bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-order host switches of hepatitis C-related viruses illustrated by a novel hepacivirus from sloths
Authors: Moreira-Soto Andres , Arroyo-Murillo Francisco , Sander Anna-Lena , Rasche Andrea , Corman Victor , Tegtmeyer Birthe , Steinmann Eike , Corrales-Aguilar Eugenia , Wieseke Nicolas , Avey-Arroyo Judy , Drexler Jan Felix 
Published: April 2020

Abstract
The genealogy of the hepatitis C virus (HCV) and the genus Hepacivirus remains elusive despite numerous recently discovered animal hepaciviruses (HVs). Viruses from evolutionarily ancient mammals might elucidate the HV macro-evolutionary patterns. Here, we investigated sixty-seven two-toed and nine three-toed sloths from Costa Rica for HVs using molecular and serological tools. A novel sloth HV was detected by reverse transcription polymerase chain reaction (RT-PCR) in three-toed sloths (2/9, 22.2%; 95% confidence interval (CI), 5.3–55.7). Genomic characterization revealed typical HV features including overall polyprotein gene structure, a type 4 internal ribosomal entry site in the viral 5′-genome terminus, an A–U-rich region and X-tail structure in the viral 3′-genome terminus. Different from other animal HVs, HV seropositivity in two-toed sloths was low at 4.5 per cent (3/67; CI, 1.0–12.9), whereas the RT-PCR-positive three-toed sloths were seronegative. Limited cross-reactivity of the serological assay implied exposure of seropositive two-toed sloths to HVs of unknown origin and recent infections in RT-PCR-positive animals preceding seroconversion. Recent infections were consistent with only 9 nucleotide exchanges between the two sloth HVs, located predominantly within the E1/E2 encoding regions. Translated sequence distances of NS3 and NS5 proteins and host comparisons suggested that the sloth HV represents a novel HV species. Event- and sequence distance-based reconciliations of phylogenies of HVs and of their hosts revealed complex macro-evolutionary patterns, including both long-term evolutionary associations and host switches, most strikingly from rodents into sloths. Ancestral state reconstructions corroborated rodents as predominant sources of HV host switches during the genealogy of extant HVs. Sequence distance comparisons, partial conservation of critical amino acid residues associated with HV entry and selection pressure signatures of host genes encoding entry and antiviral protein orthologs were consistent with HV host switches between genetically divergent mammals, including the projected host switch from rodents into sloths. Structural comparison of HCV and sloth HV E2 proteins suggested conserved modes of hepaciviral entry. Our data corroborate complex macro-evolutionary patterns shaping the genus Hepacivirus, highlight that host switches are possible across highly diverse host taxa, and elucidate a prominent role of rodent hosts during the Hepacivirus genealogy.
Cell‐Penetrating MK2 Inhibitory Peptide Blocks LPS‐Induced Expression of Proinflammatory Cytokines in HepG2 Hepatocytes
Authors: Kim Paul , Francis Tiffany , Dalrymple Durina , Yanamadala Yaswanthi , Carriere Victor M. , Poh Scott , Kim Audrey 
Published: April 2020

Mitogen‐activated protein kinase‐activated protein kinase 2 (MAPKAPK2) or MK2 is a downstream effector of the MAPK family member p38. The p38‐MK2 signaling axis is well known to regulate the inflammatory response, thus it is an important target of anti‐inflammatory drugs. For MK2, as with other intracellular targets, delivering the drug across the plasma membrane barrier represents a major challenge. Here we conjugate an anti‐inflammatory peptide (AIP‐1) selective for MK2 to a novel cell‐penetrating peptide (CPP‐AIP‐1) to enhance intracellular delivery. We evaluated the cytotoxicity, efficacy, and intracellular uptake of these therapeutic peptides in an in vitro model of liver inflammation using HepG2 human hepatoma cells challenged with lipopolysaccharides (LPS).HepG2 cells were treated with 0.1–1000 μM AIP‐1 or CPP‐AIP‐1 for 24 hours to assess cytotoxicity. A significant decrease in cell viability was observed in response to 1000 μM CPP‐AIP‐1, whereas 1000 μM AIP‐1 had no significant effect on cell viability. Treatment with either peptide at 300 μM did not alter cell viability relative to untreated control. We selected the next highest noncytotoxic dose tested ‐ 100 μM ‐ as the therapeutic dose. HepG2 cells were treated for 24 hours with 1 ng/mL LPS to induce an inflammatory response and co‐incubated with 100 μM AIP‐1 or 100 μM CPP‐AIP‐1. We observed no changes in mRNA expression of the housekeeping genes ACTB, B2M, and RPLP0 under any of the treatment conditions.We found that LPS significantly upregulated the mRNA expression of the proinflammatory cytokines CXCL8 and TNF, and that CPP‐AIP‐1 (but not AIP‐1) co‐incubation decreased expression to basal levels. Consistent with these mRNA expression data, LPS significantly increased CXCL8 secretion, and this was inhibited by CPP‐AIP‐1 only. Inflammation clearly plays an important role in the development and progression of many diseases. Our results demonstrate the functionality of a cell‐penetrating peptide in inhibiting the MK2‐mediated inflammatory response.Support or Funding InformationResearch reported in this abstract was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103424‐18, Louisiana Biomedical Research Network grant number LSU Subcontract No. PO‐0000002131 (formerly 99989), and Board of Regent – Research Competitiveness Subprogram grant number LEQSF(2018‐21)‐RD‐A‐13
Association of Hypoactive and Hyperactive Delirium With Cognitive Function After Critical Illness
Authors: Hayhurst Christina J. , Marra Annachiara , Han Jin H. , Patel Mayur B. , Brummel Nathan E. , Thompson Jennifer L. , Jackson James C. , Chandrasekhar Rameela , Ely E. Wesley , Pandharipande Pratik P. , Hughes Christopher G. 
Published: April 2020

Objectives:
Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition.

Design:
Secondary analysis of prospective multicenter cohort study.

Setting:
Academic, community, and Veteran Affairs hospitals.

Patients:
Five-hundred eighty-two survivors of respiratory failure or shock.

Interventions:
We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates.

Measurements and Results:
Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (–5.13 [–8.75 to –1.51]; p = 0.03) but not 12 (–5.76 [–9.99 to –1.53]; p = 0.08) months and with worse executive functioning at 3 (–3.61 [–7.48 to 0.26]; p = 0.03) and 12 (–6.22 [–10.12 to –2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort.

Conclusions:
Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium.
Ketamine Use for Tracheal Intubation in Critically Ill Children Is Associated With a Lower Occurrence of Adverse Hemodynamic Events
Authors: Conway J. Arden , Kharayat Priyanka , Sanders Ronald C. , Nett Sholeen , Weiss Scott L. , Edwards Lauren R. , Breuer Ryan , Kirby Aileen , Krawiec Conrad , Page-Goertz Christopher , Polikoff Lee , Turner David A. , Shults Justine , Giuliano John S. , Orioles Alberto , Balkandier Sylvain , Emeriaud Guillaume , Rehder Kyle J. , Kian Boon Joel Lim , Shenoi Asha , Vanderford Paula , Nuthall Gabrielle , Lee Anthony , Zeqo Jonida , Parsons Simon J. , Furlong-Dillard Jamie , Meyer Keith , Harwayne-Gidansky Ilana , Jung Philipp , Adu-Darko Michelle , Bysani G. Kris , McCarthy Melissa A. , Shlomovich Mark , Toedt-Pingel Iris , Branca Aline , Esperanza Maria Christina , Al-Subu Awni M. , Pinto Matthew , Tallent Sarah , Shetty Rakshay , Thyagarajan Sujatha , Ikeyama Takanari , Tarquinio Keiko M. , Skippen Peter , Kasagi Mioko , Howell Joy D. , Nadkarni Vinay M. , Nishisaki Akira 
Published: April 2020

Objectives:
Tracheal intubation in critically ill children with shock poses a risk of hemodynamic compromise. Ketamine has been considered the drug of choice for induction in these patients, but limited data exist. We investigated whether the administration of ketamine for tracheal intubation in critically ill children with or without shock was associated with fewer adverse hemodynamic events compared with other induction agents. We also investigated if there was a dose dependence for any association between ketamine use and adverse hemodynamic events.

Design:
We performed a retrospective analysis using prospectively collected observational data from the National Emergency Airway Registry for Children database from 2013 to 2017.

Setting:
Forty international PICUs participating in the National Emergency Airway Registry for Children.

Patients:
Critically ill children 0–17 years old who underwent tracheal intubation in a PICU.

Interventions:
None.

Measurements and Main Results:
The association between ketamine exposure as an induction agent and the occurrence of adverse hemodynamic events during tracheal intubation including dysrhythmia, hypotension, and cardiac arrest was evaluated. We used multivariable logistic regression to account for patient, provider, and practice factors with robust ses to account for clustering by sites. Of 10,750 tracheal intubations, 32.0% (n = 3,436) included ketamine as an induction agent. The most common diagnoses associated with ketamine use were sepsis and/or shock (49.7%). After adjusting for potential confounders and sites, ketamine use was associated with fewer hemodynamic tracheal intubation associated adverse events compared with other agents (adjusted odds ratio, 0.74; 95% CI, 0.58–0.95). The interaction term between ketamine use and indication for shock was not significant (p = 0.11), indicating ketamine effect to prevent hemodynamic adverse events is consistent in children with or without shock.

Conclusions:
Ketamine use for tracheal intubation is associated with fewer hemodynamic tracheal intubation–associated adverse events.
Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: A Systematic Review and Meta-Analysis*
Authors: Flannery Alexander H. , Bissell Brittany D. , Bastin Melissa Thompson , Morris Peter E. , Neyra Javier A. 
Published: April 2020

Objectives:
Critically ill patients routinely receive vancomycin as empiric antibiotic therapy. A continuous infusion administration strategy may be superior to intermittent infusion by minimizing peak concentrations and variability thereby optimizing safety. We performed a systematic review and meta-analysis to investigate the impact of vancomycin infusion strategy on acute kidney injury in critically ill adults.

Data Sources:
A systematic search of MEDLINE, CINAHL, Web of Science, International Pharmaceutical Abstracts, and Google Scholar was undertaken.

Study Selection:
We included randomized controlled trials and observational studies evaluating acute kidney injury in critically ill adults comparing vancomycin administered by intermittent and continuous infusion. Secondary outcomes included mortality and pharmacokinetic target attainment.

Data Extraction:
Eleven studies were identified for analysis with baseline demographics, endpoints, protocol definitions, and outcomes extracted.

Data Synthesis:
When compared with intermittent infusion, continuous infusion was associated with a reduction in acute kidney injury in critically ill adults (odds ratio, 0.47; 95% CI, 0.34–0.65) and a 2.6 greater odds of pharmacokinetic target attainment (odds ratio, 2.63; 95% CI, 1.52–4.57). No difference in mortality was observed (odds ratio, 1.04; 95% CI, 0.80–1.35).

Conclusions:
When administered via a continuous infusion, vancomycin is associated with a 53% reduction in the odds of acute kidney injury and a 2.6-fold higher odds of pharmacokinetic target attainment when compared with intermittent infusion without influencing overall mortality.
Adverse Events After Transition From ICU to Hospital Ward: A Multicenter Cohort Study*
Authors: Sauro Khara M. , Soo Andrea , de Grood Chloe , Yang Michael M. H. , Wierstra Benjamin , Benoit Luc , Couillard Philippe , Lamontagne François , Turgeon Alexis F. , Forster Alan J. , Fowler Robert A. , Dodek Peter M. , Bagshaw Sean M. , Stelfox Henry T. 
Published: April 2020

Objectives:
To examine adverse events and associated factors and outcomes during transition from ICU to hospital ward (after ICU discharge).

Design:
Multicenter cohort study.

Setting:
Ten adult medical-surgical Canadian ICUs.

Patients:
Patients were those admitted to one of the 10 ICUs from July 2014 to January 2016.

Interventions:
None.

Measurements and Main Results:
Two ICU physicians independently reviewed progress and consultation notes documented in the medical record within 7 days of patient’s ICU discharge date to identify and classify adverse events. The adverse event data were linked to patient characteristics and ICU and ward physician surveys collected during the larger prospective cohort study. Analyses were conducted using multivariable logistic regression. Of the 451 patients included in the study, 84 (19%) experienced an adverse event, the majority (62%) within 3 days of transfer from ICU to hospital ward. Most adverse events resulted only in symptoms (77%) and 36% were judged to be preventable. Patients with adverse events were more likely to be readmitted to the ICU (odds ratio, 5.5; 95% CI, 2.4–13.0), have a longer hospital stay (mean difference, 16.1 d; 95% CI, 8.4–23.7) or die in hospital (odds ratio, 4.6; 95% CI, 1.8-11.8) than those without an adverse event. ICU and ward physician predictions at the time of ICU discharge had low sensitivity and specificity for predicting adverse events, ICU readmissions, and hospital death.

Conclusions:
Adverse events are common after ICU discharge to hospital ward and are associated with ICU readmission, increased hospital length of stay and death and are not predicted by ICU or ward physicians.
Clinician Recognition of the Acute Respiratory Distress Syndrome: Risk Factors for Under-Recognition and Trends Over Time*
Authors: Schwede Matthew , Lee Robert Y. , Zhuo Hanjing , Kangelaris Kirsten N. , Jauregui Alejandra , Vessel Kathryn , Belzer Annika , Deiss Thomas , Matthay Michael A. , Liu Kathleen D. , Calfee Carolyn S. 
Published: April 2020

Objectives:
The acute respiratory distress syndrome is common in critically ill patients. Recognition is crucial because acute respiratory distress syndrome is associated with a high mortality rate, and low tidal volume ventilation improves mortality. However, acute respiratory distress syndrome often goes unrecognized. Risk factors for under-recognition and trends over time have not been fully described.

Design:
Retrospective chart review of patients with acute respiratory distress syndrome from a prospective cohort study of critically ill patients. For each patient’s ICU stay, we searched the chart for terms that indicated that acute respiratory distress syndrome was diagnosed, in the differential diagnosis, or treated with low tidal volume ventilation.

Setting:
ICUs at a tertiary hospital at the University of California, San Francisco between 2008 and 2016.

Patients:
Critically ill patients with acute respiratory distress syndrome.

Interventions:
None.

Measurements and Main Results:
Acute respiratory distress syndrome was recognized in 70% of patients, and recognition increased from 60% in 2008–2009 to 92% in 2016 (p = 0.004). Use of tidal volumes less than 6.5 mL/kg also increased (p < 0.001) from 20% to 92%. Increased acute respiratory distress syndrome severity (p = 0.01) and vasopressor use (p = 0.04) were associated with greater recognition. Clinician diagnosis of acute respiratory distress syndrome and inclusion of acute respiratory distress syndrome in the differential diagnosis were associated with tidal volumes less than 6.5 mL/kg (51% use of tidal volume ≤ 6.5 mL/kg if acute respiratory distress syndrome recognized vs 15% if not recognized; p = 0.002). Diagnosing acute respiratory distress syndrome was associated with lower tidal volume in multivariate analysis.

Conclusions:
Although acute respiratory distress syndrome recognition and low tidal volume ventilation use have increased over time, they remain less than universal. Clinician recognition of acute respiratory distress syndrome is associated with both systemic and respiratory severity of illness and is also associated with use of low tidal volume ventilation.
Factors Disrupting Melatonin Secretion Rhythms During Critical Illness
Authors: Maas Matthew B. , Lizza Bryan D. , Abbott Sabra M. , Liotta Eric M. , Gendy Maged , Eed John , Naidech Andrew M. , Reid Kathryn J. , Zee Phyllis C. 
Published: April 2020

Objectives:
The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile.

Design:
Prospective study observing a cohort for 24–48 hours beginning within the first day of ICU admission.

Setting:
Multiple specialized ICUs within an academic medical center.

Patients:
Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit.

Interventions:
None.

Measurements and Main Results:
Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2.

Conclusions:
Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.
Stress-Induced Behavioral Quiescence and Abnormal Rest-Activity Rhythms During Critical Illness
Authors: Maas Matthew B. , Lizza Bryan D. , Kim Minjee , Abbott Sabra M. , Gendy Maged , Reid Kathryn J. , Zee Phyllis C. 
Published: April 2020

Objectives:
To characterize acute alterations of circadian and ultradian rest-activity rhythms in critically ill patients and their association with brain dysfunction, systemic multiple organ dysfunction, and melatonin rhythms.

Design:
Prospective study observing a cohort for 48 hours beginning within the first day of ICU admission.

Setting:
ICUs within an academic medical center.

Patients:
Patients presenting from the community with acute onset of either intracerebral hemorrhage or sepsis as representative neurologic and systemic critical illnesses. Healthy control patients were studied in the community, during hospital bedrest, and during sleep deprivation.

Interventions:
None.

Measurements and Main Results:
Circadian and ultradian characteristics of rest-activity patterns were measured by wrist actigraphy, severity of neurologic and systemic illness by Glasgow Coma Scale and Sequential Organ Failure Assessment, and central circadian rhythm by melatonin profile. We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage, along with 53 control participants. Total daily activity was markedly reduced and rest-activity rhythmicity was undetectable, neither of which was replicated by hospital bedrest in healthy controls. Circadian rest-activity rhythm fragmentation and attenuation and ultradian disorganization was associated with Glasgow Coma Scale and Sequential Organ Failure Assessment in adjusted models. Rest-activity rhythms showed no detectable phase coherence with melatonin rhythms.

Conclusions:
Critically ill patients rapidly enter a state of behavioral quiescence proportionate to their illness severity with concomitant disturbance of circadian and ultradian rest-activity rhythms and loss of phase coherence with the melatonin rhythm. Quiescence characteristics in rest-activity rhythms were not different in patients with and without delirium, suggesting them to be distinct phenomena. Animal models of severe physiologic stress have shown that specific neural pathway separate from the sleep-wake regulatory pathway induce behavioral quiescence and rest-activity arrhythmia, and facilitate recovery of cellular homeostasis. Whether quiescence is a conserved protective response pathway in humans is not yet understood.