Implementation of Appropriate Use Criteria for Transthoracic Echocardiography in Follow-Up Care of Pediatric Patients with Congenital Heart Disease.

BACKGROUND: Indications for transthoracic echocardiography (TTE) from the 2020 Appropriate Use Criteria (AUC) for congenital heart disease (CHD) were incorporated into the institutional electronic ordering system as a clinical decision support tool. The purpose of this study was to evaluate the utilization of TTE and factors affecting the appropriateness of orders for TTE during follow-up care of patients with CHD. METHODS: All transthoracic echocardiographic studies performed during follow-up clinic visits from May 1, 2020, to November 30, 2020, were included. Indications for TTE were rated appropriate, may be appropriate, or rarely appropriate on the basis of the AUC and unclassifiable if the indication was not in the document but related to included lesions. CHD was graded as simple, moderate, or complex on the basis of the Bethesda classification. Logistic regression was used to determine the association of ratings with patient age, insurance status, CHD complexity, and clinician experience and specialty. RESULTS: Of the 5,158 studies, 3,979 (77.2%) were for CHD included in the AUC document, 322 (8%) were unclassifiable, 37 (0.7%) were for CHD not in the document, and 1,142 (22.1%) were for non-CHD indications. Of the 3,657 transthoracic echocardiographic examinations to which AUC ratings could be applied, 95.6% were rated appropriate, 2.4% may be appropriate, and 2.0% rarely appropriate. The highest utilization of TTE was for follow-up of ventricular septal defects, left ventricular outflow tract obstruction, and single ventricles; 46% for unrepaired CHD; 78% for routine surveillance; and the remaining for changes in clinical status. On multivariable analysis, the only significant factor associated with may be appropriate and rarely appropriate ratings was simple CHD (odds ratio, 11.58; 95% CI, 5.36 - 24.98; P < .001). CONCLUSIONS: Three quarters of transthoracic echocardiographic studies ordered during follow-up care in pediatric cardiology clinics are for indications related to CHD. Most examinations for follow-up of CHD were for routine surveillance and indications rated appropriate. Orders for TTE for may be appropriate and rarely appropriate ratings were associated with simple CHD. Although the 2020 AUC document successfully stratifies the majority of indications related to CHD, future documents should consider the unclassifiable CHD indications and the non-CHD indications.

Hydropneumothorax as a complication of necrotizing pneumonia in a young girl.

Bronchopleural fistula with subsequent hydropneumothorax is an important complication of necrotizing pneumonia. Chest X-ray is an excellent diagnostic tool which can suggest hydropneumothorax. When present, this requires admission for drainage. If discharged after necrotizing pneumonia, follow-up should include a chest X-ray to rule out this complication.

Alternatively activated macrophage-derived secretome stimulates ovarian cancer spheroid spreading through a JAK2/STAT3 pathway.

High-grade serous ovarian cancer (HGSOC) metastasizes when tumor spheroids detach from the primary tumor and re-attach throughout the peritoneal cavity. Once the cancer cells have implanted in these new sites, the development of metastatic lesions is dependent on the disaggregation of cancer cells from the spheroids and subsequent expansion across the collagenous extracellular matrix (ECM). As HGSOC progresses an increase in alternatively activated macrophages (AAMs) in the surrounding ascites fluid has been observed and AAMs have been shown to enhance tumor invasion and growth in a wide range of cancers. We hypothesized that soluble factors from AAMs in the peritoneal microenvironment promote the disaggregation of ovarian cancer spheroids across the underlying ECM. We determined that co-culture with AAMs significantly increased HGSOC spheroid spreading across a collagen matrix. Multivariate modeling identified AAM-derived factors that correlated with enhanced spread of HGSOC spheroids and experimental validation showed that each individual cell line responded to a distinct AAM-derived factor (FLT3L, leptin, or HB-EGF). Despite this ligand-level heterogeneity, we determined that the AAM-derived factors utilized a common signaling pathway to induce spheroid spreading: JAK2/STAT3 activation followed by MMP-9 mediated spreading. Furthermore, immunostaining demonstrated that FLT3, LEPR, EGFR, and pSTAT3 were upregulated in metastases in HGSOC patients, with substantial patient-to-patient heterogeneity. These results suggest that inhibiting individual soluble factors will not inhibit AAM-induced effects across a broad group of patients; instead, the downstream JAK2/STAT3/MMP-9 pathway should be examined as potential therapeutic targets to slow metastasis in ovarian cancer.

Loss of cAMP-specific phosphodiesterase rescues spore development in G protein mutant in dictyostelium.

Cyclic AMP (cAMP) is an important intracellular signaling molecule for many G protein-mediated signaling pathways but the specificity of cAMP signaling in cells with multiple signaling pathways is not well-understood. In Dictyostelium, at least two different G protein signaling pathways, mediated by the Gα2 and Gα4 subunits, are involved with cAMP accumulation, spore production, and chemotaxis and the stimulation of these pathways results in the activation of ERK2, a mitogen-activated protein kinase that can down regulate the cAMP-specific phosphodiesterase RegA. The regA gene was disrupted in gα2(−) and gα4(−) cells to determine if the absence of this phosphodiesterase rescues the development of these G protein mutants as it does for erk2(−) mutants. There gA(−) mutation had no major effects on developmental morphology but enriched the distribution of the Gα mutant cells to the prespore/prestalk border in chimeric aggregates. The loss of RegA function had no effect on Gα4- mediated folate chemotaxis. However, the regA gene disruption in gα4(−) cells, but not in gα2(−) cells, resulted in a substantial rescue and acceleration of spore production. This rescue in sporulation required cell autonomous signaling because the precocious sporulation could not be induced through intercellular signaling in chimeric aggregates. However, intercellular signals from regA(−) strains increased the expression of the prestalk gene ecmB and accelerated the vacuolization of stalk cells. Intercellular signaling from the gα4(−)regA(−) strain did not induce ecmA gene expression indicating cell-type specificity in the promotion of prestalk cell development. regA gene disruption in a Gα4(HC) (Gα4 overexpression) strain did not result in precocious sporulation or stalk cell development indicating that elevated Gα4 subunit expression can mask regA(−) associated phenotypes even when provided with wild-type intercellular signaling. These findings indicate that the Gα2 and Gα4-mediated pathways provide different contributions to the development of spores and stalk cells and that the absence of RegA function can bypass some but not all defects in G protein regulated spore development.