The Dissemination of Parent-Child Interaction Therapy in West Virginia during the Opioid Epidemic and COVID-19 Pandemic: A Qualitative Study.

The devastating impact of the opioid crisis on children and families in West Virginia was compounded by the COVID-19 pandemic and brought to light the critical need for greater mental health services and providers in the state. Parent-Child Interaction Therapy (PCIT) is an evidence-based treatment for child externalizing symptoms that teaches parents positive and appropriate strategies to manage child behaviors. The current qualitative study details barriers and facilitators to disseminating and implementing PCIT with opioid-impacted families across West Virginia during the COVID-19 pandemic. Therapists (n = 34) who participated in PCIT training and consultation through a State Opioid Response grant were asked to provide data about their experiences with PCIT training, consultation, and implementation. Almost all therapists (91%) reported barriers to telehealth PCIT (e.g., poor internet connection, unpredictability of sessions). Nearly half of therapists' cases (45%) were impacted directly by parental substance use. Qualitative findings about the impact of telehealth and opioid use on PCIT implementation are presented. The dissemination and implementation of PCIT in a state greatly impacted by poor telehealth capacity and the opioid epidemic differed from the implementation of PCIT training and treatment delivery in other states, highlighting the critical importance of exploring implementation factors in rural settings.

An open repository of real-time COVID-19 indicators.

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making.

Relationships among factors affecting advanced practice registered nurses' job satisfaction and intent to leave: A systematic review.

BACKGROUND AND PURPOSE: This systematic review explores relationships between advanced practice registered nurses' (APRN) job satisfaction and intent to leave. There exists a dearth of APRN providers compared with the ever-growing need for their services. Furthermore, the organizational costs associated with the APRN turnover are extremely high. It, therefore, behooves practice administrators to understand what factors most contribute to APRN job satisfaction and retention. METHODS: A search of research databases CINAHL, PubMed, and PsycINFO, using keywords "Advanced Practice Registered Nurse," "job satisfaction," "intent to leave," "anticipated turnover," and "Nurse Practitioner" to yield articles included in this review. CONCLUSIONS: The strength of existing evidence for this topic is weak. Studies have found that extrinsic factors, such as administrative support and salary, significantly contribute to job dissatisfaction, whereas intrinsic factors, such as autonomy and finding work meaningful, most significantly contribute to job satisfaction. Additional research is needed to better understand the factors relating to APRN job satisfaction and dissatisfaction, and how those factors influence practitioners' intent to leave. IMPLICATIONS FOR PRACTICE: Efforts to improve APRN job satisfaction will have positive implications for provider retention, practices, and patients. Administrators should consider the job satisfaction factors identified herein when implementing practice improvement and retention efforts.

Increased myocardial expression of angiopoietin-2 in patients undergoing urgent surgical revascularization for acute coronary syndromes.

BACKGROUND: Myocardial ischemia triggers the expression of multiple angiogenic factors including vascular endothelial growth factor and its receptors. However, vascular endothelial growth factor does not act in isolation. OBJECTIVE: To identify other genes important in the angiogenic response to clinically relevant myocardial ischemia. METHODS AND RESULTS: Paired intraoperative biopsies of ischemic and nonischemic myocardium were obtained from 12 patients with acute coronary syndromes (ACS) undergoing urgent coronary artery bypass graft surgery. Real-time polymerase chain reaction demonstrated significant upregulation of angiopoietin-2 (Ang-2) in ischemic myocardium, to a greater extent than other classical angiogenic factors. Microarray gene profiling identified Ang-2 to be among the top 10 differentially upregulated genes, in addition to genes involved in inflammation, cell signalling, remodelling and apoptosis. CONCLUSIONS: The present document is the first report of microarray analysis of patients with ACS, and supports an important role for Ang-2 in the angiogenic response to severe ischemia in the human heart. Common gene expression patterns in ACS may provide opportunities for targeted pharmacological and cellular intervention.

Cell-based angiopoietin-1 gene therapy for acute lung injury.

RATIONALE: The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. OBJECTIVES: We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury. METHODS: We used cell-based gene therapy in a rat model of ALI. Transgenic mice overexpressing Ang-1 or deficient in the Tie2 receptor were also studied to better elucidate the mechanisms of protection. MEASUREMENTS AND MAIN RESULTS: The present report provides data that support a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced acute lung injury. In a rat model, cell-based Ang-1 gene transfer improved morphological, biochemical, and molecular indices of lung injury and inflammation. These findings were confirmed in a gain-of-function conditional, targeted transgenic mouse model, in which Ang-1 reduced endothelial cell activation and the expression of adhesion molecules, associated with a marked improvement in airspace inflammation and intraalveolar septal thickening. Moreover, heterozygous Tie2-deficient mice demonstrated enhanced evidence of lung injury and increased early mortality. CONCLUSIONS: These results support a critical role for the Ang-1/Tie2 axis in modulating the pulmonary vascular response to lung injury and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress syndrome in critically ill patients.

Ischemia and reperfusion increases susceptibility to ventilator-induced lung injury in rats.

OBJECTIVES: Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome. HYPOTHESIS: HSR exacerbates mechanical stress-induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury. METHODS: Rats were subjected to HSR, and were randomized into an HSR + high tidal volume and zero positive end-expiratory pressure (PEEP) or a HSR + low tidal volume with 5 cm H(2)O PEEP. A sham-operated rat + high tidal volume and zero PEEP served as a control. RESULTS: HSR increased susceptibility to ventilator-induced lung injury as evidenced by an increase in lung elastance and the wet/dry ratio and a reduction in Pa(O(2)) as compared with the other groups. The lung injury observed in the HSR + high tidal volume group was associated with a higher level of interleukin 6 in the lung and blood, increased epithelial cell apoptosis in the kidney and small intestine villi, and a tendency toward high levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatinine in plasma. CONCLUSIONS: HSR priming renders the lung and kidney more susceptible to mechanical ventilation-induced organ injury.

Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer.

Pulmonary arterial hypertension (PAH) is characterized by widespread loss of pulmonary microvasculature. Therefore we hypothesized that angiogenic gene therapy would reverse established PAH, in part restoring the lung microcirculation. Three weeks after monocrotaline (MCT) treatment, Fisher 344 rats were randomized to receive a total of either 1.5 x 10(6) syngeneic fibroblasts (FB) transfected with vascular endothelial growth factor A (VEGF), endothelial NO synthase (eNOS), or null-plasmid transfected FBs. Right ventricular systolic pressure (RVSP) was similarly increased in all MCT-treated groups at the time of gene transfer. Animals receiving the null-vector progressed to severe PAH by Day 35 (P < 0.001). In contrast, eNOS gene transfer significantly reduced RVSP at Day 35 compared with Day 21, whereas VEGF prevented further increases in RVSP over the subsequent 2 wk but did not reverse established PAH. RV hypertrophy was significantly reduced in both the eNOS-treated and VEGF-treated groups compared with the null-transfected controls. Fluorescent microangiography revealed widespread occlusion of the pre-capillary arterioles 21 d after MCT treatment, and animals receiving eNOS gene transfer exhibited the greatest improvement in the arteriolar architecture and capillary perfusion at Day 35. Cell-based eNOS gene transfer was more effective than VEGF in reversing established PAH, associated with evidence of regeneration of pulmonary microcirculation.

Defective lung vascular development in endothelial nitric oxide synthase-deficient mice.

Normal blood vessel formation is required for the development of nearly all organs during embryogenesis, including lung. Neonatal diseases such as persistent pulmonary hypertension of the newborn and alveolar capillary dysplasia are thought to result in large part from a failure of normal lung vascular development. Therefore, in the past decade, there has been increasing interest in studying the mechanisms underlying the development of the lung circulation to better understand the pathogenesis of these often lethal neonatal lung diseases. It has now been well accepted that in addition to its protean roles in the maintenance of vascular homeostasis, endothelium-derived nitric oxide also plays a pivotal role in postnatal angiogenesis, mediating downstream signaling in response to classic angiogenic factors. Recent findings in endothelial nitric oxide synthase (eNOS)-deficient mice point to a novel and previously unrecognized role of eNOS-NO pathway in fetal lung vascular development and lung morphogenesis. The lung phenotype of eNOS mutants closely resembles alveolar capillary dysplasia in humans, a universally fatal form of persistent pulmonary hypertension of the newborn that presents with defective lung vascular development and respiratory distress in newborn. We anticipate that these new insights into the basic mechanisms of lung vascular development may lead to novel therapeutic strategies for neonatal lung diseases.

Iroquois genes influence proximo-distal morphogenesis during rat lung development.

Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in beta-tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gli(2)-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.

Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia?

Endothelium-derived NO plays a critical role in the regulation of cardiovascular function and structure, as well as acting as a downstream mediator of the angiogenic response to numerous vascular growth factors. Although endothelial NO synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities have been reported and homozygous offspring exhibit high neonatal mortality out of proportion to the severity of these defects. The aim of the present report was to determine whether abnormalities of the pulmonary vascular development could contribute to high neonatal loss in eNOS-deficient animals. We now report that eNOS-deficient mice display major defects in lung morphogenesis, resulting in respiratory distress and death within the first hours of life in the majority of animals. Histological and molecular examination of preterm and newborn mutant lungs demonstrated marked thickening of saccular septae, with evidence of reduced surfactant material. Lungs of eNOS-deficient mice also exhibited a striking paucity of distal arteriolar branches and extensive regions of capillary hypoperfusion, together with misalignment of pulmonary veins, which represent the characteristic features of alveolar capillary dysplasia. We conclude that eNOS plays a previously unrecognized role in lung development, which may have relevance for clinical syndromes of neonatal respiratory distress.

Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene.

Benzo[a]pyrene (BaP) is an agonistic ligand for the aryl hydrocarbon receptor (AhR) and a major environmental carcinogen implicated in the aetiology of lung cancer through the induction of benzo[a]pyrene diol epoxidation (BPDE) and BPDE-DNA adducts. Because BaP metabolization requires cytochrome P-450 1A1 (CYP1A1) induction through activation of the AhR, we hypothesized that resveratrol, a natural competitive inhibitor of AhR, could prevent these adverse effects of BaP on the lung. Balb-C mice were injected for 5 weeks with corn oil, BaP (5 mg kg(-1) week(-1)), resveratrol (50 mg kg(-1) week(-1)) or BaP + resveratrol. Immunohistochemistry was performed on lung sections for the determination of CYP1A1 protein, BPDE-DNA adducts and apoptosis. A semi-quantitative immunohistochemistry score (H score) was used for data analysis. Mice exposed to BaP had a significant induction of lung BPDE-DNA adducts when compared with controls (H scores: control, 26, interquartile range 18-33; BaP, 276, interquartile range 269-288; P < 0.01). The BPDE-DNA adduct induction by BaP was abrogated significantly by resveratrol (H score: BaP + resveratrol, 103, interquartile range 96-113). A similar pattern was found by immunohistochemistry for apoptosis (H scores: control, 121, interquartile range 102-137; BaP, 288, interquartile range 282-292, P < 0.05; BaP + resveratrol, 132, interquartile range 121-141, P = NS) and CYP1A1 (H scores: control, 170.3, interquartile range 164-175; BaP, 302.3, interquartile range 291-315, P < 0.05; BaP + resveratrol, 200.7, interquartile range 174-215, P = NS). Western blotting confirmed that resveratrol prevented BaP-induced CYP1A1 expression. This increase in CYP1A1 expression in response to BaP administration most likely causes BaP metabolism, BPDE-DNA adduct formation and subsequent apoptosis. All BaP-induced effects could be prevented by resveratrol, suggesting a possible chemopreventive role for this natural phytoalexin against the development of lung cancer.

Insulin-like growth factor-I receptor-mediated vasculogenesis/angiogenesis in human lung development.

The structural and functional development of the pulmonary system is dependent upon appropriate early vascularization of the embryonic lung. Our previous in vitro studies in a rat model indicated that insulin-like growth factor-I (IGF-I) is a potent angiogenic agent for fetal lung endothelial cells. To assess its role on human vascular lung development, we first examined the expression of IGF-I/II and IGF receptor type I (IGF-IR) in human embryonic and fetal lung tissues at 4-12 wk of gestation. Immunohistochemical and in situ hybridization studies revealed the presence of IGF-I/II-IGF-IR ligands and mRNA transcripts in embryonic lungs as early as 4 wk gestation. Immunotargeting using an anti-IGF-IR neutralizing antibody on human fetal lung explants demonstrated a significant blockade of IGF-IR signaling. Inactivation of IGF-IR resulted in a loss of endothelial cells, accompanied by dramatic changes in fetal lung explant morphology. Terminal transferase dUTP end-labeling assay and TEM studies of anti-IGF-IR-treated lungs demonstrated numerous apoptotic mesenchymal cells. Rat embryonic lung explant studies further validated the importance of the IGF-IGF-IR system for lung vascular development. These data provide the first demonstration of IGF-I/II expression in the human lung in early gestation and indicate that the IGF family of growth factors, acting through the IGF-IR, is required as a survival factor during normal human lung vascularization.