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Physical and mechanical restraints and seclusion are currently used as emergency procedures in public schools across the United States. Students who exhibit dangerous, aggressive, or self-injurious behaviors are more likely to be restrained or secluded in school. Since many students with autism spectrum disorder exhibit one or more of these behaviors, they are even more likely to be subjected to these restrictive interventions. Policy on restrictive interventions is not outlined in the Individuals with Disabilities Education Improvement Act (IDEIA) of 2004, the federal special education law, leaving states to determine their own policies. Issues surrounding current policy and law on restraint and seclusion, as well as recommendations, are discussed.

Nostalgic memories are highly social and revisiting them increases social connectedness and motivation. The present study offers a naturalistic approach to studying the social experience of nostalgia. Participants created scrapbooks in groups across three sessions over a period of six weeks. Nostalgia proneness, meaning, and social connection were measured prior to the first and after the final session. A follow-up survey was also administered. Participants reported higher levels of nostalgia proneness and greater connectedness to their scrapbooking group following the sessions. The more participants reported experiencing negative psychological states, the more they indicated planning to use their scrapbooks as a source of psychological comfort. The present work has important implications for art therapists and arts in health practitioners.

Abstract Face recognition is supported by selective neural mechanisms that are sensitive to various aspects of facial appearance. These include event-related potential (ERP) components like the P100 and the N170 which exhibit different patterns of selectivity for various aspects of facial appearance. Examining the boundary between faces and non-faces using these responses is one way to develop a more robust understanding of the representation of faces in extrastriate cortex and determine what critical properties an image must possess to be considered face-like. Robot faces are a particularly interesting stimulus class to examine because they can differ markedly from human faces in terms of shape, surface properties, and the configuration of facial features, but are also interpreted as social agents in a range of settings. In the current study, we thus chose to investigate how ERP responses to robot faces may differ from the response to human faces and non-face objects. In two experiments, we examined how the P100 and N170 responded to human faces, robot faces, and non-face objects (clocks). In Experiment 1, we found that robot faces elicit intermediate responses from face-sensitive components relative to non-face objects (clocks) and both real human faces and artificial human faces (computer-generated faces and dolls). These results suggest that while human-like inanimate faces (CG faces and dolls) are processed much like real faces, robot faces are dissimilar enough to human faces to be processed differently. In Experiment 2 we found that the face inversion effect was only partly evident in robot faces. We conclude that robot faces are an intermediate stimulus class that offers insight into the perceptual and cognitive factors that affect how social agents are identified and categorized.

Simple Summary: Siglec-8 has been identified as a promising target to treat eosinophilic and mast cell disorders. However, there are currently few Siglec-8 antibodies available, and therapeutic efforts have so far primarily focused on unconjugated antibodies, which may be insufficiently effective in many patients. To address these limitations, we raised a diverse panel of fully human Siglec-8 antibodies as the basis for novel therapeutics. They were all efficiently internalized, suggesting their potential to deliver cytotoxic payloads. T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-modified natural killer (NK) cells built from these Siglec-8 antibodies were highly potent against Siglec-8-positive cells even in cases of very low target antigen abundance. Importantly, mechanistic studies with target cells expressing either full-length Siglec-8 or an artificial smaller Siglec-8 variant demonstrated that T cell-engaging bispecific antibodies and CAR-modified NK cells were substantially more effective if they bound Siglec-8 closer to the cell membrane, indicating targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, tool therapeutics that bind one of the membrane-proximal C2-set domains of Siglec-8 were very effective against Siglec-8-positive target cells. Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders. Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8V-set-directed T cell-engaging BiAbs and Siglec-8V-set-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8C2-set mAbs, Siglec-8C2-set-directed T cell-engaging BiAbs, and Siglec-8C2-set-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders. [ABSTRACT FROM AUTHOR]

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these “humanized” mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

Simple Summary: Current therapies are often insufficiently effective in patients with acute myeloid leukemia (AML), prompting ongoing interest in developing new drugs for this aggressive type of blood cancer. Many efforts focus on drugs that target CD33, a cell surface protein that is widely expressed on AML cells. Gemtuzumab ozogamicin (GO), which consists of a CD33 antibody linked to a small molecule toxin, benefits some AML patients but not many others, leaving room for other CD33-targeted therapeutics. Here, we examined CC-96191, a "TriNKET" protein drug that binds CD33 on AML cells at the same time it binds two different proteins, CD16a and NKG2D, on natural killer (NK) cells, thereby activating these immune cells and engaging them to kill AML cells. In preclinical studies, we found CC-96191 to be broadly active against human AML cells that express CD33. CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a protein drug that binds CD33 and CD3 on T cells. Moreover, CC-96191 eliminated AML cells but not normal CD33+ monocytes, suggesting selectivity toward leukemic cells. Together, these findings support the clinical exploration of CC-96191 as is currently ongoing. Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655. [ABSTRACT FROM AUTHOR]

Background Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. Methods Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECM i) on cardiac MRI. Results Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs −0.53 [0.68] mL/min/g; P =.03) but not CFR by cardiac PET (0.01 [0.64] vs −0.07 [0.48]; P =.72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (−13 [28] vs 10 [26] mL; P =.03) and global circumferential strain (GCS; median [interquartile range 25th–75th]: −1.3% [−2.9%–1.0%] vs 2.3% [−0.4%–4.1%]; P =.03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = −0.65, P =.057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs −0.05 [0.36]; P =.04). Eplerenone prevented a small increase in troponin (0.00 [−0.13–0.00] vs 0.00 [0.00–0.74] ng/L; P =.03) without effects on ECM i (0.9 [−2.3–4.3] vs −0.7 [−2.2–−0.1] g/m2; P =.38). CD4+ T-cell count (127 [−38–286] vs −6 [−168–53] cells/μL; P =.02) increased in the eplerenone- versus placebo-treated groups. Conclusions RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. Clinical Trials Registration NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1). [ABSTRACT FROM AUTHOR]

Moreover, the use of an animal model in which human CD22 is only expressed on implanted tumor cells and not on normal cells precluded comprehensive assessment of "on-target, off-tumor" effects. Radioimmunotherapy (RIT) has long been pursued to improve outcomes of patients with B-cell lymphomas and leukemias [[1]]. Here, we investigated whether CD22, a cell surface glycoprotein broadly expressed on malignant cells across B-cell malignancies and normal B cells but not on other hematopoietic cell lineages [[9]], could serve as target for relatively tumor-selective SP 211 sp At-based RIT. [Extracted from the article]