Multiple pathways of programmed cell death are important in liver homeostasis. Hepatocyte death is associated with progression of nonalcoholic fatty liver disease (NAFLD) and inhibition of apoptosis partially protects against liver injury in response to high fat diets (HFD). However, the contribution of necroptosis, a caspase-independent pathway of cell death, to HFD-induced liver injury is not known. Wild-type C57BL/6 and receptor interacting protein (RIP) 3−/− mice were randomized to chow or HFD. HFD-fed C57BL/6 mice increased expression of RIP3, the master regulator of necroptosis, as well as phosphorylated mixed lineage kinase domain-like (pMLKL), an effector of necroptotic cell death, in liver. HFD did not increase pMLKL in RIP3−/− mice. HFD increased fasting insulin and glucose, as well as glucose intolerance, in C57BL/6 mice. RIP3−/− were glucose intolerant even on chow diets; HFD further increased fasting glucose and insulin, but not glucose intolerance. HFD also increased hepatic steatosis, plasma ALT activity, inflammation, oxidative stress and hepatocellular apoptosis in wild-type mice; these responses were exacerbated in RIP3−/− mice. Importantly, increased inflammation and injury was associated with early indicators of fibrosis in RIP3−/− compared to C57BL/6 mice. Culture of AML12 hepatocytes with palmitic acid increased cytotoxicity via apoptosis and necrosis. Inhibition of RIP1 with necrostatin-1 or siRNA knock-down of RIP3 reduced palmitic acid-induced cytotoxicity. Conclusion Absence of RIP3, a key mediator of necroptosis, exacerbated HFD-induced liver injury, associated with increased inflammation and hepatocyte apoptosis, as well as early fibrotic responses. These findings indicate that shifts in the mode of hepatocellular death can influence disease progression and have therapeutic implications because manipulation of hepatocyte cell death pathways is being considered as a target for treatment of NAFLD.

Objectives: To assess the impact of early triggered palliative care consultation on the outcomes of high-risk ICU patients. Design: Single-center cluster randomized crossover trial. Setting: Two medical ICUs at Barnes Jewish Hospital. Patients: Patients (n = 199) admitted to the medical ICUs from August 2017 to May 2018 with a positive palliative care screen indicating high risk for morbidity or mortality. Interventions: The medical ICUs were randomized to intervention or usual care followed by washout and crossover, with independent assignment of patients to each ICU at admission. Intervention arm patients received a palliative care consultation from an interprofessional team led by board-certified palliative care providers within 48 hours of ICU admission. Measurements and Main Results: Ninety-seven patients (48.7%) were assigned to the intervention and 102 (51.3%) to usual care. Transition to do-not-resuscitate/do-not-intubate occurred earlier and significantly more often in the intervention group than the control group (50.5% vs 23.4%; p < 0.0001). The intervention group had significantly more transfers to hospice care (18.6% vs 4.9%; p < 0.01) with fewer ventilator days (median 4 vs 6 d; p < 0.05), tracheostomies performed (1% vs 7.8%; p < 0.05), and postdischarge emergency department visits and/or readmissions (17.3% vs 38.9%; p < 0.01). Although total operating cost was not significantly different, medical ICU (p < 0.01) and pharmacy (p < 0.05) operating costs were significantly lower in the intervention group. There was no significant difference in ICU length of stay (median 5 vs 5.5 d), hospital length of stay (median 10 vs 11 d), in-hospital mortality (22.6% vs 29.4%), or 30-day mortality between groups (35.1% vs 36.3%) (p > 0.05). Conclusions: Early triggered palliative care consultation was associated with greater transition to do-not-resuscitate/do-not-intubate and to hospice care, as well as decreased ICU and post-ICU healthcare resource utilization. Our study suggests that routine palliative care consultation may positively impact the care of high risk, critically ill patients.

This study investigates activity- and consumer product-related eye injuries treated in US hospital emergency departments among children <18 years old using National Electronic Injury Surveillance System data from 1990 through 2009. An estimated 1,406,200 (95% confidence interval = 1,223,409-1,588,992) activity- and consumer product-related pediatric eye injuries occurred during the study period, averaging 70,310 annually. The annual number of injuries declined significantly by 17%. Patients ≤ 4 years of age accounted for 32% of all injuries and had the highest mean annual eye injury rate (11.31 per 10,000 population). Eye injuries associated with sports and recreation (24%) and chemicals (17%) occurred most frequently. The majority (69%) of eye injuries occurred at home. Opportunities exist to further decrease these injuries. Pediatricians should educate child caregivers and children about risks for eye injuries in the home and about use of appropriate protective eyewear during sports.

Increased inflammatory signaling by Kupffer cells contributes to alcoholic liver disease (ALD). Here we investigated the impact of small-specific sized hyaluronic acid of ~35kD (HA35) on ethanol-induced sensitization of Kupffer cells, as well as ethanol-induced liver injury in mice. Un-biased analysis of microRNA (miRNA) expression in Kupffer cells identified miRNAs regulated by both ethanol and HA35. TLR4-mediated signaling was assessed in primary cultures of Kupffer cells from ethanol- and pair-fed rats after treatment with HA35. Female C57BL6/J mice were fed ethanol or pair-fed control diets and treated or not with HA35. TLR4 signaling was increased in Kupffer cells by ethanol; this sensitization was normalized by ex vivo treatment with HA35. Next Generation Sequencing of Kupffer cell miRNA identified miRNA181b-3p as sensitive to both ethanol and HA35. Importin α5, a protein involved in p65 translocation to the nucleus, was identified as a target of miR181b-3p; importin α5 protein was increased in Kupffer cells from ethanol-fed rats, but decreased by HA35 treatment. Overexpression of miR181b-3p decreased importin α5 expression and normalized LPS-stimulated TNFα expression in Kupffer cells from ethanol-fed rats. In a mouse model of ALD, ethanol feeding decreased miR181b-3p in liver and increased expression of importin α5 in non-parenchymal cells. Treatment with HA35 normalized these changes and also protected mice from ethanol-induced liver and intestinal injury. Conclusions miR181b-3p is dynamically regulated in Kupffer cells and mouse liver in response to ethanol and treatment with HA35. miR181b-3p modulates expression of importin α5 and sensitivity of TLR4-mediated signaling. To our knowledge, this study is the first to identify a miR181b-3p→importin α5 axis in regulating inflammatory signaling pathways in hepatic macrophages.