In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

RationaleThe sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.MethodsNuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.ResultsNuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.ConclusionsThe molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions

Thrive: Success Strategies for the Modern-Day Faculty Member

The THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc. If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1000/thumbnail.jp

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Sediment dispersal and accumulation in an insular sea: deltas of Puget Sound

Thesis (Ph.D.)--University of Washington, 2014Small rivers carry several million tons of sediment annually into Puget Sound and the Strait of Juan de Fuca. Once delivered to the marine environment, processes in the water column and on the seabed dictate dispersal, deposition and accumulation of these particles. To investigate these mechanisms, water-column measurements, including long-term bottom-boundary-layer time-series, water-column profiles and shipboard velocity, and seabed sampling, such as sediment cores, multibeam bathymetry and seismic reflection profiling, were collected from 2007-2009 on the Elwha and Skagit River deltas. Tidal currents at both study sites were strong and capable of dispersing muds to more distal portions of the delta. At the Skagit delta the intertidal topset had strong ebb tidal currents that exported most of the Skagit River mud rapidly beyond the topset. The mud found on the flat was limited spatially, near channels and at the outer flat edge and temporally, following high discharge. Physical processes drive shear stresses that act on the seabed to mobilize sands and muds and rework the seabed at various frequencies and depths: on a semi-diurnal tidal timescale, both channel and flat seabeds are reworked to 1-2 cm; and over a decadal timescale, lateral channel migration acts to rework the seabed to 1-2 m, making the limited mud deposits available for export. The Skagit muds were rapidly transported > 10 km into two distinct distal basins; southward within the deep quiescent basin of Saratoga Passage mud accumulates up to 10 mm y-1 for a total of ~0.5 MT annually, and northward within the high-energy unconstrained basin of Rosario Strait some mud accumulates in small local deposits, but much is likely broadly dispersed. Throughout Puget Sound deltas typically form bay head (muddy progradation) or sidewall (broad mud dispersal), and the Skagit River dispersal system has both characteristics. The Elwha River delta is a coarse-grained sidewall delta and tidal currents act to broadly disperse muds. Over the past 10,000 years the dominant sediment sinks have shifted from foreset beds to alongshore spits. This was likely related to variations in sea level as a result of deglaciation and sediment supply. As sea-level rise slowed slightly, wave-driven longshore transport began to actively shape delta morphology and created paleospits, which formed successively one at a time, stepwise as sea-level rose. These sediment sinks were formed under similar processes as the modern spit, Ediz Hook. It is shown that deltas in insular seas can form complex deposits, and this has implications for interpreting the geologic record in areas of constrained basins. In the modern environment, basin morphology and tidal currents determine accumulation patterns. Over longer timescales, the effects of previous glaciations have a major role in delta evolution

The Elwha submarine delta, today and in the past: sediment dispersal and seabed habitats

The marine impacts of the Elwha dam removal and restoration project extend beyond the visible shoreline to encompass broader-scale seabed and associated habitat changes on the submarine delta. Our goals are to evaluate and predict transport-process and seabed evolution during and after dam removal based on studies of both modern sediment dynamics and historical geologic formation of the delta. We link time-series sediment-transport data, seabed sampling and imagery, and seismic data to understand both the past and present sediment dispersal and deposition in the marine ecosystem. In the past, Elwha River sediment load has fluctuated between two extremes, due to both human (dam placement) and natural (e.g., 100 yr flood) events. Even with this large range in sediment delivery, strong tidal currents induced by interactions with coastal morphology created a situation where fine-grained sediment likely did not accumulate except under the most infrequent floods. Thus, the coarse, gravelly lag layer found across much of the delta surface immediately prior to dam removal likely was similar to the seabed prior to dam installation. The present dam-removal conditions of highly concentrated sediment loading replicate those during episodic floods, and deliver both sand and mud to the Strait via a surface plume. Sediment disperses and settles from the thin plume, reducing light at the seabed. Understanding the dispersal mechanisms of sediment under extreme loading conditions is critical for reconstructing delta evolution and evaluating restoration programs throughout the Salish Sea. This research has been used as the foundation for a series of intensive, applied research experiences for Washington college students interested in coastal sediment dynamics and Salish Sea management issues. Through these educational activities, we train future resource managers to consider long-term system evolution as well as short-term impacts of natural processes and restoration activities in the region

Using electronic health record system triggers to target delivery of a patient-centered intervention to improve venous thromboembolism prevention for hospitalized patients: Is there a differential effect by race?

BackgroundRacial disparities are common in healthcare. Venous thromboembolism (VTE) is a leading cause of preventable harm, and disparities observed in prevention practices. We examined the impact of a patient-centered VTE education bundle on the non-administration of preventive prophylaxis by race.MethodsA post-hoc, subset analysis (stratified by race) of a larger nonrandomized trial. Pre-post comparisons analysis were conducted on 16 inpatient units; study periods were October 2014 through March 2015 (baseline) and April through December 2015 (post-intervention). Patients on 4 intervention units received the patient-centered, nurse educator-led intervention if the electronic health record alerted a non-administered dose of VTE prophylaxis. Patients on 12 control units received no intervention. We compared the conditional odds of non-administered doses of VTE prophylaxis when patient refusal was a reason for non-administration, stratified by race.ResultsOf 272 patient interventions, 123 (45.2%) were white, 126 (46.3%) were black, and 23 (8.5%) were other races. A significant reduction was observed in the odds of non-administration of prophylaxis on intervention units compared to control units among patients who were black (OR 0.61; 95% CI, 0.46-0.81, pConclusionOur finding suggests that the patient education materials, developed collaboratively with a diverse group of patients, improved patient's understanding and the importance of VTE prevention through prophylaxis. Quality improvement interventions should examine any differential effects by patient characteristics to ensure disparities are addressed and all patients experience the same benefits

Influenza A Subtyping: Seasonal H1N1, H3N2, and the Appearance of Novel H1N1

Influenza virus subtyping has emerged as a critical tool in the diagnosis of influenza. Antiviral resistance is present in the majority of seasonal H1N1 influenza A infections, with association of viral strain type and antiviral resistance. Influenza A virus subtypes can be reliably distinguished by examining conserved sequences in the matrix protein gene. We describe our experience with an assay for influenza A subtyping based on matrix gene sequences. Viral RNA was prepared from nasopharyngeal swab samples, and real-time RT-PCR detection of influenza A and B was performed using a laboratory developed analyte-specific reagent-based assay that targets a conserved region of the influenza A matrix protein gene. FluA-positive samples were analyzed using a second RT-PCR assay targeting the matrix protein gene to distinguish seasonal influenza subtypes based on differential melting of fluorescence resonance energy transfer probes. The novel H1N1 influenza strain responsible for the 2009 pandemic showed a melting profile distinct from that of seasonal H1N1 or H3N2 and compatible with the predicted melting temperature based on the published novel H1N1 matrix gene sequence. Validation by comparison with the Centers for Disease Control and Prevention real-time RT-PCR for swine influenza A (novel H1N1) test showed this assay to be both rapid and reliable (>99% sensitive and specific) in the identification of the novel H1N1 influenza A virus strain