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.

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.

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy.

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).

Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL.

Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.

Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders.

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus-the 'D-shuttle' project.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries.

Age-related changes in nanoparticle albumin-bound paclitaxel pharmacokinetics and pharmacodynamics: influence of chronological versus functional age.

PURPOSE: This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer. METHODS: Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc. RESULTS: Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041). CONCLUSION: A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.

Occupational engagement among community dwelling older people: A time-geographic perspective†.

How older people spend their time in different occupations could contribute to our understanding of everyday life in healthy ageing. This study adopted a time-geographic method and occupational perspective to explore the occupational engagement of community dwelling older people. The term occupational engagement encompasses what people do, where and with whom they spend their time and the perceived level of competence and meaningfulness of their time use. Nineteen volunteers born between 1932 and 1933, living alone in an urban area in northern Sweden and receiving no home care services, completed open time-geographic diaries for 5 days in May 2010. The diary data were analyzed using Daily Life software program. The study revealed the complexity and the diversity of the older people's occupational engagement and that most of their time was spent alone in their home. The older people reported they were very good at doing almost half of the occupations in which they engaged and that their occupations were primarily either very meaningful or meaningful. While some methodological limitations were identified, time-geographic studies of community dwelling older people living independently are considered to have potential to contribute to community and social planning for older people as they can provide interesting insights to older persons' time use and occupational needs.

Resting-state connectivity deficits associated with impaired inhibitory control in non-treatment-seeking adolescents with psychotic symptoms.

OBJECTIVE: Psychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic symptoms (the extended psychosis phenotype). METHOD: This study investigated intrinsic functional connectivity (iFC) during resting-state functional magnetic resonance imaging (fMRI; rs-fMRI). Following screening in schools, 11 non-treatment seeking, youth with psychotic symptoms (aged 11-13) and 14 community controls participated in the study. Seed regions of interest comprised brain regions previously shown to exhibit aberrant activation during inhibitory control in adolescents with psychotic symptoms. RESULTS: Relative to controls, adolescents with psychotic symptoms exhibited reduced iFC between regions supporting inhibitory control. Specifically, they showed weaker iFC between the right inferior frontal gyrus (IFG) and the cingulate, IFG and the striatum, anterior cingulate and claustrum, and precuneus and supramarginal gyrus. Conversely, the psychotic symptoms group exhibited stronger iFC between the superior frontal gyrus and claustrum and IFG and lingual gyrus. CONCLUSION: The present findings are the first to reveal aberrant functional connectivity in resting-state networks in a community sample of adolescents with psychotic symptoms and suggest that disruption in integration between distributed neural networks (particularly between prefrontal, cingulate and striatal brain regions) may be a key neurobiological feature of the extended psychosis phenotype.

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.

PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .

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 .

Neural stem cell-mediated CE/CPT-11 enzyme/prodrug therapy in transgenic mouse model of intracerebellar medulloblastoma.

Medulloblastoma is a heterogeneous diffuse neoplasm that can be highly disseminated, and is the most common malignant childhood brain tumor. Although multimodal treatments have improved survival rates for patients with medulloblastoma, these tumors are associated with high morbidity and mortality. New treatment strategies are urgently needed to improve cure rates and, importantly, to spare normal brain tissue from neurotoxicity and patients from life-long cognitive and functional deficits associated with current therapies. In numerous preclinical brain tumor models, neural stem cells (NSCs) have shown great promise as delivery vehicles for therapeutic genes. Here, we have used an established, genetically modified human NSC line (HB1.F3.CD) to deliver carboxylesterase (CE) to cerebellar tumor foci and locally activate the prodrug camptothecin-11 (CPT-11) (Irinotecan) to the potent topoisomerase I inhibitor SN-38. HB1.F3.CD NSC tumor tropism, intratumoral distribution and therapeutic efficacy were investigated in clinically relevant experimental models. Magnetic resonance imaging was used for in vivo tracking of iron nanoparticle-labeled NSCs, and to assess the therapeutic efficacy of CE-expressing HB1.F3.CD cells. As compared with controls, a significant decrease in tumor growth rate was seen in mice that received both NSCs and CPT-11 as their treatment regimen. Thus, this study provides proof-of-concept for NSC-mediated CE/CPT-11 treatment of medulloblastoma, and serves as a foundation for further studies toward potential clinical application.

Primary upper-limb lymphoedema.

BACKGROUND: Lymphoedema is a general term used to designate pathological, regional accumulation of protein-rich fluid. It can be either primary or secondary, and mainly occurs after cancer treatment. OBJECTIVES: To analyse the clinical and lymphoscintigraphic characteristics of primary upper-limb lymphoedema (ULL). METHODS: All of the patients with ULL were recruited at a single Department of Lymphology between January 2007 and December 2011. RESULTS: In total, 60 patients (33 female, 27 male) were enrolled. For the 54 noncongenital lymphoedemas, the mean age at onset was 38·5 (range 3-82) years. Lymphoedema was unilateral in 51 patients (85%). It always affected the hand, and less often the forearm (55%) or upper arm (23%). Eleven patients (18%) developed cellulitis after onset of lymphoedema, and 21 patients (35%) had associated lower-limb lymphoedema (LLL). Forty-six patients (with 49 lymphoedematous limbs) underwent lymphoscintigraphy: axillary lymph node uptake was diminished in 18 (37%), absent in 24 (49%) and normal in seven limbs (14%). Among the 43 patients with unilateral lymphoedema and lymphoscintigraphy, 28 had epitrochlear node visualization, suggesting a rerouting through the deep lymphatic system, with 15 only on the lymphoedematous limb and 22 on the contralateral nonlymphoedematous limb. The median follow-up period was 103 months, and 57/60 patients (95%) considered their lymphoedema to be stable. CONCLUSIONS: Primary ULL appears later in life than LLL, without predominance in either sex. Infectious complications are rare and patients considered the lymphoedema volume stable throughout life.

Complications of autologous lymph-node transplantation for limb lymphoedema.

OBJECTIVE: This study aims to assess potential complications of autologous lymph-node transplantation (ALNT) to treat limb lymphoedema. DESIGN: Prospective, observational study. METHOD: All limb-lymphoedema patients, followed up in a single lymphology department, who decided to undergo ALNT (January 2004-June 2012) independently of our medical team, were included. RESULTS: Among the 26 patients (22 females, four males) included, 14 had secondary upper-limb lymphoedema after breast-cancer treatment and seven had secondary and five primary lower-limb lymphoedema. Median (interquartile range, IQR) ages at primary lower-limb lymphoedema and secondary lymphoedema onset were 18.5 (13-30) and 47.4 (35-58) years, respectively. Median body mass index (BMI) was 25.9 (22.9-29.3) kg m⁻². For all patients, median pre-surgery lymphoedema duration was 37 (24-90) months. Thirty-four ALNs were transplanted into the 26 patients, combined with liposuction in four lower-limb-lymphoedema patients. Ten (38%) patients developed 15 complications: six, chronic lymphoedema (four upper limb, two lower limb), defined as ≥2-cm difference versus the contralateral side, in the limb on the donor lymph-node-site territory, persisting for a median of 40 months post-ALNT; four, post-surgical lymphocoeles; one testicular hydrocoele requiring surgery; and four with persistent donor-site pain. Median (IQR) pre- and post-surgical lymphoedema volumes, calculated using the formula for a truncated cone, were, respectively, 1023 (633-1375) ml (median: 3 (1-6) months) and 1058 (666-1506) ml (median: 40 (14-72) months; P = 0.73). CONCLUSION: ALNT may engender severe, chronic complications, particularly persistent iatrogenic lymphoedema. Further investigations are required to evaluate and clearly determine its indications.

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).

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.

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.

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.

Prospective cohort study of adverse events in older people admitted to the acute general hospital: risk factors and the impact of dementia.

BACKGROUND: Reported adverse events (RAEs) are relatively common in the acute hospital and are associated with significant mortality and morbidity. Dementia is increasing in hospital in-patients, however there have been few studies exploring risk factors for RAEs, in particular cognitive impairment and dementia. Our objective was to identify the prevalence of RAEs in older acute medical inpatients and associated demographic, clinical or cognitive risk factors. METHOD: A longitudinal cohort study set on acute medical wards in a large general hospital. We recruited 710 people aged over 70 years undergoing emergency medical admission. Dementia was diagnosed using operationalised DSM-IV criteria. Patients were assessed using standardised tools including the Confusion Assessment Method, mini-mental state examination, the Functional Assessment Staging scale, the APACHE scale and Charlson co-morbidity index. Data on adverse events was supplied independently by the hospital clinical risk department. RESULTS: 8.6% (95% CI 6.4-10.6) of patients experienced an RAE; 5.9% (95% CI 4.2-7.6) were patient-related and 2.7% (95% CI 1.5-3.8) system-related (incidence rate for all RAEs was 2.1 (95% CI 1.7-2.8)) per person year of hospital admission. Median length of admission was 8 days (inter-quartile range 4-17 days). Patient-related RAEs were associated with male gender, delirium, mild/moderate cognitive impairment and a FAST score of 2-6. Overall, 11.1% died during the admission-this was not associated with experiencing an RAE. Staff comments on incident forms indicated an apparent lack of understanding of the impact of cognitive impairment. CONCLUSIONS: RAEs were common and associated with risk factors identifiable at admission.