Characterization of Biomarkers of Hemostasis and Bleeding-Related Outcomes in Children With Cirrhosis.

OBJECTIVES: We aimed to evaluate differences in laboratory tests, bleeding, transfusions, and thrombosis between (1) children without and with cirrhosis and (2) children and adults with cirrhosis, and to correlate thromboelastography (TEG) parameters with biomarkers of hemostasis, bleeding, and transfusions in children and adults with cirrhosis. METHODS: This single-center, retrospective study included 20 children without cirrhosis, 40 children with cirrhosis, and 40 adults with cirrhosis who underwent a liver transplant (LT). We collected demographic data, preoperative laboratory values, and intraoperative TEG parameters. Biomarkers of hemostasis just prior to the start of LT surgery were analyzed including international normalized ratio (INR), platelet, fibrinogen level, R time, K time, alpha angle (α), and maximum amplitude (MA). We also collected outcome data including blood loss, transfusion requirements, and thrombosis. RESULTS: A significantly higher proportion of children with cirrhosis had abnormal PT ( P = 0.001), platelet ( P = 0.001), K time ( P = 0.02), and MA ( P = 0.05) compared to children without cirrhosis. The incidences of thrombosis, bleeding events, blood loss or PRBC transfusion were not significantly different between these 2 groups. A significantly higher proportion of adults with cirrhosis had abnormal R time ( P = 0.01) and alpha angle ( P = 0.01) than children with cirrhosis. CONCLUSIONS: Children with cirrhosis had defects in fibrinogen and platelets compared to children without cirrhosis at time of LT; however, these abnormalities did not translate into higher rates of bleeding in the former. Adults with cirrhosis had more defects in clotting factors compared to children with cirrhosis.

Postviral Gastroparesis Associated With SARS-CoV-2 Infection in a Pediatric Patient.

Postviral gastroparesis has been described in children, but it has not yet been attributed to SARS-CoV-2 infection. Our case report describes a teenager with abdominal pain, early satiety, and vomiting who likely had an asymptomatic SARS-CoV-2 infection 2 months before presentation. Through investigation of epidemiologic links, antibody testing, and clinical course, it is hypothesized that her significant reduction in gastric emptying was due to postviral gastroparesis secondary to SARS-CoV-2. She was treated with supportive care and prokinetic agents. The patient demonstrated symptom resolution and near normalization of gastric emptying by the time of 1 month follow up.

The Religious and Spiritual Needs of Patients in the Hospital Setting Do Not Depend on Patient Level of Religious/Spiritual Observance and Should be Initiated by Healthcare Providers.

According to many studies, addressing the religious and spiritual (R/S) needs of patient's increase patient satisfaction. One area of interest is how patient self-perceived level of religiosity and spirituality (R/S) influences hospital needs. In this cross-sectional study, 195 inpatients at a non-faith-based academic hospital in Toledo, OH, USA completed surveys examining self-perceived R/S levels, as well as how those R/S levels impacted preferred services, conversations, and experiences in the hospital. Patients with no religious identity (self-identified as atheist, agnostic, or no religion) were less likely to report discussions about R/S needs than religious respondents (16.7% vs. 47.3%, p = 0.039). Nevertheless, such patients were just as likely to want a R/S conversation started by their healthcare provider (75% vs. 56%, p = 0.241). Those with no R/S identity were more likely to report presumed negative assumptions by hospital staff (25% vs. 0%, p < 0.001). Our data suggests that even for a nonreligious population, it is important to consider R/S needs.

Characteristics, risk factors, and outcomes of neutropenia after liver or kidney transplantation in children.

BACKGROUND: While prior adult studies have shown that approximately 20%-38% of subjects undergoing solid-organ transplant develop neutropenia, similar analyses in pediatric subjects are scarce. METHODS: We conducted a retrospective chart review of liver transplant (LT) and kidney transplant (KT) recipients at our center during the period 2008-2018. All of the KT and none of the LT subjects during this time period had induction with either anti-thymocyte globulin (ATG) or basiliximab at time of transplant. Neutropenia was defined as absolute neutrophil count (ANC) value ≤1000/mm3 . RESULTS: One hundred subjects with LT and 82 subjects with KT were included. The incidence of neutropenia within the first year of transplant in KT was higher compared to LT (54.8% vs 39%, p = .01). The median number of hospitalizations (p = .001) and infectious complications (p = .04) was significantly higher only in the KT subjects who developed neutropenia (compared to those who did not). Multivariate analysis identified factors associated with severity of liver disease at transplant, namely h/o upper gastrointestinal bleeding (p = .02), weight deficit (p = .01), and pre-LT ANC (p = .01), along with high or moderate risk cytomegalovirus status (p = .05) as predictors of neutropenia in LT subjects. Female gender (p = .03) predicted neutropenia, while BK virus infection was protective for neutropenia (p = .04) in KT subjects. CONCLUSIONS: The incidence of and morbidity associated with neutropenia within 1 year post-transplant is higher in KT subjects compared to LT subjects. The likely reason for this is the use of induction therapy (ATG, basiliximab) at the time of transplant in KT subjects.

Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.

Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood. In this study, we investigated the mechanisms underlying the hormone-induced activation of estrogen receptor (ERα, ESR1). We show that estrogen activated PAK1 through both the ERα and GPER1 membrane receptors. Estrogen-dependent activation of PAK1 required the phosphorylation of tyrosine residues by Etk/Bmx and protein kinase A (PKA) within an assembled signaling complex comprising pTyr-PAK1, Etk/Bmx, the heterotrimer G-protein subunits Gß1, Gγ2, and/or Gγ5, PAK-associated guanine nucleotide exchange factor (ßPIX, ARHGEF7), and PKA. Moreover, the PKA RIIß subunit is a direct target of PAK1, and thus in response to estrogen, the activated pTyr-PAK1 complex reciprocally potentiated PKA activity, suggesting a positive feedback mechanism. We also demonstrate that PKA phosphorylated Ser305-ERα in response to estrogen, but pTyr-PAK1 phosphorylated Ser305-ERα in response to prolactin (PRL), implying that maximal ERα phosphorylation is achieved when cells are exposed to both PRL and estrogen. Furthermore, S305-ERα activation led to enhanced phosphorylation of Ser118-ERα and promoted cell proliferation and tumor growth. Together, these data strongly support a critical interplay between PRL and estrogen via PAK1 and suggest that ligand-independent activation of ERα through PRL/PAK1 may impart resistance to anti-estrogen therapies. Cancer Res; 76(9); 2600-11. ©2016 AACR.

A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation.

Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime mold Dictyostelium discoideum, are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cells in vitro. Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation. We examined the effect of DIF derivatives on PAK1 kinase activity in cells. We also examined the effect of DIF-3(+1) derivative on PAK1 kinase activity in vitro, cyclin D1 promoter activity and breast cancer cell proliferation. It was found that some derivatives strongly inhibited PAK1 kinase activity in human breast cancer MCF-7 cells stably over expressing PAK1. Among the derivatives, DIF-3(+1) was most potent, which directly inhibited kinase activity of recombinant purified PAK1 in an in vitro kinase assay. Furthermore, DIF-3(+1) strongly inhibited both cyclin D1 promoter activity and proliferation of MCF-7 and T47D breast cancer cells stably over expressing PAK1 in response to prolactin, estrogen, epidermal growth factor and heregulin. In the present study we propose PAK1 as DIF-3(+1) target mediating its anti-proliferative effect.