Associations between executive functions assessed in different contexts in a genetically informative sample.

Executive functions (EFs) are cognitive functions that help direct goal-related behavior. EFs are usually measured via behavioral tasks assessed in highly controlled laboratory settings under the supervision of a research assistant. Online versions of EF tasks are an increasingly popular alternative to in-lab testing. However, researchers do not have the same control over the testing environment during online EF assessments. To assess the extent to which EFs assessed in-lab and online are related, we used data from the Colorado Online Twin Study (CoTwins; 887 individual twins aged 13.98-19.05) and constructed an Lab Common EF factor and an Online Common EF factor from four EF tasks assessed in-lab and online. The Lab Common and Online Common EF factors were genetically identical (rA = 1.00) but phenotypically separable (r = .77, 95% confidence interval [0.59, 0.94]) indicating that these EF factors have the same genetic underpinnings but may be differentially influenced by environmental factors. We examined phenotypic, genetic, and environmental correlations between the EF factors and a general cognitive ability factor (g) assessed in the lab and found similar relationships between Lab Common EF and g and Online Common EF and g. Overall, these results suggest that Common EF factors assessed in different contexts are highly related to each other and similarly related to other cognitive outcomes. These findings indicate that online task-based EF assessments could be a viable strategy for increasing sample sizes in large-scale studies, particularly genetically informed studies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Limited psychological and social effects of lifetime cannabis use frequency: Evidence from a 30-year community study of 4,078 twins.

BACKGROUND: Cannabis use is associated with outcomes like income, legal problems, and psychopathology. This finding rests largely on correlational research designs, which rely at best on statistical controls for confounding. Here, we control for unmeasured confounders using a longitudinal study of twins. METHOD: In a sample of 4,078 American adult twins first assessed decades ago, we used cotwin control mixed effects models to evaluate the effect of lifetime average frequency of cannabis consumption measured on substance use, psychiatric, and psychosocial outcomes. RESULTS: On average, participants had a lifetime cannabis frequency of about one to two times per month, across adolescence and adulthood. As expected, in individual-level analyses, cannabis use was significantly associated with almost all outcomes in the expected directions. However, when comparing each twin to their cotwin, which inherently controls for shared genes and environments, we observed within-pair differences consistent with possible causality in three of the 22 assessed outcomes: cannabis use disorder symptoms (ßW-Pooled = .15, SE = .02, p = 1.7 × 10-22), frequency of tobacco use (ßW-Pooled = .06, SE = .01, p = 1.2 × 10-5), and illicit drug involvement (ßW-Pooled = .06, SE = .02, p = 1.2 × 10-4). Covariate specification curve analyses indicated that within-pair effects on tobacco and illicit drug use, but not cannabis use disorder, attenuated substantially when covarying for lifetime alcohol and tobacco use. CONCLUSIONS: The cotwin control results suggest that more frequent cannabis use causes small increases in cannabis use disorder symptoms, approximately 1.3 symptoms when going from a once-a-year use to daily use. For other outcomes, our results are more consistent with familial confounding, at least in this community population of twins. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia.

The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αß T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.

Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity.

Hemophilia A is the most common X-linked bleeding disorder affecting more than half-a-million individuals worldwide. Persons with severe hemophilia A have coagulation FVIII levels <1% and experience spontaneous debilitating and life-threatening bleeds. Advances in hemophilia A therapeutics have significantly improved health outcomes, but development of FVIII inhibitory antibodies and breakthrough bleeds during therapy significantly increase patient morbidity and mortality. Here we use sheep fetuses at the human equivalent of 16-18 gestational weeks, and we show that prenatal transplantation of human placental cells (107-108/kg) bioengineered to produce an optimized FVIII protein, results in considerable elevation in plasma FVIII levels that persists for >3 years post-treatment. Cells engraft in major organs, and none of the recipients mount immune responses to either the cells or the FVIII they produce. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth.

Evaluating longitudinal relationships between parental monitoring and substance use in a multi-year, intensive longitudinal study of 670 adolescent twins.

Introduction: Parental monitoring is a key intervention target for adolescent substance use, however this practice is largely supported by causally uninformative cross-sectional or sparse-longitudinal observational research designs. Methods: We therefore evaluated relationships between adolescent substance use (assessed weekly) and parental monitoring (assessed every two months) in 670 adolescent twins for two years. This allowed us to assess how individual-level parental monitoring and substance use trajectories were related and, via the twin design, to quantify genetic and environmental contributions to these relationships. Furthermore, we attempted to devise additional measures of parental monitoring by collecting quasi-continuous GPS locations and calculating a) time spent at home between midnight and 5am and b) time spent at school between 8am-3pm. Results: ACE-decomposed latent growth models found alcohol and cannabis use increased with age while parental monitoring, time at home, and time at school decreased. Baseline alcohol and cannabis use were correlated (r = .65) and associated with baseline parental monitoring (r = -.24 to -.29) but not with baseline GPS measures (r = -.06 to -.16). Longitudinally, changes in substance use and parental monitoring were not significantly correlated. Geospatial measures were largely unrelated to parental monitoring, though changes in cannabis use and time at home were highly correlated (r = -.53 to -.90), with genetic correlations suggesting their relationship was substantially genetically mediated. Due to power constraints, ACE estimates and biometric correlations were imprecisely estimated. Most of the substance use and parental monitoring phenotypes were substantially heritable, but genetic correlations between them were not significantly different from 0. Discussion: Overall, we found developmental changes in each phenotype, baseline correlations between substance use and parental monitoring, co-occurring changes and mutual genetic influences for time at home and cannabis use, and substantial genetic influences on many substance use and parental monitoring phenotypes. However, our geospatial variables were mostly unrelated to parental monitoring, suggesting they poorly measured this construct. Furthermore, though we did not detect evidence of genetic confounding, changes in parental monitoring and substance use were not significantly correlated, suggesting that, at least in community samples of mid-to-late adolescents, the two may not be causally related.

Exploring Relationships Between Internalizing Problems and Risky Sexual Behavior: A Twin Study.

Previous research links risky sexual behavior (RSB) to externalizing problems and to substance use, but little research has been conducted on relationships between internalizing problems (INT) and RSB. The current study addresses that literature gap, using both a twin sample from Colorado (N = 2567) and a second twin sample from Minnesota (N = 1131) in attempt to replicate initial results. We explored the hypothesis that the latent variable INT would be more strongly associated with the latent variable RSB for females than for males, examining relationships between INT and RSB via phenotypic confirmatory factor analysis and multivariate twin analyses. We found a small but significant phenotypic association between the latent variables. However, despite using two large twin samples, limited power restricted our ability to identify the genetic and environmental mechanisms underlying this association. Our sex differences hypothesis was not fully supported in either sample and requires further investigation. Our findings illustrate the complexity of the relationship between internalizing problems and risky sexual behavior.

Individual differences in adolescent and young adult daily mobility patterns and their relationships to big five personality traits: a behavioral genetic analysis.

Youth behavior changes and their relationships to personality have generally been investigated using self-report studies, which are subject to reporting biases and confounding variables. Supplementing these with objective measures, like GPS location data, and twin-based research designs, which help control for confounding genetic and environmental influences, may allow for more rigorous, causally informative research on adolescent behavior patterns. To investigate this possibility, this study aimed to (1) investigate whether behavior changes during the transition from adolescence to emerging adulthood are evident in changing mobility patterns, (2) estimate the influence of adolescent personality on mobility patterns, and (3) estimate genetic and environmental influences on mobility, personality, and the relationship between them. Twins aged Fourteen to twenty-two (N=709, 55% female) provided a baseline personality measure, the Big Five Inventory, and multiple years of smartphone GPS data from June 2016 - December 2019. Mobility, as measured by daily locations visited and distance travelled, was found via mixed effects models to increase during adolescence before declining slightly in emerging adulthood. Mobility was positively associated with Extraversion and Conscientiousness (r of 0.17 - 0.25, r of 0.10 - 0.16) and negatively with Openness (r of -0.11 - -0.13). ACE models found large genetic (A = 0.56 - 0.81) and small-moderate environmental (C of 0.12 - 0.28, E of 0.07 - 0.15) influences on mobility. A and E influences were highly shared across mobility measures (rg = 0.70, re= 0.58). Associations between mobility and personality were partially explained by mutual genetic influences (rg of -0.27 - 0.53). Results show that as autonomy increases during adolescence and emerging adulthood, we see corresponding increases in youth mobility. Furthermore, the heritability of mobility patterns and their relationship to personality demonstrate that mobility patterns are informative, psychologically meaningful behaviors worthy of continued interest in psychology.

Neurosarcoidosis of the Cauda Equina: Clinical Course, Radiographic and Electrodiagnostic Findings, Response to Treatment, and Outcomes.

BACKGROUND AND OBJECTIVES: Sarcoidosis is a multisystem granulomatous disease affecting the nervous system in 3%-5% of cases. It can affect almost any component of the nervous system. Involvement of the cauda equina is an understudied phenotype, and questions remain regarding its natural history and optimal approach to management. This study aims to study the long-term clinical evolution of neurosarcoidosis affecting the cauda equina, response to treatment, and clinical and radiographic outcomes. METHODS: Patients with neurosarcoidosis treated at Emory University between January 1, 2011, and December 8, 2021, were retrospectively evaluated for manifestations of cauda equina disease and included if disease of the cauda equina could be substantiated by MRI or EMG. RESULTS: Of 216 cases, 14 (6.5%) involved the cauda equina. The median age was 49.5 years, and most were female (85.7%) and African American (64.3%). Chronic (>28 days) presentations were most common (78.6%), but acute (<7 days, 14.3%) and subacute (7-28 days, 7.1%) were also seen. The median modified Rankin Scale (mRS) score at nadir was 3 (range 2-4). Symptoms were asymmetric in 78.6% and included leg numbness (85.7%), leg weakness (64.3%), perineal numbness (35.7%), pain (42.3%), and incontinence (21.4%). On MRI, the cauda equina enhanced in 100%, appeared nodular in 78.6%, and was diffusely involved in 71.4%. Coexisting myelitis was common (cervical 28.6%, thoracic 35.7%, and conus medullaris 28.6%). Intracranial inflammation included leptomeningitis (71.4%) and cranial neuropathies (57.1%). Electrodiagnostic studies were conducted in 3 with only one showing features consistent with a radicular process. Serum and CSF angiotensin-converting enzyme levels were elevated in 38.5% and 0.0%, respectively. CSF white blood cell and protein were elevated in 92.9%. Corticosteroids were tried in all patients with durable stabilization or improvement in only 3 (21.4%). Second-line agents associated with improvement included methotrexate/infliximab (3/4, 75%), methotrexate (3/4, 75.0%), and azathioprine (1/1, 100%). During a median follow-up of 22.5 months, the final median mRS score was 3. Relapses occurred at a median of 6 months in 21.4%. In 9 patients with MRI follow-up, 6 improved (66.7%), 1 stabilized (11.1%), and 2 worsened (22.2%). DISCUSSION: Characteristic features of cauda equina involvement by neurosarcoidosis include chronically delayed presentations, nodular enhancement on MRI, poor response to corticosteroids, and substantial resultant neurologic disability.

Thrombopoietin-based CAR-T cells demonstrate in vitro and in vivo cytotoxicity to MPL positive acute myelogenous leukemia and hematopoietic stem cells.

While targeting CD19+ hematologic malignancies with CAR T cell therapy using single chain variable fragments (scFv) has been highly successful, novel strategies for applying CAR T cell therapy with other tumor types are necessary. In the current study, CAR T cells were designed using a ligand binding domain instead of an scFv to target stem-like leukemia cells. Thrombopoietin (TPO), the natural ligand to the myeloproliferative leukemia protein (MPL) receptor, was used as the antigen binding domain to engage MPL expressed on hematopoietic stem cells (HSC) and erythropoietic and megakaryocytic acute myeloid leukemias (AML). TPO-CAR T cells were tested in vitro against AML cell lines with varied MPL expression to test specificity. TPO-CAR T cells were specifically activating and cytotoxic against MPL+ leukemia cell lines. Though the TPO-CAR T cells did not extend survival in vivo, it successfully cleared the MPL+ fraction of leukemia cells. As expected, we also show the TPO-CAR is cytotoxic against MPL expressing bone marrow compartment in AML xenograft models. The data collected demonstrate preclinical potential of TPO-CAR T cells for stem-like leukemia through assessment of targeted killing of MPL+ cells and may facilitate subsequent HSC transplant under reduced intensity conditioning regimens.

Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII.

Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA.

Social preference in rats.

Rats were given repeated choices between social and nonsocial outcomes, and between familiar and unfamiliar social outcomes. Lever presses on either of 2 levers in the middle chamber of a 3-chamber apparatus opened a door adjacent to the lever, permitting 45-s access to social interaction with the rat in the chosen side chamber. In Experiment 1, rats preferred (a) social over nonsocial options, choosing their cagemate rat over an empty chamber, and (b) an unfamiliar over a familiar rat, choosing a non-cagemate over their cagemate. These findings were replicated in Experiment 2 with 2 different non-cagemate rats. Rats preferred both non-cagemate rats to a similar degree when pitted against their cagemate, but were indifferent when the 2 non-cagemates were pitted against each other. Similar preference for social over nonsocial and non-cagemate over cagemate was seen in Experiment 3, with new non-cagemate rats introduced after every third session. Response rates (for both cagemate and non-cagemate rats) were elevated under conditions of nonsocial (isolated) housing compared to conditions of social (paired) housing, demonstrating a social deprivation effect. Together, the experiments contribute to an experimental analysis of social preference within a social reinforcement framework, drawing on methods with proven efficacy in the analysis of reinforcement more generally.

Drinking refusal self-efficacy: Impacts on outcomes from a multi-site early intervention trial.

This study examines relationships between drink refusal self-efficacy (DRSE) and outcomes in Project Options (PO), an adolescent alcohol use early intervention. 1171 US high school students (39.3% Hispanic, 59.3% girls) participated in PO, reporting their demographics, alcohol use, and drinking reduction efforts at baseline, 30 days and three months later. Items from the Drug Taking Confidence Questionnaire for Adolescents (DTCQ-A) assessed DRSE. DRSE corresponded negatively with drinking at 30 days and, among drinkers, predicted fewer use reduction attempts at 30 days and three months. Results indicate that, unlike in treatment settings, DRSE may not correspond to improved early intervention outcomes.