Assessing the association between parents' math talk and children's math performance: A preregistered meta-analysis.

The home math environment has gained considerable attention as a potential cause of variation in children's math performance, and recent research has suggested positive associations between parents' math talk and children's mathematical performance. However, the extent to which associations reflect robust causal effects is difficult to test. In a preregistered meta-analysis, we assess the association between parents' math talk and children's math performance. Our initial search identified 24,291 potential articles. After screening, we identified 22 studies that were included in analyses (k = 280 effect sizes, n = 35,917 participants). A multilevel random effects meta-analysis was employed, finding that parents' math talk is significantly associated with children's math performance (b = 0.10, SE = 0.03, p = .002). We tested whether associations differ as a function of sample characteristics, observation context, observation length, type of math talk and math performance measured, and modeling approaches to math talk variable analysis. In addition, we tested whether associations are robust to the inclusion of strong baseline covariates and found that effects attenuated when children's domain-general and/or prior math abilities are included. We discuss plausible bounds of the effects of parents' math talk on children's mathematical performance to inform power analyses and experimental work on the impact of parents' math language on children's math learning.

Fraction Ball impact on student and teacher math talk and behavior.

We assessed the impacts of Fraction Ball-a novel suite of games combining the benefits of embodied guided play for math learning-on the math language production and behavior of students and teachers. In the Pilot Experiment, 69 fifth and sixth graders were randomly assigned to play four different Fraction Ball games or attend normal physical education class. The Efficacy Experiment was implemented to test improvements made through co-design with teachers with 160 fourth through sixth graders. Researchers observed and coded for use of math language and behavior. Playing Fraction Ball resulted in consistent increases of students' and teachers' use of fraction (SDs = 0.98-2.42) and decimal (SDs = 0.65-1.64) language and number line arithmetic, but not in whole number, spatial language, counting, instructional gesturing, questioning, and planning. We present evidence of the math language production in physical education and value added by Fraction Ball to support rational number language and arithmetic through group collaboration.

Hedges, mottes, and baileys: Causally ambiguous statistical language can increase perceived study quality and policy relevance.

There is a norm in psychology to use causally ambiguous statistical language, rather than straightforward causal language, when describing methods and results of nonexperimental studies. However, causally ambiguous language may inhibit a critical examination of the study's causal assumptions and lead to a greater acceptance of policy recommendations that rely on causal interpretations of nonexperimental findings. In a preregistered experiment, 142 psychology faculty, postdocs, and doctoral students (54% female), ages 22-67 (M = 33.20, SD = 8.96), rated the design and analysis from hypothetical studies with causally ambiguous statistical language as of higher quality (by .34-.80 SD) and as similarly or more supportive (by .16-.27 SD) of policy recommendations than studies described in straightforward causal language. Thus, using statistical rather than causal language to describe nonexperimental findings did not decrease, and may have increased, perceived support for implicitly causal conclusions.

Standards for psychosocial care in pediatric cancer: adapted proposal for Latin American and Caribbean countries.

Objective: To highlight the objectives, achievements, challenges, and next steps for the World Health Organization's Global Initiative for Childhood Cancer (GICC) framework, a project designed to improve psychosocial care (PSC) in pediatric cancer centers across Latin America and the Caribbean (LAC). Methods: The project was launched in Peru, the first GICC focal country, in November 2020. The diagnosis phase included a survey and a semistructured interview with health professionals to assess PSC practices in institutions, and a needs assessment survey for caregivers. In the second phase, a strategic plan was developed to address the identified needs, including the adaptation of PSC standards, the establishment of multicenter working groups, the expansion of the proposal, and the development of materials. Results: The study found that PSC was not being adequately provided in accordance with international standards. Six adapted standards were proposed and validated, and more than 50 regional health professionals participated in online activities to support the project. The implementation process is currently ongoing, with the establishment of five multidisciplinary working groups, one regional committee, and the production of 16 technical outputs. Conclusion: This project represents a substantial step forward to improve PSC for pediatric patients with cancer and their families in LAC countries. The establishment of working groups and evidence-based interventions strengthen the proposal and its implementation. Development of health policies that include PSC according to standards is needed to achieve sustainable results in the quality of life of children with cancer and their families.

"You did a great job building that!" Links between parent-child prosocial talk and spatial language.

We investigated the extent to which parents' prosocial talk and negations relate to the quantity and diversity of parents' spatial language production. We also examined similar associations among children. Participants included 51 children of ages 4-7 years and their parents recruited from South Florida. Most of the dyads included mothers and were Hispanic and bilingual. Dyads constructed a Lego house for 10 min. Sessions were transcribed and coded for instances of parent prosocial talk (praises, reflective statements, and behavior descriptions), child general positive statements (all positive contributions to the interaction), and parent and child negations (criticisms, corrections, and disapprovals) using the Dyadic Parent-Child Interaction Coding System. Transcripts were also coded for quantity and diversity of spatial language including shape terms (e.g., square), dimensional adjectives (e.g., little), orientations (e.g., turn), locations (e.g., middle), and spatial features/properties (e.g., edge). Parents' prosocial language, but not negations, were significantly associated with the quantity and diversity of parents' spatial language. Children's general positive statements were significantly associated with children's spatial language quantity. Exploratory data analyses also revealed significant associations between parent-child talk about shapes, dimensions, and spatial features and properties. Findings suggest that variability in parent-child prosocial and spatial talk during collaborative spatial play relates to aspects of their own-and each other's-spatial language production. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Efficacy of HER2-Targeted Intraperitoneal 225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.

Design and Analytic Features for Reducing Biases in Skill-Building Intervention Impact Forecasts.

Despite policy relevance, longer-term evaluations of educational interventions are relatively rare. A common approach to this problem has been to rely on longitudinal research to determine targets for intervention by looking at the correlation between children's early skills (e.g., preschool numeracy) and medium-term outcomes (e.g., first-grade math achievement). However, this approach has sometimes over-or under-predicted the long-term effects (e.g., 5th-grade math achievement) of successfully improving early math skills. Using a within-study comparison design, we assess various approaches to forecasting medium-term impacts of early math skill-building interventions. The most accurate forecasts were obtained when including comprehensive baseline controls and using a combination of conceptually proximal and distal short-term outcomes (in the nonexperimental longitudinal data). Researchers can use our approach to establish a set of designs and analyses to predict the impacts of their interventions up to two years post-treatment. The approach can also be applied to power analyses, model checking, and theory revisions to understand mechanisms contributing to medium-term outcomes.

Escala de Significados del Sentido del Humor / Sense of Humor Meanings Scale

Resumen El Sentido del Humor (SH) es considerado un fenómeno universal, pero al mismo tiempo culturalmente específico pues cada grupo posee particularidades que modulan la forma en la éste se percibe y conceptualiza. Aunque el trabajo empírico en torno al fenómeno es amplio, éste se ha centrado en la creación de escalas que miden estilos particulares de humor o ciertos dominios humorísticos, dejando de lado el interés por explorar lo más fundamental, es decir, las percepciones y significados generales del humor. Dado lo anterior, el presente trabajo tuvo por objetivos: 1) explorar el significado atribuido al SH por hombres y mujeres, 2) desarrollar un instrumento válido y confiable para adultos mexicanos, 3) examinar la invarianza de la medición de dicho instrumento en función del sexo de los participantes e 4) identificar posibles diferencias entre hombres y mujeres al respecto de los factores de la medida validada. Los resultados mostraron la obtención de tres categorías que son congruentes con los factores obtenidos en la escala diseñada. En cuanto a sus características resultó una escala válida y confiable, que mostró equivalencia entre los sexos.

Abstract The Sense of Humor (SH) is considered a universal phenomenon, but at the same time culturally specific, since each group has particularities that modulate the way in which it is perceived and conceptualized. Although the empirical work around the phenomenon is extensive, it has focused on the creation of scales that measure styles of humor or certain humorous domains, leaving aside the interest in exploring what is most fundamental, that is, the general perceptions and meanings of humor. humor. Given the above, the present work had the objectives: 1) to explore the meaning attributed to SH by men and women, 2) to develop a valid and reliable instrument for Mexican adults, 3) to examine the invariance of the measurement of said instrument based on the gender and 4) identify possible differences between genders regarding the factors of the validated measure. The results showed the obtaining of three categories that are consistent with the factors obtained in the designed scale. Regarding its characteristics, it was a valid and reliable scale, which showed equivalence between genders.

Triangulating on developmental models with a combination of experimental and nonexperimental estimates.

Plausible competing developmental models show similar or identical structural equation modeling model fit indices, despite making very different causal predictions. One way to help address this problem is incorporating outside information into selecting among models. This study attempted to select among developmental models of children's early mathematical skills by incorporating information about the extent to which models forecast the longitudinal pattern of causal impacts of early math interventions. We tested for the usefulness and validity of the approach by applying it to data from three randomized controlled trials of early math interventions with longitudinal follow-up assessments in the United States (Ns = 1,375, 591, 744; baseline age 4.3, 6.5, 4.4; 17%-69% Black). We found that, across data sets, (a) some models consistently outperformed other models at forecasting later experimental impacts, (b) traditional statistical fit indices were not strongly related to causal fit as indexed by models' accuracy at forecasting later experimental impacts, and (c) models showed consistent patterns of similarity and discrepancy between statistical fit and models' effectiveness at forecasting experimental impacts. We highlight the importance of triangulation and call for more comparisons of experimental and nonexperimental estimates for choosing among developmental models. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Standards for psychosocial care in pediatric cancer: adapted proposal for Latin American and Caribbean countries / Normas para la atención psicosocial en el cáncer pediátrico: una propuesta adaptada para los países de América Latina y el Caribe / Padrões de atendimento psicossocial em câncer pediátrico: proposta adaptada para países da América Latina e do Caribe

ABSTRACT Objective. To highlight the objectives, achievements, challenges, and next steps for the World Health Organization's Global Initiative for Childhood Cancer (GICC) framework, a project designed to improve psychosocial care (PSC) in pediatric cancer centers across Latin America and the Caribbean (LAC). Methods. The project was launched in Peru, the first GICC focal country, in November 2020. The diagnosis phase included a survey and a semistructured interview with health professionals to assess PSC practices in institutions, and a needs assessment survey for caregivers. In the second phase, a strategic plan was developed to address the identified needs, including the adaptation of PSC standards, the establishment of multicenter working groups, the expansion of the proposal, and the development of materials. Results. The study found that PSC was not being adequately provided in accordance with international standards. Six adapted standards were proposed and validated, and more than 50 regional health professionals participated in online activities to support the project. The implementation process is currently ongoing, with the establishment of five multidisciplinary working groups, one regional committee, and the production of 16 technical outputs. Conclusion. This project represents a substantial step forward to improve PSC for pediatric patients with cancer and their families in LAC countries. The establishment of working groups and evidence-based interventions strengthen the proposal and its implementation. Development of health policies that include PSC according to standards is needed to achieve sustainable results in the quality of life of children with cancer and their families.

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RESUMO Objetivo. Destacar os objetivos, as conquistas, os desafios e as próximas etapas da Iniciativa Global para o Câncer Infantil (GICC), um projeto criado pela Organização Mundial da Saúde para melhorar a atenção psicossocial em centros de câncer pediátrico na América Latina e no Caribe. Métodos. O projeto foi lançado no Peru, o primeiro país focal da GICC, em novembro de 2020. A fase de diagnóstico incluiu uma pesquisa e uma entrevista semiestruturada com profissionais de saúde para avaliar as práticas de atenção psicossocial nas instituições, bem como uma pesquisa para avaliar as necessidades dos cuidadores. Na segunda fase, foi desenvolvido um plano estratégico para atender às necessidades identificadas, incluindo uma adaptação de padrões de atenção psicossocial, o estabelecimento de grupos de trabalho multicêntricos, a expansão da proposta e o desenvolvimento de materiais. Resultados. O estudo constatou que, de acordo com padrões internacionais, a atenção psicossocial não estava sendo adequadamente oferecida. Seis padrões adaptados foram propostos e validados, e mais de 50 profissionais de saúde da região participaram de atividades on-line para apoiar o projeto. O processo de implementação está em andamento, com a formação de cinco grupos de trabalho multidisciplinares e um comitê regional e a produção de 16 relatórios técnicos. Conclusão. Este projeto representa um avanço substancial para melhorar a atenção psicossocial para pacientes pediátricos com câncer e suas famílias nos países da América Latina e do Caribe. A criação de grupos de trabalho e intervenções baseadas em evidências fortalecem a proposta e sua implementação. É preciso desenvolver políticas de saúde que incluam atenção psicossocial segundo padrões estabelecidos para alcançar resultados sustentáveis na qualidade de vida das crianças com câncer e de suas famílias.

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Brain-Computer Interfaces Systems for Upper and Lower Limb Rehabilitation: A Systematic Review.

In recent years, various studies have demonstrated the potential of electroencephalographic (EEG) signals for the development of brain-computer interfaces (BCIs) in the rehabilitation of human limbs. This article is a systematic review of the state of the art and opportunities in the development of BCIs for the rehabilitation of upper and lower limbs of the human body. The systematic review was conducted in databases considering using EEG signals, interface proposals to rehabilitate upper/lower limbs using motor intention or movement assistance and utilizing virtual environments in feedback. Studies that did not specify which processing system was used were excluded. Analyses of the design processing or reviews were excluded as well. It was identified that 11 corresponded to applications to rehabilitate upper limbs, six to lower limbs, and one to both. Likewise, six combined visual/auditory feedback, two haptic/visual, and two visual/auditory/haptic. In addition, four had fully immersive virtual reality (VR), three semi-immersive VR, and 11 non-immersive VR. In summary, the studies have demonstrated that using EEG signals, and user feedback offer benefits including cost, effectiveness, better training, user motivation and there is a need to continue developing interfaces that are accessible to users, and that integrate feedback techniques.

Microplastic contamination and fluxes in a touristic area at the SE Gulf of California.

Microplastics (MPs) are long-lasting anthropogenic pollutants, observed in all types of natural environments. The MPs abundance and their temporal variability in beach sands, surface waters (manta trawl), and suspended sediments (sediment trap) were assessed in Mazatlán, Mexico, a tourism destination on the northern Pacific coast, under the hypothesis that MP contamination is influenced by rainfall and population density. The MP concentrations in beach sands from urban and rural areas nearby Mazatlán (4-36 MPs m-2) and in surface waters (1.7-2.0 MPs m-3) were comparable between type of sampling sites; whereas the MP fluxes in sediment trap samples varied widely (40-782 MPs m-2 day-1) with highest values during the rainfall season. The MPs recovered were mostly white/clear (48-54%), and the prevailing shapes were fragments in beach sands and surface waters (59-80%), and fibers (75%) in suspended sediments. The synthetic polymers polypropylene, polyethylene, and polyethylene terephthalate were the most abundant in the study area.

An unusual extranodal natural killer/T-cell lymphoma presenting as chronic laryngitis: A case report.

RATIONALE: Nasal-type, extranodal natural killer (NK)/T-cell lymphoma is a rare lymphoma. The tumor usually shows ulcerative and necrotic lesions in the nasal cavities and sinuses. Tissue involvement outside the nasal cavity is uncommon. PATIENT CONCERN: We describe a 30-year-old man with a 2-month history of hoarseness, weight loss, and dyspnea. DIAGNOSIS: Magnetic resonance image (MRI) showed edema of the larynx with obliteration of the airway. Laryngoscopic examination described necrotic tissue in the glottis and larynx. The biopsy showed chronic, necrotizing laryngitis, with no granulomas, vasculitis, or atypical cells. The immunologic and microbiologic study was negative. Later, after immunosuppressive therapy, the patient presented erythema and diffuse enlargement of the right arm. MRI showed myositis of the biceps and brachial muscles. Infection was rule out, and direct microscopy showed an extensive muscle infiltration by mononuclear cells and abundant mitosis. Immunohistochemistry was positive for CD3, CD8, Ki 67 (90%), and CD56 compatible with extranodal NK/T cell lymphoma. INTERVENTIONS: The patient initially received immunosuppression treatments (corticoids, cyclofosfamide, and Rituximab) with relapsing episodes. When lymphoma was diagnosed, chemotherapy was started. OUTCOMES: The patient died during chemotherapy. LESSONS: Nasal-type, extranodal NK/T-cell lymphoma should be suspected even when there are no classical findings of neoplasms on histology. Immunohistochemistry is mandatory to rule it out.

What matters when exploring fidelity when using health IT to reduce disparities?

BACKGROUND: Implementation of evidence-based interventions often involves strategies to engage diverse populations while also attempting to maintain external validity. When using health IT tools to deliver patient-centered health messages, systems-level requirements are often at odds with 'on-the ground' tailoring approaches for patient-centered care or ensuring equity among linguistically diverse populations. METHODS: We conducted a fidelity and acceptability-focused evaluation of the STAR MAMA Program, a 5-month bilingual (English and Spanish) intervention for reducing diabetes risk factors among 181 post-partum women with recent gestational diabetes. The study's purpose was to explore fidelity to pre-determined 'core' (e.g. systems integration) and 'modifiable' equity components (e.g. health coaching responsiveness, and variation by language) using an adapted implementation fidelity framework. Participant-level surveys, systems-level databases of message delivery, call completion, and coaching notes were included. RESULTS: 96.6% of participants are Latina and 80.9% were born outside the US. Among those receiving the STAR MAMA intervention; 55 received the calls in Spanish (61%) and 35 English (39%). 90% (n = 81) completed ≥ one week. Initially, systems errors were common, and increased triggers for health coach call-backs. Although Spanish speakers had more triggers over the intervention period, the difference was not statistically significant. Of the calls triggering a health coach follow-up, attempts were made for 85.4% (n = 152) of the English call triggers and for 80.0% (n = 279) of the Spanish call triggers (NS). Of attempted calls, health coaching calls were complete for 55.6% (n = 85) of English-language call triggers and for 56.6% of Spanish-language call triggers (NS). Some differences in acceptability were noted by language, with Spanish-speakers reporting higher satisfaction with prevention content (p = < 0.01) and English-speakers reporting health coaches were less considerate of their time (p = 0.03). CONCLUSIONS: By exploring fidelity by language-specific factors, we identified important differences in some but not all equity indicators, with early systems errors quicky remedied and high overall engagement and acceptability. Practice implications include: (1) establishing criteria for languge-equity in interventions, (2) planning for systems level errors so as to reduce their impact between language groups and over time; and (3) examining the impact of engagement with language-concordant interventions on outcomes, including acceptability. Trial Registration National Clinical Trials registration number: CT02240420 Registered September 15, 2014. ClinicalTrials.gov.

Engineered Cells as a Test Platform for Radiohaptens in Pretargeted Imaging and Radioimmunotherapy Applications.

Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [86Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177Lu]Lu-DOTA-Bn and [225Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.

A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.

PURPOSE: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index. EXPERIMENTAL DESIGN: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses. RESULTS: SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. CONCLUSIONS: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose.See related commentary by Capala and Kunos, p. 377.

Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses.

This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.

Interstitial lung disease and microscopic polyangiitis in chilean patients.

OBJECTIVE: To describe the clinical and serological patients characteristics with Microscopic Polyangiitis (MPA) and Interstitial lung disease (ILD). METHODS: Of all the patients with AAV diagnosed between 2007-2017 at the Hospital Clinico Universidad de Chile, those with MPA and ILD were selected and studied retrospectively. RESULTS: All patients were Hispanic; median age at diagnosis 65 years (32-84). 59% were female. All were positive for p-ANCA, 16 patients for MPO. Most common manifestations were constitutional symptoms, weight loss and fever. CT-Scans patterns were Usual Interstitial Pneumonia (UIP) in 10 patients, Nonspecific Interstitial Pneumonia (NSIP) in 6 and fibrosis not UIP or NSIP pattern in 1. In 6 cases, ILD was diagnosed 0.5-14 years before MPA and concomitantly in 11. CONCLUSIONS: Although infrequent, Microscopic Polyangiitis should be suspected in patients with ILD particularly if extra-pulmonary manifestations that rise the possibility of a systemic illness are present, regardless of the time elapsed between the latter and the diagnosis of this type of lung involvement. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 37-42).

Spatial anxiety mediates the sex difference in adult mental rotation test performance.

Mental rotation ability is associated with successful advances in STEM (science, technology, engineering, and mathematics) education and occupations. Meta-analyses have shown consistent sex disparities in mental rotation, where men outperform women on one measure of mental rotation ability, the Mental Rotations Test (MRT). Spatial anxiety, or the fear and apprehension felt when completing a task that requires spatial thinking, was proposed as a mechanism explaining the relation between sex and mental rotation test performance. This study modified the Spatial Anxiety Scale (SAS) to include questions about how anxious individuals feel when they must mentally rotate items to accomplish a task (e.g., playing Tetris). An exploratory factor analysis was conducted to assess the factorial structure of the modified spatial anxiety scale. Three factor loadings were extracted representing the ability to navigate, mentally rotate objects, and visualize objects. Furthermore, we analyzed the role of spatial anxiety and trait anxiety as potential mediators of the relation between participant sex and mental rotation performance. Spatial anxiety partially mediated the link between the sex of the participants and the MRT performance controlling for trait anxiety. Only navigation and mental rotation anxiety significantly mediated the relation between participant sex and mental rotation performance. We posit spatial anxiety as a barrier to efficient and accurate spatial thinking, and suggest that reducing spatial anxiety has the potential to improve spatial skills and reduce sex differences in mental rotation test performance. To ascertain this, an experimental design can determine whether a reduction in spatial anxiety causes changes in mental rotation test scores.