A Core Outcome Set for Interventions to Prevent and/or Treat Delirium in Palliative Care.

CONTEXT: Delirium is a serious neurocognitive syndrome which is highly prevalent in people approaching the end of life. Existing trials of interventions to prevent or treat delirium in adults receiving palliative care report heterogeneous outcomes. OBJECTIVES: To undertake an international consensus process to develop a core outcome set for trials of interventions, designed to prevent and/or treat delirium, for adults receiving palliative care. METHODS: The core outcome set development process included a systematic review, qualitative interviews, modified Delphi method and virtual consensus meetings using nominal group technique (Registration http://www.comet-initiative.org/studies/details/796). Participants included family members, clinicians, and researchers with experience of delirium in palliative care. RESULTS: Forty outcomes were generated from the systematic review and interviews informing the Delphi Round one survey. The international Delphi panel comprised 92 participants including clinicians (n = 71, 77%), researchers (n = 13, 14%), and family members (n = 8, 9%). Delphi Round two was completed by 77 (84%) participants from Round one. Following the consensus meetings, four outcomes were selected for the core outcome set: 1) delirium occurrence (incidence and prevalence); 2) duration of delirium until resolution defined as either no further delirium in this episode of care or death; 3) overall delirium symptom profile (agitation, delusions or hallucinations, delirium symptoms and delirium severity); 4) distress due to delirium (person with delirium, and/or family and/or carers [including healthcare professionals]). CONCLUSION: Using a rigorous consensus process, we developed a core outcome set comprising four delirium-specific outcomes for inclusion in future trials of interventions to prevent and/or treat delirium in palliative care.

Oxygen Plasma Substrate and Specific Nanopattern Promote Early Differentiation of HepaRG Progenitors.

Fully differentiated HepaRG™ cells are the hepatic cell line of choice for in vitro study in toxicology and drug trials. They are derived from a hepatoblast-like progenitor (HepaRG-P) that differentiates into a coculture of hepatocyte-like and cholangiocyte-like cells. This process that requires 2 weeks of proliferation followed by 2 weeks of differentiation using dimethyl sulfoxide (DMSO) can be time consuming and costly. Identifying a method to accelerate HepaRG-Ps toward a mature lineage would save both time and money. The ability to do this in the absence of DMSO would remove the possibility of confounding toxicology results caused by DMSO induction of CYP pathways. It has been shown that tissue culture substrates play an important role in the development and maturity of a cell line, and this is particularly important for progenitor cells, which retain some form of plasticity. Oxygen plasma treatment is used extensively to modify cell culture substrates. There is also evidence that patterned rather than planar surfaces have a positive effect on proliferation and differentiation. In this study, we compared the effect of standard tissue culture plastic (TCP), oxygen plasma coated (OPC), and nanopatterned substrates (NPS) on early differentiation and function of HepaRG-P cells. Since NPS were OPC we initially compared the effect of TCP and OPC to enable comparison between all three culture surfaces using OPC as control to asses if patterning further enhanced early differentiation and functionality. The results show that HepaRG-P's grown on OPC substrate exhibited earlier differentiation, proliferation, and function compared with TCP. Culturing HepaRG-P's on OPC with the addition of NPS did not confer any additional advantage. In conclusion, OPC surface appeared to enhance hepatic differentiation and functionality and could replace traditional methods of differentiating HepaRG-P cells into fully differentiated and functional HepaRGs earlier than standard methods. Impact statement We show significantly earlier differentiation and function of HepaRG progenitor cells when grown in dimethyl sulfoxide-free medium on oxygen plasma substrates versus standard tissue culture plastic. Further investigation showed that nanopatterning of oxygen plasma substrates did not confer any additional advantage over smooth oxygen plasma, although one pattern (DSQ120) showed comparable early differentiation and function.

What do adolescents want from their ED? An evaluation on the preferences and opinions of adolescents attending local EDs.

INTRODUCTION: The adolescent population comprises a significant proportion of attendances to the ED. Despite adolescent patients reporting lower levels of healthcare satisfaction compared with other age groups, their opinions are under-represented in existing literature. This prospective study investigated adolescents' expectations and preferences regarding the ED service. METHODS: A questionnaire designed by the investigators was distributed to children aged 12-16 years over a 6-month period in 2015 at two EDs in the UK. The questionnaire explored themes such as same-sex and similar-age areas, staff communication and environment. Interviews based on the questionnaire template were also conducted and guardians were permitted to accompany the participant. Verbal informed consent was obtained from both the young person and their guardian to participate in the study. RESULTS: There were 254 respondents, which represented 8.8% of adolescent attendances in the study period. 'Cleanliness' was rated the most important factor within the ED setting with 94.8% of respondents selecting 4 or 5 on a 5-point Likert scale. This was followed by 'feeling comfortable', 'clear explanation' and 'staff communication' (91.2%, 90.8% and 90.4% rating these 4 or 5, respectively). However, when participants were asked to select a single most important factor, being 'seen quickly' was selected most frequently (95/206, 46.1%). 'Entertainment' was regarded the least important with only 17.0% selecting 4 or 5 on the Likert scale. Preference for being treated in an adult ED compared with a child ED increased with age. CONCLUSIONS: Being 'seen quickly' was considered the single most important factor by adolescent patients in the ED. Notably, 'cleanliness' and aspects of communication also rated highly, with 'entertainment' regarded as least important. The additional insight into the healthcare preferences of the adolescent population provides a platform on which the future ED services can be tailored to the needs of young people.

Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.