Ithan D. Peltan

GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The β-amyloid (Aβ) precursor protein (APP) is cleaved sequentially by β-site of APP-cleaving enzyme (BACE) and γ-secretase to release the Aβ peptides that accumulate in plaques in Alzheimers disease (AD). GGA1, a member of the Golgi-localized γ-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from β-cleavage but surprisingly reduced Aβ. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP β-cleavage products from becoming substrates for γ-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP–GGA1 interactions may have pathophysiological relevance in AD.

An international normalized ratio-based definition of acute traumatic coagulopathy is associated with mortality, venous thromboembolism, and multiple organ failure after injury

Objectives:Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy’s relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio–based definitions for acute traumatic coagulopathy. Design:Multicenter prospective observational study. Setting:Nine level I trauma centers in the United States. Patients:A total of 1,031 blunt trauma patients with hemorrhagic shock. Interventions:None. Measurements and Main Results:International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock–associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. Conclusions:Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

Simulation Improves Procedural Protocol Adherence During Central Venous Catheter Placement: A Randomized Controlled Trial.

Background Simulation training may improve proficiency at and reduce complications from central venous catheter (CVC) placement, but the scope of simulation’s effect remains unclear. This randomized controlled trial evaluated the effects of a pragmatic CVC simulation program on procedural protocol adherence, technical skill, and patient outcomes. Methods Internal medicine interns were randomized to standard training for CVC insertion or standard training plus simulation-based mastery training. Standard training involved a lecture, a video-based online module, and instruction by the supervising physician during actual CVC insertions. Intervention-group subjects additionally underwent supervised training on a venous access simulator until they demonstrated procedural competence. Raters evaluated interns’ performance during internal jugular CVC placement on actual patients in the medical intensive care unit. Generalized estimating equations were used to account for outcome clustering within trainees. Results We observed 52 interns placing 87 CVCs. Simulation-trained interns exhibited better adherence to prescribed procedural technique than interns who received only standard training (P = 0.024). There were no significant differences detected in first-attempt or overall cannulation success rates, mean needle passes, global assessment scores, or complication rates. Conclusions Simulation training added to standard training improved protocol adherence during CVC insertion by novice practitioners. This study may have been too small to detect meaningful differences in venous cannulation proficiency and other clinical outcomes, highlighting the difficulty of patient-centered simulation research in settings where poor outcomes are rare. For high-performing systems, where protocol deviations may provide an important proxy for rare procedural complications, simulation may improve CVC insertion quality and safety.

Development and validation of a prehospital prediction model for acute traumatic coagulopathy

BackgroundAcute traumatic coagulopathy (ATC) is a syndrome of early, endogenous clotting dysfunction that afflicts up to 30% of severely injured patients, signaling an increased likelihood of all-cause and hemorrhage-associated mortality. To aid identification of patients within the likely therapeutic window for ATC and facilitate study of its mechanisms and targeted treatment, we developed and validated a prehospital ATC prediction model.MethodsConstruction of a parsimonious multivariable logistic regression model predicting ATC — defined as an admission international normalized ratio >1.5 — employed data from 1963 severely injured patients admitted to an Oregon trauma system hospital between 2008 and 2012 who received prehospital care but did not have isolated head injury. The prediction model was validated using data from 285 severely injured patients admitted to a level 1 trauma center in Seattle, WA, USA between 2009 and 2013.ResultsThe final Prediction of Acute Coagulopathy of Trauma (PACT) score incorporated age, injury mechanism, prehospital shock index and Glasgow Coma Score values, and prehospital cardiopulmonary resuscitation and endotracheal intubation. In the validation cohort, the PACT score demonstrated better discrimination (area under the receiver operating characteristic curve 0.80 vs. 0.70, p = 0.032) and likely improved calibration compared to a previously published prehospital ATC prediction score. Designating PACT scores ≥196 as positive resulted in sensitivity and specificity for ATC of 73% and 74%, respectively.ConclusionsOur prediction model uses routinely available and objective prehospital data to identify patients at increased risk of ATC. The PACT score could facilitate subject selection for studies of targeted treatment of ATC.

Physician Variation in Time to Antimicrobial Treatment for Septic Patients Presenting to the Emergency Department

Objectives: Delayed initiation of appropriate antimicrobials is linked to higher sepsis mortality. We investigated interphysician variation in septic patients’ door-to-antimicrobial time. Design: Retrospective cohort study. Setting: Emergency department of an academic medical center. Subjects: Adult patients treated with antimicrobials in the emergency department between 2009 and 2015 for fluid-refractory severe sepsis or septic shock. Patients who were transferred, received antimicrobials prior to emergency department arrival, or were treated by an attending physician who cared for less than five study patients were excluded. Interventions: None. Measurements and Main Results: We employed multivariable linear regression to evaluate the association between treating attending physician and door-to-antimicrobial time after adjustment for illness severity (Acute Physiology and Chronic Health Evaluation II score), patient age, prehospital or arrival hypotension, admission from a long-term care facility, mode of arrival, weekend or nighttime admission, source of infection, and trainee involvement in care. Among 421 eligible patients, 74% received antimicrobials within 3 hours of emergency department arrival. After covariate adjustment, attending physicians’ (n = 40) median door-to-antimicrobial times varied significantly, ranging from 71 to 359 minutes (p = 0.002). The percentage of each physician’s patients whose antimicrobials began within 3 hours of emergency department arrival ranged from 0% to 100%. Overall, 12% of variability in antimicrobial timing was explained by the attending physician compared with 4% attributable to illness severity as measured by the Acute Physiology and Chronic Health Evaluation II score (p < 0.001). Some but not all physicians started antimicrobials later for patients who were normotensive on presentation (p = 0.017) or who had a source of infection other than pneumonia (p = 0.006). The adjusted odds of in-hospital mortality increased by 20% for each 1 hour increase in door-to-antimicrobial time (p = 0.046). Conclusions: Among patients with severe sepsis or septic shock receiving antimicrobials in the emergency department, door-to-antimicrobial times varied five-fold among treating physicians. Given the association between antimicrobial delay and mortality, interventions to reduce physician variation in antimicrobial initiation are likely indicated.

Engulfment adaptor phosphotyrosine-binding-domain-containing 1 (GULP1) is a nucleocytoplasmic shuttling protein and is transactivationally active together with low-density lipoprotein receptor-related protein 1 (LRP1).

APP (amyloid precursor protein) and LRP1 (low-density lipoprotein receptor-related protein 1) have been implicated in the pathogenesis of AD (Alzheimers disease). They are functionally linked by Fe65, a PTB (phosphotyrosine-binding)-domain-containing adaptor protein that binds to intracellular NPxY-motifs of APP and LRP1, thereby influencing expression levels, cellular trafficking and processing. Additionally, Fe65 has been reported to mediate nuclear signalling in combination with intracellular domains of APP and LRP1. We have previously identified another adaptor protein, GULP1 (engulfment adaptor PTB-domain-containing 1). In the present study we characterize and compare nuclear trafficking and transactivation of GULP1 and Fe65 together with APP and LRP1 and report differential nuclear trafficking of adaptors when APP or LRP1 are co-expressed. The observed effects were additionally supported by a reporter-plasmid-based transactivation assay. The results from the present study indicate that Fe65 might have signalling properties together with APP and LRP1, whereas GULP1 only mediates LRP1 transactivation.

Disaster relief and recovery after a landslide at a small, rural hospital in Guatemala.

INTRODUCTION Though many reports have assessed hospital emergency responses during a disaster that affected the facilitys operations, relatively little work has been dedicated to identifying factors that aid or impede the recovery of such hospitals. PROBLEM On 05 October 2005, Hurricane Stan triggered landslides that buried an impoverished Mayan community in Santiago Atitlán, Guatemala. The six-bed Hospitalito Atitlán also was in the landslides path. Though opened just months earlier, the institution maintained 24-hour services until reopening in a new facility only 15 days after the landslides. METHODS This qualitative study examined the Hospitalito Atitláns disaster recovery using unstructured interviews with key hospital personnel and community members. Participant observation provided information about institutional and cultural dynamics affecting the hospitals recovery. Data were collected retrospectively during June-September 2006 and June 2007. RESULTS The Hospitalitos emergency responses and recovery were distinct endeavors that nonetheless overlapped in time. The initial 12 hours of disorganized emergency relief work was quickly succeeded by an organized effort by the institution to provide inpatient and clinic-based care to the few severely injured and many worried-well patients. As international aid started arriving 2-3 days post-landslide, the Hospitalitos 24-hour clinical services made it an integral organization in the comprehensive health response. Meanwhile, a subset of the Hospitalitos non-clinical staff initiated rebuilding efforts by Day 2 after the event, joined later by medical staff as outside aid allowed them to hand off clinical duties. Effective use of the Internet and conventional media promoted donations of money and supplies, which provided the raw materials used by a group determined to reopen their hospital. CONCLUSIONS Early work by a recovery-focused team coupled with a shared understanding of the Hospitalito as an institution that transcended its damaged building drove the hospitals rapid post-emergency revival. Encouraging a similar sense of mission, emulating the Hospitalitos handling of funding and material procurement, and conducting rebuilding and relief efforts in parallel may aid recovery at other health facilities.

294: CLINICIAN PERCEPTIONS REGARDING IN-HOSPITAL CARDIAC ARREST CARE IN A MULTILEVEL HEALTHCARE SYSTEM

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Outcomes from in-hospital cardiac arrest (IHCA) remain poor. Because resuscitation team members’ nontechnical skills influence IHCA care quality, we evaluated clinicians’ attitudes about treating IHCA. Methods: We conducted a web-based survey of attending physicians, residents, and nurses likely to participate in adult IHCA resuscitation at 21 hospitals within a multilevel healthcare system in Utah and Idaho. A survey instrument was developed to address domains identified by literature review and subject matter experts, iteratively revised for content and brevity, and further revised after cognitive pretesting on eligible clinicians. After pre-notification from hospital leadership, we emailed eligible clinicians a personalized link to the survey and up to 3 reminders. We excluded clinicians who responded to < 1 IHCA event every two years. Survey responses were collected anonymously. Nominal comparisons used chi-square or Fisher’s exact tests as appropriate. We used multivariable linear regression to identify determinants of clinician confidence when leading IHCA teams. Results: Among 1,642 eligible clinicians, 984 (60%) responded to the survey, 979 provided complete survey responses, and 876 were eligible for study inclusion (190 attendings, 576 nurses, and 110 residents). Forty-one percent of respondents practiced primarily at community or rural hospitals and most (74%) participated in ≤6 IHCA events per year. Most residents (63%) and many attendings (36%) but fewer nurses (18%) worried about making errors during an IHCA response (p < 0.001). Clinicians worried about making errors nevertheless felt confident (50%) or very confident (33%) participating in IHCA response. Residents and nurses were slightly less likely than attendings to feel confident participating in IHCA resuscitations (86% vs 91% vs 96% respectively, p = 0.008) but were much less likely to feel confident leading IHCA teams (52% vs 73% vs 95%, p < 0.001). In the multivariable analysis, confidence leading IHCA teams was associated with more frequent IHCA response involvement and non-trainee status but was not significantly associated with ACLS certification, recent mock code participation, hospital type, critical care specialty, sex, or years of experience. Conclusions: Many clinicians worry they make errors while participating in IHCA resuscitations. Residents expected to lead IHCA teams commonly lack confidence in this role.

1421: PREHOSPITAL LEVEL OF CARE, PREHOSPITAL IV ACCESS, AND TIMING OF ANTIBIOTICS IN SEPSIS

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) the impact of the cut-off value for 48-h PVPI on outcome. Results: Median age was 66 (inter quartile range, IQR 52, 74) years, 44/59 patients (75%) survived and 19/59 patients (32%) had pneumonia. Median VFD was 20 (IQR 2, 23) days, the median first-day SOFA score was 10 (IQR 7, 13) and the median 48-h PVPI was 1.7 (IQR 1.4, 2.6). The cut-off value for 48-h PVPI was 2.0 (sensitivity 0.73, specificity 0.77, and area under the curve 0.77, p < 0.01). The odds ratio of 48-h PVPI≥2 was 18.9 (95% Confidence Interval 3.4–155, p < 0.01). Conclusions: The conventional upper limit of PVPI was thus considered to be too high, and the valid value for septic shock patients was determined to be 2.0.