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1.
J Affect Disord ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38897303

ABSTRACT

BACKGROUND: Military veterans with posttraumatic stress disorder (PTSD) commonly experience posttraumatic guilt. Guilt over commission or omission evolves when responsibility is assumed for an unfortunate outcome (e.g., the death of a fellow combatant). Survivor guilt is a state of intense emotional distress experienced by the weight of knowing that one survived while others did not. METHODS: This study of the Translational Research Center for TBI and Stress Disorders (TRACTS) analyzed structural and diffusion-weighted magnetic resonance imaging data from 132 male Iraq/Afghanistan veterans with PTSD. The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) was employed to classify guilt. Thirty (22.7 %) veterans experienced guilt over acts of commission or omission, 34 (25.8 %) experienced survivor guilt, and 68 (51.5 %) had no posttraumatic guilt. White matter microstructure (fractional anisotropy, FA), cortical thickness, and cortical volume were compared between veterans with guilt over acts of commission or omission, veterans with survivor guilt, and veterans without guilt. RESULTS: Veterans with survivor guilt had significantly lower white matter FA compared to veterans who did not experience guilt (p < .001), affecting several regions of major white matter fiber bundles. There were no significant differences in white matter FA, cortical thickness, or volumes between veterans with guilt over acts of commission or omission and veterans without guilt (p > .050). LIMITATIONS: This cross-sectional study with exclusively male veterans precludes inferences of causality between the studied variables and generalizability to the larger veteran population that includes women. CONCLUSION: Survivor guilt may be a particularly impactful form of posttraumatic guilt that requires specific treatment efforts targeting brain health.

2.
Nat Med ; 30(5): 1320-1329, 2024 May.
Article in English | MEDLINE | ID: mdl-38480922

ABSTRACT

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .


Subject(s)
ErbB Receptors , Glioblastoma , Immunotherapy, Adoptive , Interleukin-13 Receptor alpha2 Subunit , Receptors, Chimeric Antigen , Humans , Glioblastoma/therapy , Glioblastoma/immunology , Glioblastoma/diagnostic imaging , Glioblastoma/pathology , Interleukin-13 Receptor alpha2 Subunit/immunology , Middle Aged , Male , Receptors, Chimeric Antigen/immunology , Female , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathology , Adult , Aged , Brain Neoplasms/immunology , Brain Neoplasms/therapy , Brain Neoplasms/pathology , Injections, Spinal , Maximum Tolerated Dose
3.
J Neurotrauma ; 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38323539

ABSTRACT

Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.

4.
Nat Cancer ; 5(3): 517-531, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38216766

ABSTRACT

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.


Subject(s)
Antibodies, Monoclonal, Humanized , Glioblastoma , Humans , Glioblastoma/therapy , ErbB Receptors , Neoplasm Recurrence, Local/metabolism , T-Lymphocytes , Tumor Microenvironment
5.
JBI Evid Implement ; 2023 Dec 29.
Article in English | MEDLINE | ID: mdl-38153118

ABSTRACT

OBJECTIVE: The objective of this scoping review is to identify factors that influence the implementation of innovation in aged care. INTRODUCTION: Aged care is a dynamic sector experiencing rapid change. Implementation of innovations in aged care has received relatively little research attention compared to health care. INCLUSION CRITERIA: This review included studies of any design, that examined the implementation of innovations in aged care settings. METHODS: Searches were conducted in MEDLINE, CINAHL, AgeLine, and ProQuest Social Sciences Premium Collection for studies published between January 1, 2012 and December 31, 2022. The titles and abstracts of retrieved citations were screened by two independent reviewers. Full-text articles were screened by one reviewer to determine inclusion. Data were extracted in NVivo using a tool developed by the research team. Factors that influenced implementation were inductively coded, interpreted, and grouped into categories in a series of workshops. RESULTS: Of the 2530 studies that were screened, 193 were included. Of the included papers, the majority (74%) related to residential aged care, 28% used an implementation theory or framework, and 15% involved consumers. Five key categories of factors influencing implementation were identified: organizational context including resourcing and culture; people's attitudes and capabilities; relationships between people; the intervention and its appropriateness; and implementation actions such as stakeholder engagement and implementation strategies. CONCLUSIONS: Our findings can be used to develop practical resources to support implementation efforts, and highlight the importance of resourcing for successful implementation. Attention to community-based aged care, and greater engagement with theory and community is needed to promote research rigor, relevance and applicability.

6.
Child Maltreat ; : 10775595231210017, 2023 Nov 02.
Article in English | MEDLINE | ID: mdl-37917022

ABSTRACT

Youth suicidal ideation is a prevalent experience, particularly among youth exposed to maltreatment, with a variety of indicators such as youth statements of ideation. To better understand suicidal ideation, and the associations with youth mental health outcomes, a fruitful path may be through the study of the dimensions (e.g., severity, frequency) of maltreatment exposure. While there exists extensive work on methods to best operationalize casefile records of maltreatment, such work has not been undertaken for youth self-reports, which are an important indicator of youth functioning following exposure. To address the lack of clarity of how to best operationalize youth self-reports of maltreatment, a multiverse analytic approach was taken to operationalize severity and frequency in a sample of 471 8- to 17-year-old children in foster care. We examined differences across measurement models and the models' associations with caregiver reports of youth suicidal ideation statements. Results indicate that the operationalizations used to define maltreatment resulted in differing measurement models that further differed in their associations with reports of youth suicidal ideation. This study highlights the importance of how researchers operationalize their data and the role dimensions of maltreatment have in further elucidating differential outcomes for youth exposed to maltreatment.

7.
Cancer Res Commun ; 3(5): 821-829, 2023 05.
Article in English | MEDLINE | ID: mdl-37377890

ABSTRACT

Purpose: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results: Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance: Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.


Subject(s)
Melanoma , Triple Negative Breast Neoplasms , Humans , Middle Aged , RNA/metabolism , T-Lymphocytes , Immunotherapy, Adoptive/adverse effects , Melanoma/therapy , Triple Negative Breast Neoplasms/therapy
8.
BMC Pregnancy Childbirth ; 23(1): 444, 2023 Jun 14.
Article in English | MEDLINE | ID: mdl-37316792

ABSTRACT

BACKGROUND: Disrespect and abuse violates women's basic human rights and autonomy and can traumatize women who are already in a vulnerable position during childbirth and deter them from utilizing skilled care for future childbirth. This study explored women's perspectives on the acceptability of disrespect and abuse during facility-based childbirth in Ethiopia. METHODS: A qualitative descriptive design using five focus group discussions and fifteen in-depth, semi-structured, interviews was conducted with women between October 2019 to January 2020 in north Showa zone of Oromia region, central Ethiopia. Using purposive sampling, women who had given birth at public health facilities of North Showa zone during the twelve months preceding data collection were recruited, regardless of birth outcome. Inductive thematic analysis using Open Code software was used to explore the perspectives of participants. RESULTS: While women reject disrespectful and abusive acts during childbirth generally, they may consider some disrespectful acts as acceptable and or necessary under certain circumstances. Four emerging themes were identified. (1) Disrespect and abuse is not acceptable, (2) Disrespectful and abusive actions are acceptable only if intended to save lives, (3) Disrespectful and abusive actions are an accepted part of everyday practice to prevent complications and adverse outcomes, (4) Disrespectful and abusive actions are necessary to discipline disobedient women. CONCLUSION: Women's perceptions of disrespectful and abusive acts of care providers is deeply rooted within the context of violence in Ethiopia and the societal hierarchies that have systematically disempowered women. Given the pervasiveness of disrespect and abusive actions during childbirth, policymakers, clinical managers and care providers must take these essential contextual and societal norms into account and devise comprehensive clinical interventions that addresses the root causes.


Subject(s)
Attitude of Health Personnel , Delivery, Obstetric , Emotional Abuse , Parturition , Professional-Patient Relations , Female , Humans , Pregnancy , Ethiopia , Focus Groups , Parturition/psychology , Qualitative Research , Emotional Abuse/psychology , Maternal Health Services/ethics , Cultural Characteristics
9.
Behav Ther ; 54(2): 330-345, 2023 03.
Article in English | MEDLINE | ID: mdl-36858763

ABSTRACT

This study investigated the associations between momentary emotion dynamics and posttraumatic stress disorder (PTSD) symptoms. Using a sample of 61 couples (N = 122 individuals) in which all individuals were trauma exposed and at least one partner screened positive for PTSD, we examined the intra- and interpersonal regulation of vocally encoded emotional arousal (fundamental frequency [f0]) and how these momentary emotion regulatory patterns relate to specific PTSD symptoms during two couple conversations: one designed to elicit conflict and one to elicit intimacy. PTSD symptoms were assessed using a gold standard clinical interview. In both conversations, higher reexperiencing symptoms were associated with greater emotional inertia (i.e., more resistance to change in emotional state following deviation from one's emotional equilibrium), and higher avoidance symptoms were associated with less emotional inertia (i.e., quicker return to emotional equilibrium). In the intimacy conversations, individuals also responded to their partners' arousal. Furthermore, individuals whose partners exhibited higher emotional numbing symptoms exhibited more emotional inertia, suggesting that emotion regulation may be a function of both one's own and one's partner's PTSD symptoms. Attending to the interpersonal context of emotion dynamics during PTSD treatment may enhance outcomes.


Subject(s)
Emotional Regulation , Stress Disorders, Post-Traumatic , Humans , Syndrome , Emotions , Arousal
10.
J Fam Violence ; : 1-14, 2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36743687

ABSTRACT

Purpose: The perspectives of children and young people with disability who experience domestic and family violence are under-researched, impeding the development of approaches that meet their needs. Knowledge gaps stem from the layered discursive positioning of disability, childhood/youth, or domestic and family violence in addition to the methodological, ethical and pragmatic complexity of research needed to understand their priorities and be attuned to their lived experience. This article explores methodological, ethical and practical challenges to centring their voices in research about domestic and family violence. Method: A conceptual framework of feminist disability theory and intersectionality informed our co-designed research, across three phases: (1) quantitative large-scale data linkage and case file analysis; (2) qualitative research with children and young people, their families and service providers and (3) stakeholder engagement workshops. Results: We reflect on how our research was able to prioritise the contextual agency of children and young people with disability, ways it could not, and other constraints. Conclusion: Children and young people with disability experiencing domestic and family violence hold an expert and unique vantage point on what happens to them. Amplifying their priorities for directing policy and organisational change requires more of researchers in terms of methods, but also more flexibility in how projects are funded to enable creativity and innovation. We call for collective attention to frameworks for supported decision-making and child ethics to progress inclusive research which recognises the importance of participation for children and young people with disability.

11.
Aggress Behav ; 49(1): 33-48, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36037395

ABSTRACT

Research with military veterans has established that distress may arise in response to perpetrating violent behaviors that violate individuals' moral beliefs. To date, no studies have similarly examined morally-related cognitive and emotional responses specifically among intimate partner violence (IPV) perpetrators. However, research on moral cognitions and emotions in response to IPV perpetration may inform understanding of the behavior and potential mechanisms for intervention. In the current series of four studies, we used classical test theory to develop a measure of moral distress following IPV perpetration that focuses on thoughts about the actions (assimilated cognitions), thoughts about the self due to one's actions (accommodated cognitions), and emotions experienced due to one's actions (moral emotions). Items were developed and tested among two samples of undergraduate students, and psychometric properties of the final measure were confirmed among two community samples. The final measure consists of three subscales consisting of five items each. Results demonstrate support for internal consistency and test-retest reliability, convergent, discriminant, and incremental validity, and factor structure. This measure can be used in future research designed to examine how individuals respond to their IPV perpetration, and to study the implications this may have for long-term outcomes and behavioral change.


Subject(s)
Intimate Partner Violence , Humans , Reproducibility of Results , Intimate Partner Violence/psychology , Emotions , Aggression/psychology , Morals
12.
Brain ; 146(3): 850-857, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36315647

ABSTRACT

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans, at the relevant time period in utero. To address this, we established an in vitro assay to study the impact of gene variants on the developing human brain by using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14-17 post-conception week brain tissue (www.hdbr.org). We were able to maintain cultures for several months, during which time the gross anatomical structures of the cortical plate, subplate and marginal zone persisted, while neurons continued to develop morphologically and form new synaptic networks. This preparation thus permits the study of genetic manipulations and their downstream effects on an intact developing human cortical network. We focused on STXBP1 haploinsufficiency, which is among the most common genetic causes of developmental and epileptic encephalopathy. This was induced using shRNA interference, leading to impaired synaptic function and a reduced density of glutamatergic synapses. We thereby provide a critical proof-of-principle for how to study the impact of any gene of interest on the development of the human cortex.


Subject(s)
Brain Diseases , Epilepsy, Generalized , Humans , Neurons/metabolism , Synapses/metabolism , Brain/metabolism , Munc18 Proteins/genetics
13.
Psychol Violence ; 13(5): 405-414, 2023 Sep.
Article in English | MEDLINE | ID: mdl-38882041

ABSTRACT

Objective: Interview assessments of intimate partner violence (IPV) may provide more accurate behavior frequency estimates than self-report questionnaires. However, concerns have been raised about whether participants underreport IPV during interviews due to an emotional response to the interviewer. Method: Participants were 42 mixed gender community couples (83 individuals) in which at least one partner endorsed physical IPV perpetration or victimization in their relationship. We examined whether participants were emotionally responsive to the interviewer during an interview about physical IPV. Responsivity was defined as the extent to which participants' emotional arousal, indexed by vocal fundamental frequency (f0), was predicted by interviewers' emotional arousal at the previous talk turn on a moment-by-moment basis. We then examined whether participants' responsivity predicted interview-based reporting of IPV relative to their own self-report on an IPV measure and to the highest other available report (including partner report). Results: Repeated measures actor-partner interdependence models conducted in a multi-level modeling framework indicated that, on average, participants were responsive to interviewers' emotional arousal, even when controlling for responsivity to their own arousal, and that responsivity varied across participants. However, participants' responsivity to interviewer arousal did not significantly predict reporting of IPV perpetration or victimization during the interview relative to their own self-report or to the highest other available report. Conclusions: Participants are emotionally responsive to interviewer arousal, but this responsivity does not appear to reduce interview-based reporting of IPV relative to self-report, supporting the utility of IPV interviews in clinical and research settings.

14.
Behav Res Ther ; 154: 104108, 2022 07.
Article in English | MEDLINE | ID: mdl-35596972

ABSTRACT

Aggressive behavior is a major public health issue for which there are few efficacious treatments. Although much of information processing is automatic, there are few studies of early-stage decoding biases (e.g., attention bias to threat) and aggressive behavior, potentially resulting in missed opportunities for identifying targets of intervention. Previous studies are limited by indirect measures of attention bias and little consideration of proximal factors like state fear, which organizes perception and motivates defensive behaviors. We used laboratory methods (i.e., eye-tracking, idiographic mood induction, and the Point Subtraction Aggression Paradigm), to examine the association between attention bias to physical and negative evaluation threat and in vivo defensive responding (i.e., aggression and escape) and the potential moderating role of state fear among 74 undergraduate students. As predicted, attention bias to threat was positively associated with in vivo aggression. Fear did not potentiate aggression or modify the relationship between attentional bias to threat and aggression; however, in the fear condition, greater attentional bias to threat was associated with less escape behavior. Findings add to the sparse literature identifying early-stage decoding processes as possible risk factors of aggression and suggest a need for additional research on freeze behavior in response to threat and provocation.


Subject(s)
Attentional Bias , Affect , Aggression , Anxiety , Attentional Bias/physiology , Cognition , Fear/physiology , Humans
15.
JCI Insight ; 7(11)2022 06 08.
Article in English | MEDLINE | ID: mdl-35536669

ABSTRACT

BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.


Subject(s)
COVID-19 Drug Treatment , Cyclosporine/therapeutic use , Cytokines , Humans , Oxygen , SARS-CoV-2
16.
Nat Med ; 28(4): 724-734, 2022 04.
Article in English | MEDLINE | ID: mdl-35314843

ABSTRACT

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-ß. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-ß receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-ß-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Chimeric Antigen , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Male , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , T-Lymphocytes , Transforming Growth Factor beta/metabolism , Tumor Microenvironment
17.
Fam Process ; 61(2): 823-840, 2022 06.
Article in English | MEDLINE | ID: mdl-34355392

ABSTRACT

Early childhood is critical to the development of children's social-emotional competence, which predicts peer relations and school adjustment in later periods of childhood. The effects of experiencing or witnessing aggression on children's social-emotional development are well known, yet the role of conflict resolution within the family has not been sufficiently studied. Social information processing models suggests that children who experience positive forms of conflict resolution within the family are likely to generalize these experiences and related skills outside the family, and thus develop greater social-emotional competence. In this longitudinal study, 128 parents (representing 79 families) participated in four quarterly telephone interviews in which they described aggressive conflicts that occurred in their family for which their children were present, including the degree to which each conflict was resolved. They also reported on the frequency of intimate partner aggression (IPA) and parent-to-child aggression (PCA) that occurred while the child was in toddlerhood and preschool as well as children's social-emotional competence at the end of the study. Multi-level models reveal that parents' reports of positive conflict resolution mitigated the concurrent and longitudinal negative effects of children's exposure to both IPA and PCA on their social-emotional competence. These findings reinforce prevention scientists' emphasis on conflict resolution skills as an essential component of parent education programs.


La primera infancia es fundamental para el desarrollo de la competencia socioemocional de los niños, la cual predice las relaciones entre pares y la adaptación escolar en periodos posteriores de la niñez. Se conocen muy bien los efectos que producen el sufrir o ser testigos de agresión en el desarrollo socioemocional de los niños, sin embargo, aún no se ha estudiado de manera suficiente el papel que desempeña la resolución de conflictos dentro de la familia. Los modelos de procesamiento de la información social sugieren que los niños que viven formas positivas de resolución de conflictos dentro de la familia son propensos a generalizar estas experiencias y las habilidades afines fuera de la familia y, por lo tanto, a desarrollar una mayor competencia socioemocional. En este estudio longitudinal, 128 padres (que representaban 79 familias) participaron en cuatro entrevistas telefónicas cada tres meses en las cuales describieron conflictos agresivos que hubo en su familia en los cuales sus hijos estuvieron presentes, incluido el grado en el cual se resolvió cada conflicto. También informaron la frecuencia de agresión en la pareja y de agresión de padres a hijos que tuvo lugar durante sus primeros años de vida y en la etapa del preescolar, así como la competencia socioemocional de los niños al final del estudio. Los modelos multinivel indican que los informes de los padres sobre la resolución positiva de los conflictos mitigaron los efectos negativos longitudinales y simultáneos de la exposición de los niños a la agresión en la pareja y a la agresión de padres a hijos en su competencia socioemocional. Estos resultados refuerzan el énfasis en las habilidades de resolución de conflictos de los científicos de la prevención como componente esencial de los programas de educación para padres.


Subject(s)
Aggression , Negotiating , Aggression/psychology , Child, Preschool , Family Conflict/psychology , Humans , Longitudinal Studies , Parent-Child Relations , Parents/psychology , Social Skills
18.
AIDS Care ; 34(12): 1595-1601, 2022 12.
Article in English | MEDLINE | ID: mdl-34851784

ABSTRACT

Previous research has identified that self-efficacy is an essential factor in the process of self-management; however, the evidence is lacking concerning factors influencing self-efficacy in low-income countries. Therefore, this study examined factors influencing self-efficacy. A validated survey tool was orally administered to 415 adults living with HIV. Many of the respondents, 82.4%, do not have a regular job while one-fourth (25.5%) of the respondents were from a rural area. A mean self-efficacy score, 19.76 ± 0.12 out of a maximum of 24 was identified. This self-efficacy score was positively correlated with age, educational level, income and job status, but negatively correlated with gender, residency and drug side effects. Income, residency in rural, and experiencing drug side effects were significant predictors of self-efficacy and explained 5.4% of the variance. Better income (ß = 0.514, p = 0.029) was associated with a higher self-efficacy score but living in rural areas (ß = -0.520, p = 0.043) and experiencing drug side effects (ß = -1.246, p = 0.001) were associated with a lower self-efficacy score. The use of Individual and Family Self-Management Theory helps clinician and patients to work together to identify factors influencing self-efficacy and to intervene.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , HIV Infections , Self-Management , Adult , Humans , HIV Infections/drug therapy , HIV Infections/complications , Self Efficacy , Ethiopia
19.
J Fam Psychol ; 36(1): 69-79, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33764085

ABSTRACT

Relationship difficulties are common during the transition to parenthood and may persist for years. Strategies that enhance couples' daily relational experiences early in the parenting years may serve a protective role. In general, engaging in a capitalization attempt (i.e., sharing personal good news) with one's romantic partner and perceiving the partner to be responsive are associated with better relationship outcomes among committed couples. However, it is unknown whether these relational benefits extend to the early parenting years or to other relational domains such as coparenting, which plays a central role in family functioning. The current study examined same-day associations between couples' capitalization process and relationship closeness and perceived coparenting support in a dyadic context during the first year of parenthood. A subsample of primarily non-Hispanic White coresident mixed-gender couples who participated in a randomized controlled trial of a transition to parenthood program (N = 141) completed daily diaries at 10 months postpartum for 8 consecutive days. On days when mothers shared, both partners reported greater closeness. On days when fathers shared, mothers reported greater closeness and perceived coparenting support. Furthermore, perceived partner responsiveness was associated with greater closeness for both partners and greater coparenting support for fathers. Fathers also perceived greater closeness and coparenting support on days when mothers shared about the child. Findings highlight the potential benefits of capitalization in early parenthood for both closeness and perceived coparenting support and suggest that capitalization may be a low cost, high yield strategy for enhancing new parents' daily relational experiences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Subject(s)
Parenting , Parents , Child , Female , Humans , Mothers , Postpartum Period
20.
Front Psychol ; 13: 1028375, 2022.
Article in English | MEDLINE | ID: mdl-36778165

ABSTRACT

Exposure to intimate partner violence (IPV), including physical, sexual, and psychological violence, aggression, and/or stalking, impacts overall health and can have lasting mental and physical health consequences. Substance misuse is common among individuals exposed to IPV, and IPV-exposed women (IPV-EW) are at-risk for transitioning from substance misuse to substance use disorder (SUD) and demonstrate greater SUD symptom severity; this too can have lasting mental and physical health consequences. Moreover, brain injury is highly prevalent in IPV-EW and is also associated with risk of substance misuse and SUD. Substance misuse, mental health diagnoses, and brain injury, which are highly comorbid, can increase risk of revictimization. Determining the interaction between these factors on the health outcomes and quality of life of IPV-EW remains a critical need. This narrative review uses a multidisciplinary perspective to foster further discussion and research in this area by examining how substance use patterns can cloud identification of and treatment for brain injury and IPV. We draw on past research and the knowledge of our multidisciplinary team of researchers to provide recommendations to facilitate access to resources and treatment strategies and highlight intervention strategies capable of addressing the varied and complex needs of IPV-EW.

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