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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. We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury. 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. 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. 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.

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.

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.

Background Parent–Child Interaction Therapy—Toddler (PCIT-T) is an attachment-informed intervention model designed to meet the specific developmental needs of toddlers aged 12–24 months presenting with challenging behaviors. Methods This study used a randomized controlled design to evaluate outcomes of PCIT-T for children aged 14–24 months with disruptive behaviors. Ninety toddlers with parent-reported disruptive behavior were randomly allocated to PCIT-T (intervention), an active control condition (Circle of Security– Parenting™; COS-P), or a non-treatment control condition (wait-list; WL). Outcomes were assessed at baseline (Time 1), post treatment/post waitlist (Time 2) and 4-month follow-up (Time 3). Results At follow-up, the PCIT-T group displayed the highest levels of parenting sensitivity and positive parental verbalizations, and the lowest levels of negative child-directed verbalizations and non-attuned mind-minded statements. Of the three groups, the PCIT-T group showed the greatest degree of change on these variables, followed by the COS-P group and then the non-treated controls. The PCIT-T group were also the only group to show significant within-group improvements in sensitivity, self-reported parental reflectiveness, empathy and emotional understanding, parent-reported child social competence, child internalizing problems, and general behavior issues. Significant reductions in parental stress, child externalizing behaviors and parenting behaviors were seen for both the PCIT-T and COS-P groups. Conclusions Delivered in the early intervention period of toddlerhood, Parent–Child Interaction Therapy—Toddler has the potential to bring about significant changes for children presenting with early onset behavioral issues. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), 12,618,001,554,257. Registered 24 September 2018 – retrospectively registered, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618001554257 .

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.

Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome. HSR exacerbates mechanical stress-induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury. 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. 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. HSR priming renders the lung and kidney more susceptible to mechanical ventilation-induced organ injury.

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.

Trophoblast differentiation during the first trimester of pregnancy involves cell proliferation and invasion and extracellular matrix (ECM) remodeling. Reports have indicated that, in a variety of cell types, processes such as proliferation, invasion, and ECM remodeling require the turnover of focal adhesions mediated by a cytoplasmic tyrosine kinase named focal adhesion kinase (FAK). Therefore, in the present study we examined the expression and spatial localization of FAK during early human placental development. Immunocytochemical and immunoblot analysis showed that FAK and a focal adhesion-associated protein named paxillin were highly expressed between the 5th and 8th weeks of gestation, specifically in villous cytotrophoblast and extravillous trophoblast (EVT) cells. Activated FAK, phosphorylated on Tyr-397, colocalized with α5 integrin and matrix metalloproteinase-2 (MMP2) expression in EVT cells within a previously characterized intermediate, invasive-restrained region. FAK and paxillin expression dramatically decreased after 10 to 12 weeks of gestation coincident with increasing pO2 levels. Exposure of human villous explants of 5 to 8 weeks to a 3% O2 environment resulted in increased trophoblast outgrowth, cell proliferation, and detection of α5 integrin and MMP2, as well as increased activation of FAK in EVT cells compared with explants grown in a 20% O2 environment. To determine whether FAK was a key requisite for trophoblast differentiation, villous explants of 5 weeks gestation were grown in Matrigel in a 3% O2 environment and incubated with 20-mer antisense FAK oligonucleotides. A dramatic reduction of trophoblast outgrowth was observed in antisense-treated explants compared with missense and control cultures, and, in addition, cell proliferation and MMP2 activity in antisense-treated explants were dramatically reduced. These data suggest that FAK is a key kinase involved in early trophoblast cell differentiation and plays a role in regulating cell proliferation and motility during early placental development.

Emotion regulation is an important developmental task during toddlerhood that is associated with positive psychosocial outcomes (Zeman et al., 2006). The development of adaptive emotion regulation during early childhood occurs largely within the context of a supportive caregiverchild relationship (Morris et al., 2007). Thus, parent-mediated interventions are a promising medium through which emotion regulation problems in toddlers can be treated. However, few interventions specifically designed to treat behavioral and emotion regulation difficulties are available for children in the toddler age range, and these interventions have yet to establish a solid evidence base supporting their efficacy. To fill this gap in the literature, the current study investigated the efficacy of two parenting interventions designed to improve emotion regulation in toddlers: Parent-Child Interaction Therapy-Toddler (PCIT-T; Girard et al., 2018) and Circle of Security-Parenting (COS-P; Cooper et al., 2009). Using a randomized controlled trial design, 76 parent-child dyads were randomly assigned to PCIT-T, COS-P, or waitlist control groups. Of the 76 dyads, 51 completed both Time 1 and Time 2 assessments. Observational coding and parentreport questionnaires were used to measure child and parent emotion regulation and related constructs at pre-treatment and post-treatment. Two-way mixed ANOVA were conducted to examine effects of group, time, and group-by-time interaction on parent and child emotion regulation. No significant interaction effects were found for any of the analyses. However, significant and large main effects of time were found for observed parent negative talk, observed maternal support-seeking, parent-reported child dysregulation, and parent-reported child externalizing behavior. Results are discussed in light of study limitations and future directions.

Although there is a small yet growing body of evidence supporting Parent-Child Interaction Therapy (PCIT) as an effective treatment for disruptive behaviors among children with autism spectrum disorder (ASD; Scudder et al., 2019), further study is warranted, particularly with more robust methodology (e.g., larger sample sizes, comparison groups). Furthermore, preliminary studies have demonstrated improvements in symptoms of autism following the completion of PCIT, including improvements in frequency of child verbalizations (Hansen & Shillingsburg, 2016), caregiver report of social skills and social responsiveness (Zlomke et al., 2017), time spent in pretend toy play (Lieneman et al., 2019), and shared positive affect (Solomon et al., 2008). These studies, however, relied heavily on single case methodology or parent report of ASD symptoms. The current study explored the effectiveness of PCIT on core features of autism among children with and without an autism diagnosis referred to a private practice behavioral health clinic. A combination of caregiver report measures, an observer report measure, and behavioral coding systems were used to assess changes in verbalizations, play behavior, and joint engagement for both groups at pre- and post-treatment. Parent-child interactions were coded for child verbalizations and child behavior during play sessions. ANOVA and t-tests (or nonparametric alternatives) were conducted to examine pre-post changes in core features of autism and group differences between those with and without autism. Significant pre-post improvements in child disruptive behavior and compliance to parental commands were found in both groups, yet there were no significant pre-post improvements in child verbalizations, play behavior, or joint engagement. Limitations of the study (e.g., small sample size, methodological issues) and future directions are discussed.