) and 248 had complete data. Veterans (M age = 49.4 years) were mostly White (86.7%), women (60.9%), and married (79.0%). The Arizona Sexual Experience Scale was used to screen for sexual dysfunction., Results: Half of veterans, 62.3% of women and 32.0% of men, screened positive for sexual dysfunction. More than 60% of veterans agreed that the primary care team should provide information, proactively ask, and inquire on medical history forms about sexual problems; 59.3% were open to meeting with behavioral health providers., Conclusions: Primary care providers should ask veterans about sexual health, as sexual dysfunction was prevalent, especially among women and among men over age 65. Most veterans were receptive to being asked about sexual problems in primary care and preferred to be asked rather than bring it up., Competing Interests: Conflict of interest: None declared., (© Copyright 2021 by the American Board of Family Medicine.)

Intimate partner aggression among community couples has been conceptualized as representing an occasional, situationally provoked response to a conflict. Yet, relatively few studies have considered the situational factors that contribute to the occurrence of an aggressive episode. The present study used thematic analysis to understand how episodes of physical aggression come about from the participant's perspective. We examined narrative descriptions of relationship conflicts that included physical aggression to gain insight into the types of aggressive incidents experienced, the reasons and motives behind the aggression, and the meaning of these events. Married and cohabiting couples (ages 18-45 at baseline) were recruited from the community to participate in a longitudinal study of relationships. Heavy drinking couples were oversampled. At Wave 3, participants were asked to describe the most severe conflict they had experienced over the past year and to answer questions about severity and impact. Narratives that described use of partner physical aggression by one or both partners were subject to thematic analysis. Using narratives provided by 27 male and 29 female respondents (representing 51 different couples), we identified three primary motives or reasons for aggression: Expressive, Instrumental, and Punishment. Narratives suggested as a primary theme that participants view partner violence as unusual, undesirable, and hence, meaningful. This was particularly true for male-to-female violence, which appeared objectively and subjectively different from female-to-male violence. Findings provide unique insight into the function and meaning of partner violence, including its gendered nature, within a community sample. Implications for measurement of partner aggression are also discussed.

Background: Targeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects., Methods: In this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo., Results: Transduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model., Conclusions: The ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity., Competing Interests: Competing interests: The technology used to generate genetically engineered macrophages in this manuscript is covered under patent #US20170087185A1, Genetic engineering of macrophages for immunotherapy., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies., Methods: Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies., Results: Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins., Conclusions: Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics., Competing Interests: Competing interests: The authors declare the following competing interests: CAC, KWM, NAPL and MCJ are inventors on 'Genetic Engineering of Macrophages for Immunotherapy,' Patent Number: US20170087185A1, which pertains to the development and use of GEMs as immunotherapy. CAC receives research support and is on the scientific advisory board for BlueRock Therapeutics. MCJ receives research support from Juno Therapeutics, A Bristol-Myers Squibb Company., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Most glioblastomas recur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an "abscopal effect," whereby unirradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-programmed cell death ligand 1 (PD-L1) demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remain unknown., Methods: We modified an immune-competent, genetically driven mouse glioma model (forced platelet derived growth factor [PDGF] expression + phosphatase and tensin homolog loss) where a portion of the tumor burden is irradiated (PDGF) and another unirradiated luciferase-expressing tumor (PDGF + luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of epidermal growth factor receptor variant III (EGFRvIII) (PDGF + EGFRvIII). Statistical tests were two-sided., Results: Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the unirradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF + luciferase, n = 8), the abscopal response occurred via anti-PD-L1 driven, extracellular signal-regulated kinase-mediated, bone marrow-derived macrophage phagocytosis of adjacent unirradiated tumor cells, with modest survival implications (median survival 41 days vs radiation alone 37.5 days, P = 0.03). In PDGF-driven gliomas with tumor neoepitope (PDGF + EGFRvIII, n = 8), anti-PD-L1 enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs radiation alone 28 days, P = 0.001)., Conclusion: Our results indicate that anti-PD-L1 immunotherapy enhances a radiation- induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tumor-associated macrophages (TAMs) are a complex and heterogeneous population of cells within the tumor microenvironment. In many tumor types, TAMs contribute toward tumor malignancy and are therefore a therapeutic target of interest. Here, three major strategies for regulating TAMs are highlighted, emphasizing the role of biomaterials in these approaches. First, systemic methods for targeting tumor-associated macrophage are summarized and limitations to both passive and active targeting approaches considered. Second, lessons learned from the significant literature on wound healing and macrophage response to implanted biomaterials are discussed with the vision of applying these principles to localized, biomaterial-based modulation of tumor-associated macrophage. Finally, the developing field of engineered macrophages, including genetic engineering and integration with biomaterials or drug delivery systems, is examined. Analysis of major challenges in the field along with exciting opportunities for the future of macrophage-based therapies in oncology are included., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The current study aimed to contribute to the understanding of the session to session relationship between craving and drinking during the course of treatment via the incorporation into the analysis of both a) motivation to avoid alcohol and 2) pretreatment change, given that half of all individuals entering treatment change their drinking prior to the first session., Methods: Sixty-three treatment-seeking participants received 12 weeks of CBT for alcohol dependence and completed assessments of approach inclinations, avoidance inclinations and drinking behaviors at the end of each session., Results: Consistent with our hypothesis, motivations to avoid alcohol and pretreatment change significantly interacted with craving to predict both number of drinking days and heavy drinking days during the interval between sessions. Specifically, among lower pretreatment changers, motivation to avoid alcohol moderated the effect of craving on number of drinking days and number of heavy drinking days, such that craving positively predicted drinking among those lower on motivations to avoid only. In contrast, among higher pretreatment changers, cravings positively predicted drinking among those higher on motivations to avoid alcohol., Conclusions: These findings highlight the importance of measuring both desire to consume and desire to avoid consuming alcohol simultaneously, and suggest that ambivalence may function differently depending on whether one is initiating (low pretreatment change) versus maintaining change (high pretreatment change)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Caffeinated alcoholic beverage (CAB) use is associated with general victimization beyond the use of alcohol alone. Materials and Methods: No prior research has evaluated the association between CAB use and intimate partner violence (IPV) victimization. This study evaluated the CAB-IPV victimization relationship using the responses of 100 (40 female) respondents to an online survey. Results: Results of logistic regression analyses indicated that CAB use was associated with IPV physical and sexual victimization after adjusting for demographics and heavy alcohol use. Exploratory analyses detected little evidence of sex differences in the strength of the relationship between CAB use and IPV victimization. Conclusions: The current results provide initial evidence that CAB use may place males and females at greater risk of IPV victimization., Competing Interests: No competing financial interests exist.

Acute alcohol use appears to exert a small but significant effect on female perpetrated aggression in the laboratory but there has been no effort to evaluate comprehensively the situational moderators of this relationship. This preliminary review was intended to explore the moderating effects of provocation and target gender on alcohol-related aggression among females in this understudied area of research. Moderator analyses were conducted on 14 studies. Despite limitations imposed by the sparsity of laboratory based research on alcohol-related aggression among females, initial results suggest that alcohol may exert stronger effects over female aggression following high ( d = 0.25, k = 8, p < .01, 95% CI = 0.10-0.40) rather than low ( d = -0.07, k = 6, p = .52, 95% CI = -0.29-0.15) provocation and when targets of aggression are female ( d = 0.19, k = 9, p = .01, 95% CI = 0.04-0.34) rather than male ( d = -0.06, k = 4, p = .61, 95% CI = -0.30-0.18). Results offer initial insight into situational risk factors pertinent to research and treatment of alcohol-related aggression among females while serving as an impetus for future research in this critical, neglected area of study.

Intimate partner aggression (IPA) is a critical public health problem that requires clear and testable etiological models that may translate into effective interventions. While alcohol intoxication and a pattern of heavy alcohol consumption are robust correlates of IPA perpetration, there has been limited research that examines this association from a dyadic perspective. In the present review, we discuss compelling reasons for understanding dyadic factors that assist our understanding of alcohol-facilitated IPA, review the relatively small number of studies that have investigated such factors, and provide a theoretical and methodological framework for researchers to conceptualize how to model alcohol-facilitated IPA from a dyadic framework.

Background : Problematic alcohol use is a recognized risk factor for intimate partner violence (IPV) perpetration. Objective : The use of caffeinated alcoholic beverages (CAB) appears to be associated with high-risk drinking behavior but the relationship between CAB use and IPV has yet to be explored. Methods : Sixty male and 40 female married or dating participants responded to an online survey including measures of past-year alcohol use and partner violence. Results : Logistic regression analyses revealed that CAB users were significantly more likely to perpetrate physical assault and partner injury after controlling for age, sex, ethnicity, income, and heavy alcohol use. The relationship between CAB use and perpetration of sexual coercion was better accounted for by heavy alcohol use. Conclusion : Results from the current study suggest that there exists an independent link between CAB use and partner violence perpetration.

Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal CNS tumor diagnosed in 300 American children per year. Radiation is the only effective treatment and extends overall survival to a median of 11 months. Due to its location in the brainstem, DIPG cannot be surgically resected. Immunotherapy has the ability to target tumor cells specifically; however, little is known about the tumor microenvironment in DIPGs. We sought to characterize infiltrating immune cells and immunosuppressive factor expression in pediatric low- and high-grade gliomas and DIPG., Methods: Tumor microarrays were stained for infiltrating immune cells. RNA was isolated from snap-frozen tumor tissue and Nanostring analysis performed. DIPG and glioblastoma cells were co-cultured with healthy donor macrophages, T cells, or natural killer (NK) cells, and flow cytometry and cytotoxicity assays performed to characterize the phenotype and function, respectively, of the immune cells., Results: DIPG tumors do not have increased macrophage or T-cell infiltration relative to nontumor control, nor do they overexpress immunosuppressive factors such as programmed death ligand 1 and/or transforming growth factor β1. H3.3-K27M DIPG cells do not repolarize macrophages, but are not effectively targeted by activated allogeneic T cells. NK cells lysed all DIPG cultures., Conclusions: DIPG tumors have neither a highly immunosuppressive nor inflammatory microenvironment. Therefore, major considerations for the development of immunotherapy will be the recruitment, activation, and retention of tumor-specific effector immune cells.

Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

The current study evaluates a therapy for substance-dependent perpetrators of partner violence. Sixty-three males arrested for partner violence within the past year were randomized to a cognitive behavioral substance abuse-domestic violence (SADV; n = 29) or a drug counseling (DC; n = 34) condition. Seventy percent of offenders completed eight core sessions with no differences between SADV and DC conditions in the amount of substance or aggression at pretreatment. SADV participants had fewer cocaine-positive toxicology screens and breathalyzer results during treatment, were less likely to engage in aggressive behavior proximal to a drinking episode, and reported fewer episodes of violence than DC participants at posttreatment follow-up. SADV shows promise in decreasing addiction and partner violence among substance-dependent male offenders., (© 2017 American Association for Marriage and Family Therapy.)

While observational studies have found that alcohol consumption is associated with serodiscordant condomless sex among people living with HIV (PLHIV), no meta-analysis has yet examined this trend. We conducted a meta-analysis to synthesize empirical evidence on the association between alcohol and condomless sex with partners at risk of HIV acquisition. To meet inclusion criteria, studies: (1) specifically targeted PLHIV or provided stratified data for HIV-infected participants; (2) provided a quantitative measure of alcohol use; (3) provided a quantitative measure of condomless sex with serodiscordant partners; and (4) reported the results of statistical tests examining the relationship between alcohol use and serodiscordant condomless sex. Using random-effects models, weighted effect sizes were calculated. Three separate analyses were conducted to examine serodiscordant condomless sex in association with any alcohol consumption, binge/problematic drinking, and alcohol in a sexual context. A total of 36 independent effect sizes from 27 studies (including 25,065 HIV-infected participants) were pooled in the meta-analysis. Any alcohol consumption, binge/problematic drinking, and alcohol use in a sexual context were each associated with condomless sex with serodiscordant partners [OR 1.64 (95% CI 1.46-1.85); OR 1.65 (95% CI 1.14-2.39); OR 2.88 (95% CI 2.01-4.12), respectively]. Meta-analytic findings demonstrate a consistent positive relationship between alcohol use and serodiscordant condomless sex among PLHIV. Future public health programming for HIV-infected individuals needs to address the role of alcohol consumption in sexual risk-taking behavior.

Background and Objectives: Cyber aggression has emerged as a modern form of intimate partner violence which has yet to undergo sufficient research necessary to identify risk factors that may increase the likelihood or severity of cyber aggressive behavior toward a relationship partner. Prior research offers contradictory findings pertaining to the relationship between problematic alcohol use and cyber aggression., Methods: We recruited 100 (40 female) adult participants through online crowdsourcing to complete a series of questionnaires assessing traditional partner violence, cyber aggression, and problematic alcohol use., Results: Forty-two percent of the sample reported perpetrating cyber relational aggression and 35% reported perpetrating cyber privacy invasion during the year prior to study participation. Traditional partner violence was associated with both forms of cyber aggression. Problematic alcohol use was only associated with privacy invasion after accounting for demographic factors and traditional partner violence., Discussion and Conclusions: Cyber aggression was prevalent among the current adult sample. Results suggest that problematic alcohol use is a risk factor for cyber privacy invasion but not cyber relational aggression., Scientific Significance: Findings add to and clarify the nascent, conflicting results that have emerged from prior research on alcohol-related cyber aggression. (Am J Addict 2018;XX:1-7)., (© 2018 American Academy of Addiction Psychiatry.)

Alcohol problems have variable outcomes for marital relationships depending on whether drinking patterns are concordant or discordant among the members of the dyad; however, it is unclear what impact these variations in drinking patterns have on children. The current study was designed to explore several gaps and limitations in the parent heavy drinking literature. In particular, the prospective associations over 3years between parent heavy drinking, parenting, and child externalizing behavior were investigated in an integrated model to examine the influence of concordant and discordant drinking within couples on subsequent outcomes for their children. The study consisted of 180 couples recruited by mailings with children primarily between the ages of 4 and 11years old (52% male children). Parent-report of marital conflict, parenting, alcohol use, and child externalizing behavior were measured in a longitudinal study. Actor-Partner Interdependence Model analyses were conducted. Higher levels of maladaptive parenting were associated with higher externalizing for children of concordant drinking couples as opposed to discordant drinking couples. Implications for research and practice are discussed, including investigating mediators and moderators of the current findings such as quality of the parent-child relationship., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: With the growing recognition that, for some, significant changes in drinking occur before the first treatment session (i.e., pretreatment change), researchers have called for the careful assessment of when change occurs and its potential impact on mechanism of behavior change (MOBC) research. Using a commonly hypothesized MOBC variable, alcohol abstinence self-efficacy, the primary aim of this study was to examine the effect of pretreatment change on the study of MOBCs., Method: Sixty-three individuals diagnosed with alcohol dependence were recruited to participate in a 12-week cognitive-behavioral treatment. Participants completed weekly assessments of self-efficacy and drinking behaviors., Results: Multilevel time-lagged regression models indicated that pretreatment change significantly moderated the effect of self-efficacy on the number of drinking days, such that among those higher on pretreatment change, higher self-efficacy ratings predicted lower rates of drinking days in the week until the next treatment session. In contrast, pretreatment change did not moderate the effect of self-efficacy on the rate of heavy drinking days., Conclusions: Results from the current study add to a small but growing body of research highlighting the importance of pretreatment change when studying MOBCs. Further, these results provide important insights into the conditions in which self-efficacy may play an important role in treatment outcomes.

Introduction: Adverse effects and toxicities related to standard treatments for brain tumors significantly reduce patients' quality of life. Although most immunotherapy approaches for solid tumors have not been successful, several early-phase clinical trials are beginning to reveal a potential role for immunotherapy in the treatment of brain tumors. In particular, methods that activate the innate immune system and induce a polyclonal anti-cancer response have demonstrated that brain tumors are susceptible to immune-mediated tumor destruction. Compared with conventional therapies, modulation of the immune system may improve both survivorship and quality of life during and following treatment. Areas covered: An overview of mechanisms of immunotherapy in the context of current treatments for adult and pediatric brain tumors is provided. Results from recent clinical trials will be discussed, focusing on the favorable safety and efficacy profiles of immunotherapeutics. Expert commentary: Although it is too early to judge the long-term safety of immunotherapy for the treatment of patients with brain tumors, early results suggest that these drugs are well-tolerated and may improve survival and quality of life. Importantly, approaches that activate an anti-tumor immune response lay the framework for iterative development of immunotherapies that can reliably treat patients with brain tumors.

Current methods of identifying intimate partner violence (IPV) perpetration rely upon lengthy screening instruments, partner injury, and legal involvement. There exist no viable, brief screening tools to facilitate the rapid and early identification of IPV perpetration. The development of a brief IPV screening tool would reduce participant burden and compensation in research as well as aid in self-identification and appropriate consultation for treatment. Three samples were recruited and administered an IPV assessment measure. Receiver Operating Characteristic (ROC) curve analyses were used to determine a critical subset of items that could be rapidly administered and used to accurately detect physical IPV perpetrators. A set of four items emerged that were capable of differentiating between partner violent and nonviolent participants in Samples 1 (the Area Under the ROC Curve (AUC) = .95, SE = .02), 2 (AUC = .98, SE =.01), and 3 (AUC = .94, SE = .04). Internal consistency of the screening items was acceptable across samples and the scores on the screening tool were significantly associated in the expected direction with all assessed risk factors for IPV. Initial evaluation of the rapid IPV perpetration screening tool suggests that it may help satisfy the growing need to quickly determine research eligibility and to help college students self-identify risk, offering objective data upon which to base the decision for follow-up consultation., (© 2017 Wiley Periodicals, Inc.)

Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and ex vivo -expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion in vivo . These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches. Although highly effective in lysing transformed cells, to date, few clinical trials have demonstrated antitumor function or persistence of transferred NK cells. Several recent studies describe methods to expand NK cells for adoptive transfer, although the effects of ex vivo expansion are not fully understood. We therefore explored the impact of a clinically validated 12-day expansion protocol using a K562 cell line expressing membrane-bound IL-15 and 4-1BB ligand with high-dose soluble IL-2 on the phenotype and functions of NK cells from healthy donors. Following expansions using this protocol, we found expression of surface proteins that implicate preferential expansion of NK cells that are not fully mature, as is typically associated with highly cytotoxic NK cell subsets. Despite increased expression of markers associated with functional exhaustion in T cells, we found that ex vivo -expanded NK cells retained cytokine production capacity and had enhanced tumor cell cytotoxicity. The preferential expansion of an NK cell subset that is phenotypically immature and functionally pleiotropic suggests that adoptively transferred cells may persist better in vivo when compared with previous methods using this approach. Ex vivo expansion does not quell killer immunoglobulin-like receptor diversity, allowing responsiveness to various factors in vivo that may influence activation and inhibition. Collectively, our data suggest that in addition to robust NK cell expansion that has been described using this method, expanded NK cells may represent an ideal cell therapy that is longer lived, highly potent, and responsive to an array of activating and inhibitory signals.

Background: Efforts designed to investigate the effects of recent alcohol use on the perception of intimate partner aggression have been stultified by significant financial and logistical barriers that warrant the development of supplemental research methods that may result in more prolific investigation of the phenomenon., Objectives: The current study explored the viability of using online crowdsourcing to assess the effects of recent alcohol use on the perception of partner aggression., Method: Mechanical Turk was used to recruit a convenience sample of 60 males who were asked to provide information on their own use of partner aggression, their most recent episode of alcohol use, and their perception of the behaviors and characters depicted in a written partner aggression vignette. Data were evaluated using five separate hierarchical multiple regression models predicting participant perception., Results: Analyses revealed that 35% of the sample had used partner aggression in the past year and that 22% of the sample had consumed alcohol in the past day. Nonviolent participants perceived the aggressor and the behavior more negatively than partner violent participants. Some indicators revealed that recent alcohol use was associated with more positive perceptions of partner aggression., Conclusion: Expected associations among prior partner aggression, recent alcohol use, and perception of partner aggression vignettes were observed. Crowdsourcing may represent a source for data evaluating the effects of recent alcohol use on perceptions of aggression. Methodological refinement will benefit research and, ultimately, clinical prevention and intervention.

Intimate partner violence (IPV) is prevalent among samples with diagnosed alcohol use disorders (AUDs), but few studies have evaluated the factors that account for this increased risk, and none have systematically evaluated the risk posed by comorbid physical health conditions. The present study evaluated the likelihood of perpetrating IPV among alcohol diagnosed offenders with medical health problems relative to healthy counterparts. Physical health and partner violence data provided by 655 criminal offenders with AUDs diagnosed during a court-ordered substance abuse evaluation were examined. One third of participants (35.3%) endorsed a physical health condition, and 46.4% reported perpetrating physical IPV. The odds of perpetrating IPV among participants with a physical health condition were 2.29 times larger than among healthy participants. Specific conditions emerged as risk factors for IPV, including brain injury, cardiac issues, chronic pain, liver issues, gastrointestinal symptoms, hepatitis, and recent injury. Findings highlight the importance of identifying and managing physical health conditions that may complicate IPV treatment efforts. Integrated behavioral and medical health treatment approaches may increase treatment compliance and reduce the risk of future partner violence among offenders with co-occurring issues, such as mental illness, addiction, and physical health conditions.

Experimental research on alcohol-related aggression has focused largely upon male participants, providing only a limited understanding of the proximal effects of acute alcohol use on aggression among females extrapolated from the male literature. The current meta-analysis was undertaken to summarize the effects of alcohol, compared to placebo or no alcohol, on female aggression as observed across experimental investigations. A review of the literature yielded 11 articles and 12 effect sizes for further analysis. The overall effect size of alcohol on female aggression was small and reached statistical significance (d = .17, p = .02, 95% confidence interval [.03, .30]). Meta-analytic examination of the experimental literature indicated that alcohol is a significant factor in female aggression. The overall alcohol-aggression effect was smaller than has been observed among male samples. Additional research is required to evaluate the influence of other factors on alcohol-related aggressive responding among female participants. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses. A newly described lentiviral expression system was validated for the generation of transduced monocytes and monocyte-derived macrophages, and transgene expression was shown to be stable over the course of weeks to months, both in vitro and in a mouse xenograft model of GBM. Furthermore, the genetically engineered macrophages (GEMs) neither caused morbidity in animals nor contributed to accelerated tumor growth. The versatility of GEMs is also highlighted by showing that they can be engineered to secrete proteins that either reduce immune suppression, such as the soluble transforming growth factor beta receptor II, or promote immune cell activation, by expressing interleukin 21. There is also the potential to prevent GEM-mediated immune suppression by using the CRISPR system to knock out genes responsible for dysfunction of cytotoxic cells, including interleukin 10 and programmed death-ligand 1. Together, these results suggest that GEMs are an ideal cell type for transforming the tumor microenvironment and enhancing antitumor immunity. Importantly, it is anticipated that these findings will have broad applicability to other types of tumors with microenvironments that currently preclude successful immunotherapeutic approaches.

Issues: Male-to-female intimate partner violence remains a worldwide public health issue with adverse physical and psychological consequences for victims, perpetrators and children. Personality disorders, addiction, trauma and mood symptoms are established risk factors for intimate partner violence perpetration and factor prominently into a recovery-oriented treatment approach., Approach: We reviewed the partner violence literature for detailed reports of traditional as well as innovative, integrated treatment approaches. Empirically based recommendations for intervention programs and the policies that guide intervention efforts are offered., Key Findings: Nascent research suggests that integrated treatment models utilising a holistic approach to account for psychological comorbidity and interventions that involve a motivational interviewing component appear promising in terms of significantly improving intimate partner violence treatment compliance and reducing subsequent acts of physical partner violence. Further, methodologically rigorous research is required to fully assess the benefits of traditional and integrated treatment options., Implications: We have advanced several recommendations, including the development of and exclusive reliance upon empirically supported treatments, conducting a thorough risk and needs assessment of the offender and the immediate family to facilitate appropriate treatment referrals, integrating content to foster the offender's internal motivation to change maladaptive behaviours, and attempting to minimise offender treatment burdens through the strategic use of integrated treatment models., Conclusions: Intimate partner violence is a complicated and nuanced problem that is perpetrated by a heterogeneous population and requires greater variability in integrated treatment options. [Crane CA, Easton CJ. Integrated treatment options for male perpetrators of intimate partner violence. Drug Alcohol Rev 2017;36:24-33]., (© 2017 Australasian Professional Society on Alcohol and other Drugs.)

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

The current meta-analytic review examined the experimental literature to quantify the causal effect of acute alcohol consumption on self-reported and observed indicators of male-to-female general, sexual, and intimate partner aggression. Database and reference list searches yielded 22 studies conducted between 1981 and 2014 that met all criteria for inclusion and that were subjected to full text coding for analysis. Results detected a significant overall effect (d = .36), indicating that male participants who consumed alcohol evidenced greater aggressive behavior toward females while completing a subsequent laboratory aggression paradigm than male participants who received no alcohol. We found homogeneity across all categories of potential moderator variables. Results further indicated that alcohol resulted in comparable increases of male-to-female sexual (d = .32) and intimate partner (d = .45) aggression. Further research is required to draw meaningful conclusions about individual and situational factors that may interact with acute alcohol consumption to produce the highest levels of risk., (© The Author(s) 2015.)

The social and economic cost of intimate partner violence (IPV) is exorbitant and highlights the need for policy reform as it pertains to IPV interventions at a global level. There are multiple variables associated with the aetiology of IPV and, hence, multiple treatment needs must be considered. Substance use is one of several factors likely to influence the occurrence of IPV, but often goes unaddressed in standard treatment approaches. This review will discuss several treatment models for substance using offenders of IPV, including Psycho-educational Models, Cognitive Behavioural Therapy, Couples' Treatments, Parenting Programmes, Integration of Care Models, and Pharmacotherapies. Clinical recommendations will be discussed. Treatment outcomes among substance using offenders of IPV may be improved by implementing changes in protocol that increase diagnostic evaluations, integrate care with evidence-based models, require limits to the number of offenders in a group, and require qualifications for clinicians who treat offenders (licensed and trained psychologists, social workers, and/or psychiatrists).

Self-reported marijuana use has been associated with poor relationship functioning and decreased stability over time. The present study examined the behavioral interactions of couples with concordant and discordant patterns of marijuana use during conflict, using individual self-reports and observation by independent coders. Heavy drinking community couples (N = 149) participated in a conflict resolution paradigm. Interactions were recorded and coded by naïve coders. Approximately 30% of the sample reported past year marijuana use. Actor-Partner Interdependence Models and analysis of covariance (ANCOVA) were used to evaluate the individual and interactive effects of dyadic marijuana use on maladaptive relationship functioning. A Robust Actor × Partner Marijuana Use interaction was detected for a range of behavioral outcomes, assessed by both self-report and direct observation, including relationship satisfaction, anger experience, patterns of demand and withdrawal during conflict, constructive behaviors, and overall relationship quality. Specifically, couples in which both partners used or abstained from marijuana displayed more adaptive relationship functioning across indicators relative to couples in which only 1 partner identified as a marijuana user. This pattern was particularly strong for couples in which the female partner used marijuana and the male partner did not. Couples with discordant, rather than concordant, marijuana use displayed distinct conflict resolution behaviors that were consistent with the long-term negative relationship outcomes that have been observed in previous studies. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

While previous studies find mixed evidence of an association between opioid use and intimate partner violence perpetration among community samples, initial evidence has detected increased rates of partner violence among individuals receiving pharmacological intervention for opioid dependence. The current study evaluated the role of current comorbid substance use diagnoses, a robust risk factor for violent behavior, on the likelihood of perpetrating partner violence among a high risk sample of offenders receiving pharmacological intervention for opioid dependence. The authors analyzed self-report data provided by 81 (55 male) opioid dependent offenders during a court-ordered substance use interview. Approximately one-third of the sample evidenced the recent use of intimate partner violence. Findings indicated that cocaine and benzodiazepine use were independently associated with an increased likelihood of reporting physical partner violence. Alcohol and cannabis use were not associated with partner violence. The current results offer further support for the ongoing need to conduct routine partner violence screenings among substance involved offenders and highlight the importance of developing individualized treatment plans that address comorbid substance use and partner-violent behaviors among individuals in treatment for opioid dependence.

Introduction: Recent years have seen rapid growth in cancer treatments that enhance the anti-tumor activities of the immune system. Collectively known as immunotherapy, modulation of the immune system has shown success treating some hematological malignancies, but has yet to be successfully applied to the treatment of patients with brain tumors., Areas Covered: This review highlights mechanistic insights from murine studies and compiled recent clinical trial data, focusing on the most aggressive brain tumor, glioblastoma (GBM). The field has recently accumulated a critical mass of data, and we discuss past treatment failures in the context of newly developed approaches now entering clinical trials. This article provides an overview of the immunotherapeutic armamentarium currently in development for the treatment of patients with GBM, who are in dire need of safe and effective therapies. Expert commentary: Themes that emerge include the importance of mitigating the effects of an immunosuppressive tumor microenvironment and the potential for innate immune cell activation to enhance cytotoxic anti-tumor activity. Consideration of these studies as a collective may inform the design of new immunotherapies, as well as the immune monitoring protocols for patients participating in clinical trials.

Alcohol use and impulsivity are 2 known risk factors for intimate partner violence (IPV). The current study examined the independent and interactive effects of problematic drinking and 5 facets of impulsivity (i.e., negative urgency, positive urgency, sensation seeking, lack of premeditation, and lack of perseverance) on perpetration of physical IPV within a dyadic framework. Participants were 289 heavy drinking heterosexual couples (total N = 578) with a recent history of psychological and/or physical IPV recruited from 2 metropolitan U.S. cities. Parallel multilevel actor partner interdependence models were used and demonstrated actor problematic drinking, negative urgency, and lack of perseverance were associated with physical IPV. Findings also revealed associations between partner problematic drinking and physical IPV as well as significant Partner Problematic Drinking × Actor Impulsivity (Negative Urgency and Positive Urgency) interaction effects on physical IPV. Findings highlight the importance of examining IPV within a dyadic framework and are interpreted using the I3 metatheoretical model. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Background: Although readiness to change is associated with mandated partner violence treatment compliance and subsequent violent behaviour among male offenders (e.g. Scott and Wolfe, 2003; Eckhardt et al., 2004), our understanding of the factors associated with pretreatment change remains limited. Offender research indicates that individual and dyadic violent behaviour are highly variable and that such variability may provide insight into levels of pretreatment change (Holtzworth-Munroe and Stuart, 1994; Archer, 2002)., Aims/hypotheses: We sought to examine the associations between indicators of change and individual as well as dyadic violence frequency in a sample of male partner violence offenders., Method: To determine whether severity and perceived concordance in the use of violence among male offenders and their female partners influenced readiness to change at pretreatment, 82 recently adjudicated male perpetrators of intimate partner violence were recruited into the current study and administered measures of readiness to change violent behaviour (Revised Safe at Home Scale; Begun et al., 2008) as well as partner violence experiences (Revised Conflict Tactics Scale; Straus et al., 1996)., Results: Analyses revealed an interaction between offender-reported male and female violence in the prediction of pretreatment readiness to change such that greater male violence was associated with greater readiness to change among males who reported that their female partners perpetrated low, but not high, levels of violence. Consistently, greater female violence was associated with lower readiness to change only among the most violent male offenders., Conclusions and Implications for Clinical Practice: Results provide support for the assertion that the most violent offenders may be the most resistant to partner violence intervention efforts, particularly when they perceive themselves to be victims as well. Enhanced motivational and couples programming may facilitate treatment engagement among the high-risk group of male offenders who report concordant relationship violence., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: This study sought to examine how exerting self-control to inhibit stereotype use affects alcohol consumption. In addition, we sought to expand previous findings via examination of how individual differences in motivations to approach or avoid alcohol consumption interact with self-control depletion to determine the regulation of ad-lib drinking behavior., Methods: Sixty-one social drinkers (31 female) were recruited to participate in a socially relevant self-control depletion task in which they were randomly assigned to 1 of 2 creative writing conditions: (i) the self-control depletion condition with explicit instructions to refrain from using stereotypes, or (ii) the nondepletion condition in which no instructions were given regarding the use of stereotypes. Participants then completed an ad-lib drinking task and self-report questionnaires pertaining to their motivation to consume alcohol., Results: As predicted, results indicated a significant 3-way interaction between depletion condition, approach inclinations, and avoidance inclinations. Specifically, self-control depletion predicted greater drinking disinhibition (i.e., mean sip size, total alcohol consumption) only among participants high in both approach and avoidance., Conclusions: Taken together, results from this study highlight the importance of both approach and avoidance inclinations in the failure to regulate alcohol consumption following a routine, socially relevant form of self-control depletion. Our results also suggest that the high approach/high avoidance motivational profile may predict the greatest risk among those actively trying to regulate their drinking., (Copyright © 2015 by the Research Society on Alcoholism.)

Objective: Treatment programs for intimate partner violence (IPV) evidence high rates of noncompliance, which is associated with repeat offending. Problematic alcohol use is reported in approximately half of all partner violent offenders and represents a strong risk factor for treatment noncompliance. However, previous research with IPV offenders mandated to treatment has not evaluated methods to mitigate the effects of alcohol misuse on treatment compliance., Method: In the current study, 60 male IPV offenders (25 binge drinkers) were randomly assigned to a single-session brief motivational interview (BMI) or control intervention prior to treatment commencement. Treatment compliance data were collected 6 months later., Results: Findings indicated that binge drinkers had lower treatment compliance than non-binge-drinking participants, and that binge-drinking BMI participants attended more treatment sessions and evidenced lower dropout rates than binge-drinking control participants., Conclusions: Findings highlight the importance of individualized treatment planning for IPV offenders in order to maximize available resources while accommodating the needs of males at greatest risk for noncompliance and continued violence., ((c) 2015 APA, all rights reserved).)

The current study examined whether there is a bidirectional association between changes in alcohol use and psychopathic features during the transition into emerging adulthood. The nature of this association was investigated among a large sample of serious male adolescent offenders (N = 1,170) across 7 annual assessments (ages ∼17-23), with a focus on disaggregating between- and within-person change. Findings indicated that there was significant variability between participants in their rate of change of psychopathic features and alcohol use throughout this period of development. Both, between- and within-person increases in alcohol use tended to parallel increases in psychopathic features during the transition into emerging adulthood. In addition, evidence indicated that during years when adolescents consumed more alcohol than normal, they experienced higher than usual levels of self-reported psychopathic features at the subsequent assessment. The relevance of these findings for public policy and their potential to inform treatments and interventions are discussed., ((c) 2015 APA, all rights reserved).)