Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

When eco-anger (but not eco-anxiety nor eco-sadness) makes you change! A temporal network approach to the emotional experience of climate change.

Research on the emotional experience of climate change has become a hot topic. Yet uncertainties remain regarding the interplay between climate change-related emotions (i.e., eco-anxiety, eco-anger, eco-sadness), general emotions (i.e., regardless of climate change), and pro-environmental behaviors. Most previous research has focused on cross-sectional studies, and eco-emotions in everyday life have seldom been considered. In this preregistered study, 102 participants from the general population rated their eco-emotions (i.e., eco-anxiety, eco-anger, eco-sadness), general emotions (i.e., anxiety, anger, sadness), and pro-environmental intentions and behaviors daily over a 60-day period. Using a multilevel vector autoregressive approach, we computed three network models representing temporal (i.e., from one time-point to the next), contemporaneous (i.e., during the same time-frame), and between-subject (i.e., similar to cross-sectional approach) associations between variables. Results show that eco-anger was the only predictor of pro-environmental intentions and behaviors over time. At the contemporaneous level, the momentary experience of each eco-emotion was associated with the momentary emotional experience of the corresponding general emotion, indicating the distinctiveness of each eco-emotion and the correspondence between its experience and that of its general, non-climate-related emotion. Overall, our findings 1) emphasize the driving role of eco-anger in prompting pro-environmental behaviors over time, 2) suggest a functional and experiential distinction between eco-emotions, and 3) provide data-driven clues for the field's larger quest to establish the scientific foundations of eco-emotions.

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8+ T cells in the cerebrospinal fluid (CSF) over time. Additionally, of the five patients evaluable for disease response, three experienced transient radiographic and/or clinical benefit not meeting protocol criteria for response. The first three patients received CAR T cells alone; later patients received lymphodepletion before the first infusion. There were no dose limiting toxicities (DLTs). Aside from expected cytopenias in patients receiving lymphodepletion, serious adverse events possibly attributed to CAR T cell infusion were limited to one episode of headache and one of liver enzyme elevation. One patient withdrew from treatment during the DLT period due to a Grade 3 catheter-related infection and was not evaluable for disease response, although this was not attributed to CAR T cell infusion. Importantly, scRNA- and scTCR-sequence analyses provided insights into CAR T cell interaction with the endogenous immune system. In particular, clonally expanded endogenous CAR- T cells were recovered from the CSF, but not the peripheral blood, of patients who received intraventricular IL13BBζ-CAR T cell therapy. Additionally, although immune infiltrates in CSF and post-therapy tumor did not generally correlate, a fraction of expanded T cell receptors (TCRs) was seen to overlap between CSF and tumor. This has important implications for what samples are collected on these trials and how they are analyzed. These initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children with brain tumors.

Considering community care in public health responses: A national study regarding palliative care during a prolonged coronavirus disease 2019 lockdown.

OBJECTIVE: To describe changes in palliative care characteristics, utilisation and outcomes in Victoria during a period of enhanced public health management and a prolonged lockdown due to coronavirus disease 2019. METHODS: A national retrospective cohort study with palliative care service setting comparisons in Victoria and other mainland states was conducted. RESULTS: Analysis of 48 non-Victorian services (n=53,428 patients) and 20 Victorian services (n=31,125 patients) showed that for community services, patient volume, average length of stay, functional dependency and the proportion of admissions in a deteriorating phase increased during the lockdown in Victoria, yet little changed in comparator states. Regarding inpatient services, the management of family/carer problems remained constant in comparator states, yet substantial fluctuations in outcomes in Victoria were observed. CONCLUSIONS: As health systems adapt to changing circumstances during the pandemic, the ability to upscale community services is critical. Addressing the implications of shifting inpatient care to the community needs attention. IMPLICATIONS FOR PUBLIC HEALTH: Our study highlights the need to ensure community care providers are adequately considered within public health management responses. 'Joined up' policy and implementation across care settings are essential, especially as major barriers to infection control and increased utilisation may be evident in the community during the coronavirus disease 2019 pandemic.

Is There an All-Embracing "Intolerance to Uncertainty" Construct? French Adaptation and Validation of the Intolerance to Uncertainty Scale-Revised.

Objective: Intolerance to uncertainty is a trait-like disposition largely studied in psychopathology and known to be involved in many psychological disorders. Yet, the very operationalization of this construct has prompted debate in the literature. Three different models have regularly been discussed: a correlated two-factor solution, a bifactorial solution, and a single-factor structure. A growing body of evidence suggests that the bifactorial model represents the adequate factorial solution; however, its validity has never been tested in a large French-speaking sample. Moreover, uncertainty remains regarding the associations between IUS-R and other psychological constructs, especially stress and depression. This project was designed to overcome these limitations. Method: To do so, we translated the scale into French and tested (n = 728) via confirmatory factor analyses (CFA) whether the French version would better fit with a bifactorial-, correlated, or single-factor structure, as implied by previous works. We also examined the internal reliability of the IUS-R, as well as its associations with concurrent measures of stress, depression, anxiety, and worry. Results: The results pointed to a bifactorial structure as the best-fitting model and provided evidence for a strong general intolerance of uncertainty factor that was more reliable and accounted for significantly more common variance than each subscale factor individually. Conclusions: We discuss how this bifactorial structure impacts the conceptualization of IU.

Parental burnout features and the family context: A temporal network approach in mothers.

Many parents have days where they encounter emotional exhaustion, emotional distance from their children, and feeling fed up with being a parent. Some parents experience these characteristics to a severe extent-a clinical phenomenon termed parental burnout. Parental burnout arises when parents chronically endure severe stress without sufficient resources to cope, which may lead to detrimental consequences not only for the parent but also for their partner (e.g., marital conflict) and children (i.e., neglect and violence). However, uncertainty remains regarding how these features interact and trigger one another over time (potentially becoming increasingly severe), nor how the daily variations of the family context influence these features. Therefore, in this study, we recruited 50 parents (with main analyses focusing on 43 mothers with a co-parent, and sensitivity analyses with the full sample) from the general population to rate the core features of parental burnout and the family context daily over 56 days. We used multilevel vector autoregressive models to generate network models. Results suggest that exhaustion contributes to parental burnout: It self-predicts and is closely associated with feeling fed up and finding children difficult to manage. Distance, by contrast, is mainly negatively connected to sharing positive moments with children. Contextual variables also interact with parental burnout features, illustrating the relevance of examining parenting within the family system context. If future research confirms a central role of exhaustion in parental burnout development, prevention efforts can focus on decreasing parental exhaustion. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Auditing the research practices and statistical analyses of the group-level temporal network approach to psychological constructs: A systematic scoping review.

Network analyses have become increasingly common within the field of psychology, and temporal network analyses in particular are quickly gaining traction, with many of the initial articles earning substantial interest. However, substantial heterogeneity exists within the study designs and methodology, rendering it difficult to form a comprehensive view of its application in psychology research. Since the field is quickly growing and since there have been many study-to-study variations in terms of choices made by researchers when collecting, processing, and analyzing data, we saw the need to audit this field and formulate a comprehensive view of current temporal network analyses. To systematically chart researchers' practices when conducting temporal network analyses, we reviewed articles conducting temporal network analyses on psychological variables (published until March 2021) in the framework of a scoping review. We identified 43 articles and present the detailed results of how researchers are currently conducting temporal network analyses. A commonality across results concerns the wide variety of data collection and analytical practices, along with a lack of consistency between articles about what is reported. We use these results, along with relevant literature from the fields of ecological momentary assessment and network analysis, to formulate recommendations on what type of data is suited for temporal network analyses as well as optimal methods to preprocess and analyze data. As the field is new, we also discuss key future steps to help usher the field's progress forward and offer a reporting checklist to help researchers navigate conducting and reporting temporal network analyses.

An Experience Sampling Measure of the Key Features of Rumination.

Objective: Research indicates that rumination can be viewed as a dynamic process that fluctuates over time, within hours and days. An increasing number of intensive longitudinal studies on rumination are accordingly being conducted and published using experiencing sampling methodology (ESM), a technique with measurements in everyday life. Yet, this literature suffers from a profound caveat: rumination has so far been conceptualized and measured as a unitary construct in these ESM studies. This is unfortunate, since such a unitary view contrasts with prominent contemporary models that regard rumination as a multifaceted construct, wherein the key features are not interchangeable and should therefore be measured separately. Moreover, no validated ESM measure of the key features of rumination has yet been developed. Therefore, we developed and validated an ESM protocol and the first ESM questionnaire to assess rumination as a multifaceted construct, measuring five features of rumination. Method: We conducted an ESM study in a community sample of 40 French-speaking participants. They answered the five rumination ESM items in French four times a day for fourteen days. At the end of the ESM assessment period, participants completed trait-like questionnaires of rumination, depression, and general anxiety. Results: The ESM rumination items exhibited good psychometric properties, including excellent within-person variability and convergent validity with corresponding trait-like constructs. Conclusions: Although further validation is warranted, this novel ESM assessment protocol of rumination as a multifaceted construct (validated in French and translated into English) will allow future researchers to study how rumination's features fluctuate and interact with other constructs over time.

Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine.

T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24+ cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals.

On the Measurement of Climate Change Anxiety: French Validation of the Climate Anxiety Scale.

The notion of climate change anxiety has gained traction in the last years. Clayton & Karazsia (2020) recently developed the 22-item Climate Change Anxiety Scale (CAS), which assesses climate change anxiety via a four-factor structure. Yet other research has cast doubts on the very structure of the CAS by calling either for a shorter (i.e. 13 items) two-factor structure or for a shorter single-factor structure (i.e. 13 items). So far, these three different models have not yet been compared in one study. Moreover, uncertainty remains regarding the associations between the CAS and other psychological constructs, especially anxiety and depression. This project was designed to overcome these limitations. In a first preregistered study (n = 305), we translated the scale into French and tested, via confirmatory factor analyses (CFA), whether the French version would better fit with a four-, two-, or single-factor structure, as implied by previous works. We also examined how the CAS factors related to depression, anxiety, and environmental identity. In a second preregistered study, we aimed at replicating our comparison between the three CFA models in a larger sample (n = 905). Both studies pointed to a 13-item version of the scale with a two-factor structure as the best fitting model, with one factor reflecting cognitive and emotional features of climate change anxiety and the other reflecting the related functional impairments. Each factor exhibited a positive association with depression and environmental identity but not with general anxiety. We discuss how this two-factor structure impacts the conceptualization of climate change anxiety.

CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma.

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.

A network approach to the five-facet model of mindfulness.

Despite the large-scale dissemination of mindfulness-based interventions, debates persist about the very nature of mindfulness. To date, one of the dominant views is the five-facet approach, which suggests that mindfulness includes five facets (i.e., Observing, Describing, Nonjudging, Nonreactivity, and Acting with Awareness). However, uncertainty remains regarding the potential interplay between these facets. In this study, we investigated the five-facet model via network analysis in an unselected sample (n = 1704). We used two distinct computational network approaches: a Gaussian graphical model (i.e., undirected) and a directed acyclic graph, with each model determining the relations between the facets and their relative importance in the network. Both computational approaches pointed to the facet denoting Acting with Awareness as playing an especially potent role in the network system. Altogether, our findings offer novel data-driven clues for the field's larger quest to ascertain the very foundations of mindfulness.

Physical health, behavioral and emotional functioning in children of gulf war veterans.

OBJECTIVE: We examined whether the prevalence of medical and behavioral conditions is higher in children of deployed veterans (DVs) versus non-deployed veterans (NDVs) after the 1991 Gulf War. METHODS: We examined 1387 children of 737 veterans. Children ages 2-18 had physical exams and parental reports of physical history and behavior. RESULTS: Physical health was analyzed using GEE models. Behavioral health [total, internalizing, and externalizing behavior problems (TBP, IBP, EBP)] was analyzed with mixed-effects regression models. Analyses were conducted by age group (2-3, 4-11, 12-18), and gender (ages 4-11, 12-18). Children of DVs ages 2-3 had significantly worse dentition (13.9% vs. 4.8%, P = 0.03) and more EBP {least square means (lsmeans) 54.31 vs. 47.59, P = 0.02}. Children of DVs ages 4-11 had significantly more obesity (18.8% vs. 12.7%, P = 0.02). Among children 4-11, male children of DVs had significantly more TBP (lsmeans 70.68 vs. 57.34, P = 0.003), IBP (lsmeans 63.59 vs. 56.16, P = 0.002) and EBP (lsmeans 61.60 vs. 52.93, P = 0.03), but female children did not. For children ages 12-18, male children of DVs had more EBP (lsmeans 63.73 vs. 43.51, P = 0.008), while female children of DVs had fewer EBP (lsmeans 45.50 vs. 50.48, P = 0.02). Veteran military characteristics and mental health, and children's social status and health, including obesity, predicted children's TBP for one or more age groups. CONCLUSIONS: Children of DVs experienced worse dentition, greater obesity, and more behavioral problems compared to NDV children, suggesting adverse health effects associated with parental deployment in need of further exploration.

Phase II study of neratinib in older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer.

OBJECTIVE: The tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60. METHODS: Patients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated. RESULTS: 25 patients were enrolled with median age of 66 (range 60-79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0-11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56-5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]). CONCLUSIONS: Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.

Outcome for bilateral cochlear implantation in patients with congenital Cytomegalovirus infection.

OBJECTIVES: To analyze the impact of bilateral cochlear implantation (CI) on perceptual and linguistic development in hearing-impaired children with congenital Cytomegalovirus (CMV) infection. PATIENTS AND METHOD: A retrospective study was performed for the period 1991-2016 in a pediatric CI reference center. Closed Set Word (CSW) recognition scores, Categories of Auditory Performance (CAP) and linguistic level on the MT Lenormand scale (MTL) were compared between bilateral (Bi) and unilateral (Uni) groups 12, 24 and 36 months after first CI (CI-1). RESULTS: 84 patients with congenital CMV infection who underwent CI were included, in 2 groups: sequential or simultaneous bilateral CI (Bi) (N=20), and unilateral CI (Uni) (N=64). Twelve, 24 and 36 months after CI-1, CSW scores were 35.56%, 64.52% and 82.93% in Uni and 60.3%, 85% (P=0.0084*), and 100% (P=0.00085*) in Bi. CAP scores 12, 24 and 36 months after CI-1 were 2.57, 3.85 and 4.3 in Uni and 3.91 (P=0.0068*), 5.00 (p=0.029*) and 5.50 (P=0.051*) in Bi. MTL linguistic level scores at 12, 24 and 36 months were 0.72, 1.25 and 1.65 in Uni, and 1.72, 3 (P=0.033) and 3.11 (P=0.045) in Bi. These significantly better scores in Bi at 24 and 36 months after CI-1 were also found on analysis of subgroups with no associated neurologic disorder (P=0.046* and P=0.032*), no associated psychiatric pathology (P=0.0055* and P=0.0073*), and no other associated disorder (P=0.0018* and P=0.035*), and for all subgroups together (P=0.0036 and P=0.037). CONCLUSION: Bilateral CI is a faster way than unilateral CI for patients with congenital CMV infection to achieve structured fluent oral language. 50% of the series showed cerebral abnormalities on MRI, without difference between groups. This was not in itself predictive of poor progression of oral communication, unless associated with major neurologic disorder. Some children made little or no use of their CI in the medium term.

Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients.

Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas. CD-NSCs were given every 2 weeks using an indwelling brain catheter, followed each time by a 7-d course of oral 5-FC (and leucovorin in the final patient cohort). Fifteen evaluable patients received a median of 4 (range 2-10) intracerebral CD-NSC doses; doses were escalated from 50 × 106 to 150 × 106 CD-NSCs. Neuropharmacokinetic data confirmed that CD-NSCs continuously produced 5-FU in the brain during the course of 5-FC. There were no clinical signs of immunogenicity, and only three patients developed anti-NSC antibodies. Our results suggest intracerebral administration of serial doses of CD-NSCs is safe and feasible and identified a recommended dose for phase II testing of 150 × 106 CD-NSCs.

A network approach to parental burnout.

BACKGROUND: The use of network analyses in psychology has increasingly gained traction in the last few years. A network perspective views psychological constructs as dynamic systems of interacting elements. OBJECTIVE: We present the first study to apply network analyses to examine how the hallmark features of parental burnout - i.e., exhaustion related to the parental role, emotional distancing from children, and a sense of ineffectiveness in the parental role - interact with one another and with maladaptive behaviors related to the partner and the child(ren), when these variables are conceptualized as a network system. PARTICIPANTS AND SETTING: In a preregistered fashion, we reanalyzed the data from a French-speaking sample (n = 1551; previously published in Mikolajczak, Brianda et al., 2018), focusing on seven specific variables: the three hallmark parental burnout features, partner conflict, partner estrangement, neglectful behavior toward children, and violent behavior toward children. METHODS: We computed two types of network models, a graphical Gaussian model to examine network structure, potential communities, and influential nodes, and a directed acyclic graph to examine the probabilistic dependencies among the different variables. RESULTS: Both network models pointed to emotional distance as an especially potent mechanism in activating all other nodes. CONCLUSIONS: These results suggest emotional distance as critical to the maintenance of the parental burnout network and a prime candidate for future interventions, while affirming that network analysis can successfully expose the structure and relationship of variables related to parental burnout and its consequences related to the partner and the child(ren).

Why we should move from reductionism and embrace a network approach to parental burnout.

Network science has allowed varied scientific fields to investigate and visualize complex relations between many variables, and psychology research has begun to adopt a network perspective. In this paper, we consider how leaving behind reductionist approaches and instead embracing a network perspective can advance the field of parental burnout. Although research into parental burnout is in its early stages, we argue that a network approach to parental burnout could set the scene for radically new vistas in parental burnout research. We claim that such an approach can allow simultaneous investigations (and clear visualizations) of many variables related to parental burnout and their interactions, integrates smoothly with prior family systems theories, and prioritizes dynamic research questions. We likewise discuss potential future clinical applications, such as interventions targeting central nodes and treatment personalized to a specific family's network system. We also review practical considerations, limitations, and future directions for researchers interested in applying a network approach to parental burnout research.

Systemic Anti-PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid.

IMPORTANCE: Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in the central nervous system. Such information is critical for advancing checkpoint antibody therapies for treatment of brain tumors. OBJECTIVE: To evaluate pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid (CSF) after intravenous administration. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid and blood samples were collected from 10 adult patients with high-grade gliomas who were participating in clinical trials of intracranially administered chimeric antigen receptor (CAR) T cells and intravenous pembrolizumab at City of Hope in Duarte, California, from 2017 through 2019. Neuropharmacokinetic and immunologic correlative studies were performed on CSF and serum samples. INTERVENTIONS OR EXPOSURES: Pembrolizumab, 200 mg, was given intravenously every 3 weeks with a median of 2 cycles (range, 1-8). CAR T cells were administered intracranially every 1 to 4 weeks. Cerebrospinal fluid and blood samples were collected on the day of CAR T-cell administration and then 24 hours later for a total of 100 paired samples. MAIN OUTCOMES AND MEASURES: Pembrolizumab concentrations were measured by enzyme-linked immunosorbent assay, PD-1 blocking on T cells by flow cytometry, and results of PD-1 blockade on CAR T-cell function by in vitro tumor rechallenge assays. RESULTS: Of the 10 patients included in this study, the mean (SD) age was 45.7 (11.0) years, and 6 (60%) were women. Steady-state pembrolizumab concentrations in the CSF were achieved by 24 hours after initial intravenous administration, with a mean CSF:serum ratio of 0.009 (95% CI, 0.004-0.014). The CSF concentrations of pembrolizumab effectively blocked PD-1 on both endogenous T cells and intracranially administered CAR T cells in the CSF, with flow cytometric detection of surface PD-1 on the T cells decreasing from a mean (SD) of 39.3% (20.2%) before pembrolizumab to a mean (SD) of 3.8% (5.8%) 24 hours after pembrolizumab infusion. Steady-state concentrations in the CSF were maintained throughout the 21-day cycle of pembrolizumab, as was the PD-1 blocking effect, evidenced by no increase in detectable surface PD-1 on T cells in the CSF during that time period. Incubation of PD-1-expressing T cells with CSF samples from patients treated with pembrolizumab also resulted in PD-1 blockade. CONCLUSIONS AND RELEVANCE: Results of this study demonstrate steady-state concentrations of pembrolizumab in CSF after intravenous administration as well as CSF concentrations that are sufficient for blocking PD-1 on endogenous and adoptively transferred T cells. This provides mechanistic insight regarding the ability of systemically administered PD-1 blocking antibodies to modulate T-cell activity in the brain.