Characterization of marine-derived halogenated indoles as ligands of the aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor thought to mediate a number of physiological roles in the body, is becoming a target of interest for the development of new therapeutics. However, previous research has demonstrated that the downstream effects of AhR ligands cannot be predicted based simply on whether a ligand acts as an agonist or antagonist and the persistence of AhR signaling is thought to be a key determining feature. The current study investigated the AhR activity of four halogenated indoles isolated from the New Zealand red alga, Rhodophyllis membranacea: 4,7-dibromo-2,3-dichloroindole (4DBDCI), 7-bromo-2,3-dichloro-6-iodoindole (BDCII), 6,7-dibromo-2,3-dichloroindole (6DBDCI) and 2,6,7-tribromo-3-chloroindole (TBCI). Their ability to activate AhR signaling, measured as CYP1A1 activity via the ethoxyresorufin O-deethylase (EROD) assay, was determined in human HepG2, mouse Hepa1c1c7 and rat H4IIE liver cancer cells. All four compounds induced CYP1A1 activity in HepG2 cells, suggesting they all acted as AhR agonizts. 4DBDCI was particularly efficacious, inducing an 11-fold increase. Hepa1c1c7 and H4IIE cells, however, were generally less responsive to the halogenated indoles. All four compounds were persistent AhR agonizts, inducing peak CYP1A1 activity after 72 h. Moreover, the 2,3,6,7-substituted BDCII, 6DBDCI and TBCI, but not 4DBDCI, competed with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for AhR binding as observed by the inhibition of TCDD-induced CYP1A1 activity. Overall, the current study has characterized four previously untested AhR ligands, highlighting differences in species sensitivity and persistence of signaling to provide a framework for their potential future use.

Functional genomics and metabolomics advance the ethnobotany of the Samoan traditional medicine "matalafi".

The leaf homogenate of Psychotria insularum is widely used in Samoan traditional medicine to treat inflammation associated with fever, body aches, swellings, wounds, elephantiasis, incontinence, skin infections, vomiting, respiratory infections, and abdominal distress. However, the bioactive components and underlying mechanisms of action are unknown. We used chemical genomic analyses in the model organism Saccharomyces cerevisiae (baker's yeast) to identify and characterize an iron homeostasis mechanism of action in the traditional medicine as an unfractionated entity to emulate its traditional use. Bioactivity-guided fractionation of the homogenate identified two flavonol glycosides, rutin and nicotiflorin, each binding iron in an ion-dependent molecular networking metabolomics analysis. Translating results to mammalian immune cells and traditional application, the iron chelator activity of the P. insularum homogenate or rutin decreased proinflammatory and enhanced anti-inflammatory cytokine responses in immune cells. Together, the synergistic power of combining traditional knowledge with chemical genomics, metabolomics, and bioassay-guided fractionation provided molecular insight into a relatively understudied Samoan traditional medicine and developed methodology to advance ethnobotany.

Quality improvement initiative for improved patient communication in an ED rapid assessment zone.

INTRODUCTION: Patient-clinician communication in the Emergency Department (ED) faces challenges of time and interruptions, resulting in negative effects on patient satisfaction with communication and failure to relieve anxiety. Our aim was to improve patient satisfaction with communication and to decrease related patient anxiety. METHODS: A multistage quality improvement (QI) initiative was conducted in the ED of Toronto General Hospital, a quaternary care centre in Ontario, Canada, from January to May 2018. We engaged stakeholders widely including clinicians, allied health and patients. We developed a 5-point Likert scale survey to measure patient and clinician rating of their communication experience, along with open-ended questions, and a patient focus group. Inductive analyses yielded interventions that were introduced through three Plan-Do-Study-Act (PDSA) cycles: (1) a clinician communication tool called Acknowledge-Empathize-Inform; (2) patient information pamphlets; and (3) a multimedia solution displaying patient-directed material. Our primary outcome was to improve patient satisfaction with communication and decrease anxiety by at least one Likert scale point over 6 months. Our secondary outcome was clinician-perceived interruptions by patients. We used statistical process control (SPC) charts to identify special cause variation and two-tailed Mann-Whitney U tests to compare means (statistical significance p<0.05). RESULTS: A total of 232 patients and 104 clinicians were surveyed over baseline and three PDSA cycles. Communication about wait times, ED process, timing of next steps and directions to patient areas were the most frequently identified gaps, which informed our interventions. Measurements at baseline and during PDSA 3 showed: patient satisfaction increased from 3.28 (5 being best; n=65) to 4.15 (n=59, p<0.0001). Patient anxiety decreased from 2.96 (1 being best; n=65) to 2.31 (n=59, p<0.001). Clinician-perceived interruptions by patients changed from 4.33 (5 being highest; n=30) to 4.18 (n=11, p=0.98) and did not meet significance. SPC charts showed special cause variation temporally associated with our interventions. CONCLUSIONS: Our pragmatic low-cost QI initiative led to statistically significant improvement in patient satisfaction with communication and decreased patient anxiety while narrowly missing our a priori improvement aim of one full Likert scale point.

Checklist for Head Injury Management Evaluation Study (CHIMES): a quality improvement initiative to reduce imaging utilisation for head injuries in the emergency department.

Over 90% of patients with head trauma seen in emergency departments (EDs) are diagnosed with minor head injuries. Over-utilisation of CT scans results in unnecessary exposure to radiation and increases healthcare utilisation. Using recommendations from the Choosing Wisely Canada (CWC) campaign and quality improvement (QI) methodology, we aimed to reduce the CT scan rate for head injuries by 10% over a 6-month period.Baseline CT scan rates were determined through a 27-month retrospective cohort review. We used stakeholder engagement and provider surveys to develop our driver diagram and Plan-Do-Study-Act (PDSA) cycles, which included (1) improving provider knowledge about the CWC campaign recommendations; (2) testing, refining and implementing a modified Canadian CT Head Rule checklist; (3) developing CWC-themed head injury-specific patient handouts; and (4) feedback on CT scan group ordering rates to providers. Our primary outcome measure was the number of CT scans performed for patients with head injuries. Process measures included the number of checklists completed and ED length of stay (LOS). Our balancing measure was return ED visits within 72 hours (with or without admission).Baseline CT scan rates prior to our interventions was 46.1%. Our QI initiative resulted in a 'shift' in the Statistical Process Control chart of the weekly CT scan rates, associated with the first and second PDSA cycles, resulting in a 13.9% reduction in CT rates during the initial 3 months, and a sustained reduction of 8% at 16 months (p<0.05). Mean ED LOS for all patients with head injuries decreased by 1.5 min (p=0.74). 33% of checklists were completed. 72-hour return visits did not change significantly (p=0.68).Through provider and patient education, and the creation of a user-friendly evidence-based tool, our local QI initiative was successful in achieving long-term reduction in CT rates for patients presenting to EDs with head injuries.

Improving timely analgesia administration for musculoskeletal pain in the emergency department.

Delays to adequate analgesia result in worse patient care, decreased patient and provider satisfaction and increased patient complaints. The leading presenting symptom to emergency departments (EDs) is pain, with approximately 34 000 such patients per year in our academic hospital ED and 3300 visits specific for musculoskeletal (MSK) injuries. Our aim was to reduce the time-to-analgesia (TTA; time from patient triage to receipt of analgesia) for patients with MSK pain in our ED by 55% (to under 60 min) in 9 months' time (May 2018). Our outcome measures included mean TTA and ED length of stay (LOS). Process measures included rates of analgesia administration and of use of medical directives. We obtained weekly data capture for Statistical Process Control (SPC) charts, as well as Mann-Whitney U tests for before-and-after evaluation. We performed wide stakeholder engagement, root cause analyses and created a Pareto Diagram to inform Plan-Do-Study-Act (PDSA) cycles, which included: (1) nurse-initiated analgesia at triage; (2) a new triage documentation aid for medication administration; (3) a quick reference medical directive badge for nurses; and (4) weekly targeted feedback of the project's progress at clinical team huddle. TTA decreased from 129 min (n=153) to 100 min (22.5%; n=87, p<0.05). Special cause variation was identified on the ED LOS SPC chart with nine values below the midline after the first PDSA. The number of patients that received any analgesia increased from 42% (n=372) to 47% (n=192; p=0.13) and those that received them via medical directives increased from 22% (n=154) to 44% (n=87; p<0.001). We achieved a significant reduction of TTA and an increased use of medical directives through front-line focused improvements.

Halogenated Meroditerpenoids from a South Pacific Collection of the Red Alga Callophycus serratus.

A detailed examination of the red alga Callophycus serratus collected in Tonga led to the isolation of six new halogenated meroditerpenoids: callophycol C (1), callophycoic acid I (2), iodocallophycols E (3) and F (4), iodocallophycoic acid B (5), and callophycoic acid J (6). Of these, compounds 3-5 are new iodinated additions to the growing family of Callophycus meroditerpenoids. The relative configurations of compounds 1-6 were deduced by analyses of 1D NOE data and 1H-1H scalar coupling constants, and 3-6 are proposed to differ from the closely related compounds reported in the literature, iodocallophycoic acid A and iodocallophycols A-D. Iodocallophycol E (3) exhibited moderate cytotoxicity against the promyelocytic leukemia cell line HL-60 with an IC50 value of 6.0 µM.

Polyhalogenated Indoles from the Red Alga Rhodophyllis membranacea: The First Isolation of Bromo-Chloro-Iodo Secondary Metabolites.

An unusual tetrahalogenated indole with the exceptionally rare inclusion of the three halogens bromine, chlorine, and iodine was found using mass spectrometry within a fraction of a semipurified extract obtained from the red alga Rhodophyllis membranacea. We report herein the isolation and structure elucidation, using a combination of NMR spectroscopy and mass spectrometry, of 11 new tetrahalogenated indoles (1-11), including four bromochloroiodoindoles (5-7, 10). Several were evaluated for cytotoxic and antifungal activities against the HL-60 promyelocytic cell line and Saccharomyces cerevisiae, respectively.