Development and Pilot of a Checklist for Management of Acute Liver Failure in the Intensive Care Unit

Introduction Acute liver failure (ALF) is an ideal condition for use of a checklist. Our aims were to develop a checklist for the management of ALF in the intensive care unit (ICU) and assess the usability of the checklist among multiple providers. Methods The initial checklist was developed from published guidelines and expert opinion. The checklist underwent pilot testing at 11 academic liver transplant centers in the US and Canada. An anonymous, written survey was used to assess the usability and quality of the checklist. Written comments were used to improve the checklist following the pilot testing period. Results We received 81 surveys involving the management of 116 patients during the pilot testing period. The overall quality of the checklist was judged to be above average to excellent by 94% of users. On a 5-point Likert scale, the majority of survey respondents agreed or agreed strongly with the following checklist characteristics: the checklist was easy to read (99% agreed/agreed strongly), easy to use (97%), items are categorized logically (98%), time to complete the checklist did not interfere with delivery of appropriate and safe patient care (94%) and was not excessively burdensome (92%), the checklist allowed the user the freedom to use his or her clinical judgment (80%), it is a useful tool in the management of acute liver failure (98%). Web-based and mobile apps were developed for use of the checklist at the point of care. Conclusion The checklist for the management of ALF in the ICU was shown in this pilot study to be easy to use, helpful and accepted by a wide variety of practitioners at multiple sites in the US and Canada

Reducing the Probability of Capture into Resonance

A migrating planet can capture planetesimals into mean motion resonances. However, resonant trapping can be prevented when the drift or migration rate is sufficiently high. Using a simple Hamiltonian system for first and second order resonances, we explore how the capture probability depends on the order of the resonance, drift rate and initial particle eccentricity. We present scaling factors as a function of the planet mass and resonance strength to estimate the planetary migration rate above which the capture probability drops to less than 1/2. Applying our framework to multiple extra solar planetary systems that have two planets locked in resonance, we estimate lower limits for the outer planet's migration rate allowing resonance capture of the inner planet. Mean motion resonances are comprised of multiple resonant subterms. We find that the corotation subterm can reduce the probability of capture when the planet eccentricity is above a critical value. We present factors that can be used to estimate this critical planet eccentricity. Applying our framework to the migration of Neptune, we find that Neptune's eccentricity is near the critical value that would make its 2:1 resonance fail to capture twotinos. The capture probability is affected by the separation between resonant subterms and so is also a function of the precession rates of the longitudes of periapse of both planet and particle near resonance.Comment: Accepted for publication in MNRA

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Antibiotic Exposure Promotes Fat Gain

Recent research suggests that obesity may be influenced not only by dietary and genetic risk factors, but also by the trillions of microorganisms inhabiting our gastrointestinal tract. Consistent with this notion, Cho et al. (2012) use mice to demonstrate that subtherapeutic antibiotic treatment promotes adiposity

A stem cell marker-expressing subset of enteroendocrine cells resides at the crypt base in the small intestine

The spatial orientation of the enteroendocrine cells along the crypt-villus axis is closely associated with their differentiation in the intestine. Here we studied this relationship using primary duodenal crypts and an ex vivo organoid system established from cholecystokinin-green fluorescent protein (CCK-GFP) transgenic mice. In the primary duodenal crypts, GFP+ cells were found not only in the upper crypt but also at the crypt base, where the stem cells reside. Many GFP+ cells below +4 position were positive for the putative intestinal stem cell markers, leucine-rich repeat-containing G protein-coupled receptor 5, CD133, and doublecortin and CaM kinase-like-1, and also for the neuroendocrine transcription factor neurogenin 3. However, these cells were neither stem nor transient amplifying precursor cells because they were negative for both Ki-67 and phospho-Histone H3 and positive for the mature endocrine marker chromogranin A. Furthermore, these cells expressed multiple endocrine hormones. Tracking of GFP+ cells in the organoids from CCK-GFP mice indicated that GFP+ cells were first observed around the +4 position, some of which localized to the crypt base later in the culture period. These results suggest that a subset of enteroendocrine cells migrates down to the crypt base or stays localized at the crypt base, where they express stem and postmitotic endocrine markers. Further investigation of the function of this subset may provide novel insights into the genesis and development of enteroendocrine cells as well as enteroendocrine tumorigenesis