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Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality.From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden.Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

This systematic review explores the topic of Part C Early Intervention (EI) dosage reporting and decision-making factors. From an extensive search following PRISMA guidelines, we identified 14 interdisciplinary studies (combination of descriptive, correlational, mixed method, qualitative, and single case design) that met the criteria and synthesized them based on the reported definitions and data of EI dosage components, including frequency, duration, and intensity, as well as factors associated with this data at child, family, and community levels. Results indicate frequency was most reported, whereas duration and intensity were inconsistently reported, as were service delivery models. The inconsistency of reporting did not allow for interpretations of effective dosage; however, disparities based on different factors are shared. Results and discussion are provided for each level of factors, such as family demographics, insurance enrollment, and disability classification. Implications for further research and practice, especially for EI dosage decision-making and reporting, are included.

BackgroundAmong subjects with exercise intolerance and suspected early-stage pulmonary hypertension (PH), early identification of pulmonary vascular disease (PVD) with noninvasive methods is essential for prompt PH management.HypothesisRest gas exchange parameters (minute ventilation to carbon dioxide production ratio: VE /VCO2 and end-tidal carbon dioxide: ETCO2 ) can identify PVD in early-stage PH.MethodsWe conducted a retrospective review of 55 subjects with early-stage PH (per echocardiogram), undergoing invasive exercise hemodynamics with cardiopulmonary exercise test to distinguish exercise intolerance mechanisms. Based on the rest and exercise hemodynamics, three distinct phenotypes were defined: (1) PVD, (2) pulmonary venous hypertension, and (3) noncardiac dyspnea (no rest or exercise PH). For all tests, *p  40 mm Hg and rest ETCO2   40 mm Hg and ETCO2

This article proposes a reconceptualization of the relationship between two early childhood professional standards, the "Professional Standards and Competencies for Early Childhood Educators" (NAEYC, 2019) and the "Practice-Based Professional Preparation Standards for Early Interventionists/Early Childhood Special Educators" (CEC & DEC, 2020), from an aligned or a parallel approach to an integration approach that advances the shared equity agenda in early childhood education. In the integrative approach, the ECE Standards are viewed as the foundation for educating all children with diverse social identities (i.e., ability, race, language, socioeconomic) and the EI/ECSE Standards as the expansion on the foundation specifically for children with differing abilities. A rationale is provided for integrating the standards and the process of integration is exemplified around three broad themes central to both sets of standards: inclusion and diversity, responsive and relevant practices, and building partnerships. Integrating the two professional standards will guide educator preparation programs for inclusion, provide clarity and unity around the knowledge and competencies of early childhood professionals across settings, and unify the workforce in ECE and EI/ECSE for the shared goal of promoting inclusion and equity. Our aim is for the audience to consider the integrative approach as a conceptual framework for building shared values, visions, and knowledge in ECE and EI/ECSE to promote inclusive, equitable early childhood learning opportunities and to unify educators around the shared equity agenda.

The purpose of this special issue is to introduce ways in which the field of early childhood special education can use the Initial Practice-Based Professional Preparation Standards for Early Interventionists/Early Childhood Special Educators (EI/ECSE) (birth through age 8). In this article, the following applications are identified and guidance is provided in using the standards for: (1) educator preparation programs as they engage in curriculum development and accreditation; (2) states as they develop credentials for professionals engaged in early childhood education (ECE) and early childhood special education; (3) professional development and technical assistance providers as they identify and develop content to build the capacity of personnel; (4) practicing professionals as they engage in reflection on and engagement in continuous improvement of their practices; (5) families as they advocate for services and supports for their child and family; (6) other professionals/disciplines both at an individual and systems level as they consider how to improve practice with young children and their families; and (7) researchers as they development EI/ECSE research agendas to guide the field's understanding of effective practices. Before describing each of these applications, foundational information is provided on the term "standards" as used in early childhood education, to facilitate a shared understanding. A brief introduction to the EI/ECSE Standards is also presented.

RationaleObesity is associated with pulmonary arterial hypertension (PAH), but its impact on outcomes such as health-related quality of life (HRQoL), hospitalizations and survival is not well understood.ObjectivesTo assess the effect of obesity on health-related quality of life (HRQoL), hospitalizations and survival in patients with PAH.MethodsWe performed a cohort study of adults with PAH from the Pulmonary Hypertension Association Registry, a prospective multicenter registry. Multivariate linear mixed effects regression was used to examine the relationship between weight categories and HRQoL using the Short Form-12 (SF-12) and emPHasis-10 (e10). We used multivariable negative binomial regression to estimate hospitalization incidence rate ratios (IRRs) and Cox regression to estimate hazard ratios (HRs) for transplant-free survival by weight status.Results767 subjects were included: mean age of 57 years, 74% female, 33% overweight and 40% obese, with median follow-up duration of 527 days. Overweight and obese patients had higher baseline e10 scores (worse HRQoL), which persisted over time (p

Background: This study was the first attempt to investigate the status of implementation and sustainability of early childhood positive behavior support (PBS) via the lens of implementation science for community-based child care centers in a Midwest state of the United States. Objective: Obtain state-level data and gain insights on PBS implementation and sustainability in target child care centers. Method: Through a total population sampling method, we recruited administrators (N = 94, 12% of the full population) of target child care centers to participate in a survey. Results: The results suggested that the majority of the responding centers (59.57%) had not received PBS professional development (PD) indicating PBS PD opportunities had not been disseminated in the majority of community-based child care centers in the target state. Nearly half of the programs were not implementing PBS practices after they received PBS PD, which raised questions about continuous use of PBS and the return on investment of PBS PD efforts. The results of ANOVA found that the scope of PBS training significantly affected the level of PBS implementation; the type of training significantly affected the level of PBS sustainability. Simple linear regression revealed programs that had a higher level of PBS implementation also had a higher level of PBS sustainability. Conclusions: Using implementation science theories and tools, we developed two preliminary measures to obtain meaningful information about early childhood PBS implementation and sustainability in community-based child care centers. Understanding the factors associated with implementation can provide insights for the improvement of PD programs when disseminating the use of evidence-based PBS practices.

Hispanic college students attending a Hispanic Serving Institution (HSI) in the southwest United States were administered the short grit survey during new student orientation for 2 consecutive years (N = 496) to ascertain the association with grit scores and retention after the first year of university attendance. Results indicate that there was a gender difference in grit scores and retention. Few grit survey items were associated with retention, thus suggesting that the grit survey may not be an appropriate predictor of retention for first-generation Hispanic college students.

Controlled differentiation of human embryonic stem cells (hESCs) can be utilized for precise analysis of cell type identities during early development. We established a highly efficient neural induction strategy and an improved analytical platform, and determined proteomic and phosphoproteomic profiles of hESCs and their specified multipotent neural stem cell derivatives (hNSCs). This quantitative dataset (nearly 13,000 proteins and 60,000 phosphorylation sites) provides unique molecular insights into pluripotency and neural lineage entry. Systems-level comparative analysis of proteins (e.g., transcription factors, epigenetic regulators, kinase families), phosphorylation sites, and numerous biological pathways allowed the identification of distinct signatures in pluripotent and multipotent cells. Furthermore, as predicted by the dataset, we functionally validated an autocrine/paracrine mechanism by demonstrating that the secreted protein midkine is a regulator of neural specification. This resource is freely available to the scientific community, including a searchable website, PluriProt.

A redox-regulated import pathway consisting of Mia40 and Erv1 mediates the import of cysteine-rich proteins into the mitochondrial intermembrane space. Mia40 is the oxidoreductase that inserts two disulfide bonds into the substrate simultaneously. However, Mia40 has one redox-active cysteine pair, resulting in ambiguity about how Mia40 accepts numerous electrons during substrate oxidation. In this study, we have addressed the oxidation of Tim13 in vitro and in organello. Reductants such as glutathione and ascorbate inhibited both the oxidation of the substrate Tim13 in vitro and the import of Tim13 and Cmc1 into isolated mitochondria. In addition, a ternary complex consisting of Erv1, Mia40, and substrate, linked by disulfide bonds, was not detected in vitro. Instead, Mia40 accepted six electrons from substrates, and this fully reduced Mia40 was sensitive to protease, indicative of conformational changes in the structure. Mia40 in mitochondria from the erv1-101 mutant was also trapped in a completely reduced state, demonstrating that Mia40 can accept up to six electrons as substrates are imported. Therefore, these studies support that Mia40 functions as an electron sink to facilitate the insertion of two disulfide bonds into substrates.

Transition to kindergarten can be a pivotal experience for children because of its potential long-term impact on school performance. As the importance of relationships among contextual factors surrounding a child has been recognized, many schools have made efforts to establish strong ties with families in order to make kindergarten transition experiences as seamless as possible. Our current understanding of the role of family involvement in kindergarten transitions and the specific outcomes, however, is still somewhat limited. Using a combination of quantitative and qualitative research methods, this study investigated the impact of family involvement in kindergarten transition activities on children's transition to kindergarten and their early school adjustment. Although quantitative results revealed that family involvement is not a significant predictor of children's early school adjustment, qualitative evidence suggests that families believe their involvement in kindergarten transition has a positive influence. In addition, qualitative results provide information concerning barriers, which interfered with family involvement in the transition process. Based on these findings suggestions for schools and families of young children are provided.

Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

Clinical inertia, or failure to intensify treatment when indicated, leads to suboptimal blood pressure control. Interventions to overcome inertia and increase antihypertensive prescribing have been modestly successful in part because their effectiveness varies based on characteristics of the provider, the patient, or the provider-patient interaction. Understanding for whom each intervention is most effective could help target interventions and thus increase their impact. This three-arm, randomized trial tests the effectiveness of 2 interventions to reduce clinical inertia in hypertension prescribing compared to usual care. Forty five primary care providers (PCPs) caring for patients with hypertension in need of treatment intensification completed baseline surveys that assessed behavioral traits and were randomized to one of three arms: 1) Pharmacist e-consult, in which a clinical pharmacist provided patient-specific recommendations for hypertension medication management to PCPs in advance of upcoming visits, 2) Social norming dashboards that displayed PCP's hypertension control rates compared to those of their peers, or 3) Usual care (no intervention). The primary outcome was the rate of intensification of hypertension treatment. We will compare this outcome between study arms and then evaluate the association between characteristics of providers, patients, their clinical interactions, and intervention responsiveness. Forty-five primary care providers were enrolled and randomized: 16 providers and 173 patients in the social norming dashboards arm, 15 providers and 143 patients in the pharmacist e-consult arm, and 14 providers and 150 patients in the usual care arm. On average, the mean patient age was 64 years, 47% were female, and 73% were white. Baseline demographic and clinical characteristics of patients were similar across arms, with the exception of more Hispanic patients in the usual care arm and fewest in the pharmacist e-consult arm. This study can help identify interventions to reduce inertia in hypertension care and potentially identify the characteristics of patients, providers, or patient-provider interactions to understand for whom each intervention would be most beneficial. Clinicaltrials.gov (NCT, Registered: NCT04603560) [ABSTRACT FROM AUTHOR]

BACKGROUND: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. METHODS: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (?11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/ (kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. RESULTS: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (logrank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. CONCLUSIONS: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise. [ABSTRACT FROM AUTHOR]