IMPORTANCE: Pediatric emergency department (ED) visits for mental health crises are increasing. Patients who frequently use the ED are of particular concern, as pediatric mental health ED visits are ...commonly repeat visits. Better understanding of trends and factors associated with mental health ED revisits is needed for optimal resource allocation and targeting of prevention efforts. OBJECTIVE: To describe trends in pediatric mental health ED visits and revisits and to determine factors associated with revisits. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data were obtained from 38 US children’s hospital EDs in the Pediatric Health Information System between October 1, 2015, and February 29, 2020. The cohort included patients aged 3 to 17 years with a mental health ED visit. EXPOSURES: Characteristics of patients, encounters, hospitals, and communities. MAIN OUTCOMES AND MEASURES: The primary outcome was a mental health ED revisit within 6 months of the index visit. Trends were assessed using cosinor analysis and factors associated with time to revisit using mixed-effects Cox proportional hazards regression. RESULTS: There were 308 264 mental health ED visits from 217 865 unique patients, and 13.2% of patients had a mental health revisit within 6 months. Mental health visits increased by 8.0% annually (95% CI, 4.5%-11.4%), whereas all other ED visits increased by 1.5% annually (95% CI, 0.1%-2.9%). Factors associated with mental health ED revisits included psychiatric comorbidities, chemical restraint use, public insurance, higher area measures of child opportunity, and presence of an inpatient psychiatric unit at the presenting hospital. Patients with psychotic disorders (hazard ratio HR, 1.42; 95% CI, 1.29-1.57), disruptive or impulse control disorders (HR, 1.36; 95% CI, 1.30-1.42), and neurodevelopmental disorders (HR, 1.22; 95% CI, 1.14-1.30) were more likely to revisit. Patients with substance use disorders (HR, 0.60; 95% CI, 0.55-0.66) were less likely to revisit. CONCLUSIONS AND RELEVANCE: Markers of disease severity and health care access were associated with mental health revisits. Directing hospital and community interventions toward identified high-risk patients is needed to help mitigate recurrent mental health ED use and improve mental health care delivery.
Photoimmunotherapy is a highly cell-selective cancer therapy based on an armed antibody conjugate with a phthalocyanine-based photosensitizer, IR700. Photoimmunotherapy induces rapid and highly ...specific necrosis in targeted cancer cells after exposure to near-infrared (NIR) light. Cells not expressing the antigen are not affected. To date, photoimmunotherapy has been demonstrated only with full antibody-IR700 conjugates. In this study, small and bivalent antibody fragments, including anti-prostate-specific membrane antigen (PSMA) diabody (Db) and minibody (Mb), were compared with intact IgG for their effectiveness as photoimmunotherapy agents.
Radioiodinated antibody and antibody fragments with (125)I were used to determine the timing of maximum binding of each anti-PSMA antibody fragment on the cell surface in vivo in mice bearing either PSMA-positive or -negative PC3 tumors. Then therapeutic efficacy of photoimmunotherapy was examined by exposing mice to NIR light at 2 time points based on the time of maximum cell surface binding at 6 h after injection for Db-IR700 and 24 h after injection for Mb-IR700 and IgG-IR700 as well as 24 h after the peak uptake times.
Photoimmunotherapy with the same molar concentration of PSMA-Db-IR700, PSMA-Mb-IR700, and PSMA-IgG-IR700 conjugate showed similar therapeutic effects in vitro and in vivo on PSMA-positive PC3 tumor xenografts in cytotoxicity and survival curves (P > 0.05).
The use of PSMA-Db-IR700 conjugate results in the shortest time interval between injection and NIR exposure without compromising therapeutic effects of photoimmunotherapy.
Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in ...hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.
Mechanical and thermal properties of stereolithography 3D-printed thermoset polymers have been investigated with an emphasis on understanding how the layer-by-layer printed morphology affects their ...physical properties. Due to the finite UV penetration depth into the photocurable resins in the stereolithography, the 3D-printed polymers resulted in periodic surface undulation. The length scale of the surface undulation periodicity is determined by the 3D printing processing parameter of slice thickness (Δt) and has a strong effects on the mechanical and thermal properties of the 3D-printed thermoset polymers. Upon decreasing the Δt from 200 µm to 50 µm, the 3D printing produces more frequent UV curing of crosslinked layers along the printing direction to result in the increase of Young’s modulus and the more pronounced high glass transition peak in dynamic mechanical analysis. However, when the Δt is further decreased to 25 µm, its Young’s modulus is lower than the 50 µm printed samples. This decrease is attributed to the weaker inter-layer crosslinking, when there are not enough less-cured monomers to promote the crosslinking between densely crosslinked layers during the successive layer-by-layer photopolymers in stereolithography.
Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small ...polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.
The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the ...standard upper proliferative criteria-as defined largely based on early-stage carcinoids-in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm
and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm
are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.
Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been ...limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.
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Priceman, Murad, and colleagues describe an immunocompetent model that demonstrates the safety and efficacy of CAR T cells for the treatment of PSCA+ solid tumors. Importantly, CAR T cell treatment with cyclophosphamide pre-conditioning provides pro-inflammatory immune modulation resulting in reversion of local T cell exclusion and promotion of protective anti-tumor immunity.
Babesia is a protozoal, tick-borne parasite that can cause life-threatening disease in humans, wildlife and domestic animals worldwide. However, in Southeast Asia, little is known about the ...prevalence and diversity of Babesia species present in wildlife and the tick vectors responsible for its transmission. Recently, a novel Babesia species was reported in confiscated Sunda pangolins (Manis javanica) in Thailand. To investigate the presence of this parasite in Singapore, we conducted a molecular survey of Babesia spp. in free-roaming Sunda pangolins and their main ectoparasite, the Amblyomma javanense tick. Ticks and tissue samples were opportunistically collected from live and dead Sunda pangolins and screened using a PCR assay targeting the 18S rRNA gene of Babesia spp. DNA barcoding of the cytochrome oxidase subunit I (COI) mitochondrial gene was used to confirm the species of ticks that were Babesia positive. A total of 296 ticks and 40 tissue samples were obtained from 21 Sunda pangolins throughout the 1-year study period. Babesia DNA was detected in five A. javanense ticks (minimum infection rate = 1.7%) and in nine different pangolins (52.9%) located across the country. Phylogenetic analysis revealed that the Babesia 18S sequences obtained from these samples grouped into a single monophyletic clade together with those derived from Sunda pangolins in Thailand and that this evolutionarily distinct species is basal to the Babesia sensu stricto clade, which encompasses a range of Babesia species that infect both domestic and wildlife vertebrate hosts. This is the first report documenting the detection of a Babesia species in A. javanense ticks, the main ectoparasite of Sunda pangolins. While our results showed that A. javanense can carry this novel Babesia sp., additional confirmatory studies are required to demonstrate vector competency. Further studies are also necessary to investigate the role of other transmission pathways given the low infection rate of ticks in relation to the high infection rate of Sunda pangolins. Although it appears that this novel Babesia sp. is of little to no pathogenicity to Sunda pangolins, its potential to cause disease in other animals or humans cannot be ruled out.
Ventricular paced rhythm is thought to obscure the electrocardiographic diagnosis of acute coronary occlusion myocardial infarction. Our primary aim was to compare the sensitivity of the modified ...Sgarbossa criteria (MSC) to that of the original Sgarbossa criteria for the diagnosis of occlusion myocardial infarction in patients with ventricular paced rhythm.
In this retrospective case-control investigation, we studied adult patients with ventricular paced rhythm and symptoms of acute coronary syndrome who presented in an emergency manner to 16 international cardiac referral centers between January 2008 and January 2018. The occlusion myocardial infarction group was defined angiographically as thrombolysis in myocardial infarction grade 0 to 1 flow or angiographic evidence of coronary thrombosis and peak cardiac troponin I ≥10.0 ng/mL or troponin T ≥1.0 ng/mL. There were 2 control groups: the "non-occlusion myocardial infarction-angio" group consisted of patients who underwent coronary angiography for presumed type I myocardial infarction but did not meet the definition of occlusion myocardial infarction; the "no occlusion myocardial infarction" control group consisted of randomly selected emergency department patients without occlusion myocardial infarction.
There were 59 occlusion myocardial infarction, 90 non-occlusion myocardial infarction-angio, and 102 no occlusion myocardial infarction subjects (mean age, 72.0 years; 168 66.9% men). For the diagnosis of occlusion myocardial infarction, the MSC were more sensitive than the original Sgarbossa criteria (sensitivity 81% 95% confidence interval CI 69 to 90 versus 56% 95% CI 42 to 69). Adding concordant ST-depression in V4 to V6 to the MSC yielded 86% (95% CI 75 to 94) sensitivity. For the no occlusion myocardial infarction control group of ED patients, additional test characteristics of MSC and original Sgarbossa criteria, respectively, were as follows: specificity 96% (95% CI 90 to 99) versus 97% (95% CI 92 to 99); negative likelihood ratio (LR) 0.19 (95% CI 0.11 to 0.33) versus 0.45 (95% CI 0.34 to 0.65); and positive LR 21 (95% CI 7.9 to 55) versus 19 (95% CI 6.1 to 59). For the non-occlusion myocardial infarction-angio control group, additional test characteristics of MSC and original Sgarbossa criteria, respectively, were as follows: specificity 84% (95% CI 76 to 91) versus 90% (95% CI 82 to 95); negative LR 0.22 (95% CI 0.13 to 0.38) versus 0.49 (95% CI 0.35 to 0.66); and positive LR 5.2 (95% CI 3.2 to 8.6) versus 5.6 (95% CI 2.9 to 11).
For the diagnosis of occlusion myocardial infarction in the presence of ventricular paced rhythm, the MSC were more sensitive than the original Sgarbossa criteria; specificity was high for both rules. The MSC may contribute to clinical decisionmaking for patients with ventricular paced rhythm.
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