High-Throughput Cell-Based Screening of Small Molecule KRAS Signaling Inhibitors Using a Homogeneous Time-Resolved Fluorescence (HTRF) Assay.

With recent advances proving that effective inhibition of KRAS is possible, there have been significant efforts made to develop inhibitors of specific mutant alleles. Here we describe a detailed protocol that employs homogeneous time-resolved fluorescence (HTRF) to identify compounds acting on KRAS signaling in malignant cell lines. This method allows for high-throughput, cell-based screens of large compound libraries for the development of RAS-targeted therapeutics.

FLAG-KRAS4B as a Model System for KRAS4B Proteoform and PTM Evaluation by Mass Spectrometry.

Prior analysis of intact and modified protein forms (proteoforms) of KRAS4B isolated from cell lines and tumor samples by top-down mass spectrometry revealed the presence of novel posttranslational modifications (PTMs) and potential evidence of context-specific KRAS4B modifications. However, low endogenous proteoform signal resulted in ineffective characterization, making it difficult to visualize less abundant PTMs or perform follow-up PTM validation using standard proteomic workflows. The NCI RAS Initiative has developed a model system, whereby KRAS4B bearing an N-terminal FLAG tag can be stably expressed within a panel of cancer cell lines. Herein, we present a method for combining immunoprecipitation with complementary proteomic methods to directly analyze N-terminally FLAG-tagged KRAS4B proteoforms and PTMs. We provide detailed protocols for FLAG-KRAS4B purification, proteoform analysis by targeted top-down LC-MS/MS, and validation of abundant PTMs by bottom-up LC-MS/MS with example results.

Shattered Kidney After Renal Trauma: Should It Be Classified As an American Association for the Surgery of Trauma Grade V Injury?

OBJECTIVE: To study the prevalence and management of shattered kidney and to evaluate if the new description of "loss of identifiable renal anatomy" in the 2018 American Association for the Surgery of Trauma (AAST) organ injury scale (OIS) would improve the ability to predict bleeding control interventions. METHODS: We used high-grade renal trauma data from 21 Level-1 trauma centers from 2013 to 2018. Initial CT scans were reviewed to identify shattered kidneys, defined as a kidney having ≥3 parenchymal fragments displaced by blood or fluid on cross-sectional imaging. We further categorized patients with shattered kidney in two models based on loss of identifiable renal parenchymal anatomy and presence or absence of vascular contrast extravasation (VCE). Bleeding interventions were compared between the groups. RESULTS: From 861 high-grade renal trauma patients, 41 (4.8%) had shattered kidney injury. 25 (61%) underwent a bleeding control intervention including 18 (43.9%) nephrectomies and 11 (26.8%) angioembolizations. 18 (41%) had shattered kidney with "loss of identifiable parenchymal renal anatomy" per 2018 AAST OIS (model-1). 28 (68.3%) had concurrent VCE (model-2). Model-2 had a statistically significant improvement in area under the curve over model-1 in predicting bleeding interventions (0.75 vs 0.72; P = .01). CONCLUSION: Shattered kidney is associated with high rates of active bleeding, urinary extravasation, and interventions including nephrectomy. The definition of shattered kidney is vague and subjective and our definition might be simpler and more reproducible. Loss of identifiable renal anatomy per the 2018 AAST OIS did not provide better distinction for bleeding control interventions over presence of VCE.

Grade V renal trauma management: results from the multi-institutional genito-urinary trauma study.

PURPOSE: To investigate management trends for American Association for the Surgery of Trauma (AAST) grade V renal trauma with focus on non-operative management. METHODS: We used prospectively collected data as part of the Multi-institutional Genito-Urinary Trauma Study (MiGUTS). We included patients with grade V renal trauma according to the AAST Injury Scoring Scale 2018 update. All cases submitted by participating centers with radiology images available were independently reviewed to confirm renal trauma grade. Management was classified as expectant, conservative (minimally invasive, endoscopic or percutaneous procedures), or operative (renal-related surgery). RESULTS: Eighty patients were included, 25 of whom had complete imaging and had independent confirmation of AAST grade V renal trauma. Median age was 35 years (Interquartile range (IQR) 25-50) and 23 (92%) had blunt trauma. Ten patients (40%) were managed operatively with nephrectomy. Conservative management was used in nine patients (36%) of which six received angioembolization and three had a stent or drainage tube placed. Expectant management was followed in six (24%) patients. Transfusion requirements were progressively higher with groups requiring more aggressive treatment, and injury characteristics differed significantly across management groups in terms of hematoma size and laceration size. Vascular contrast extravasation was more likely in operatively managed patients though a statistically significant association was not found. CONCLUSION: Successful use of nonoperative management for grade V injuries is used for a substantial subset of patients. Lower transfusion requirement and less severe injury radiologic phenotype appear to be important characteristics delineating this group.

Accelerating the Availability of Medications to Pediatric Patients by Optimizing the Use of Extrapolation of Efficacy.

Improving pediatric therapeutic development is a mission of universal importance among health authorities, pharmaceutical companies, academic institutions, and healthcare professionals. Following the passage of legislation in the United States and Europe, we witnessed the most significant advancement yet in pediatric data generation, resulting in added pediatric use information to almost 700 product labels. Tools to accelerate generation of data for the pediatric population are available for use today, and when utilized in accordance with current practices and laws, these tools could increase the amount and timeliness of pediatric information available for clinicians and patients. If we utilize the current laws that allow regulators to incentivize and require evidence generation, apply extrapolation, and utilize modeling and simulation, as well as including adolescents in the pivotal studies alongside adults as appropriate, two strategic goals could be achieved by 2030: (1) reduce the time to pediatric approval by 50%, and (2) renew pediatric labeling information for 15 priority pediatric drugs without patent and/or exclusivity.

Professionalism of Admitting and Consulting Services and Trauma Patient Outcomes.

OBJECTIVE: To determine whether trauma patients managed by an admitting or consulting service with a high proportion of physicians exhibiting patterns of unprofessional behaviors are at greater risk of complications or death. SUMMARY BACKGROUND DATA: Trauma care requires high-functioning interdisciplinary teams where professionalism, particularly modeling respect and communicating effectively, is essential. METHODS: This retrospective cohort study used data from 9 level I trauma centers that participated in a national trauma registry linked with data from a national database of unsolicited patient complaints. The cohort included trauma patients admitted January 1, 2012 through December 31, 2017. The exposure of interest was care by 1 or more high-risk services, defined as teams with a greater proportion of physicians with high numbers of patient complaints. The study outcome was death or complications within 30 days. RESULTS: Among the 71,046 patients in the cohort, 9553 (13.4%) experienced the primary outcome of complications or death, including 1875 of 16,107 patients (11.6%) with 0 high-risk services, 3788 of 28,085 patients (13.5%) with 1 high-risk service, and 3890 of 26,854 patients (14.5%) with 2+ highrisk services (P < 0.001). In logistic regression models adjusting for relevant patient, injury, and site characteristics, patients who received care from 1 or more high-risk services were at 24.1% (95% confidence interval 17.2% to 31.3%; P < 0.001) greater risk of experiencing the primary study outcome. CONCLUSIONS: Trauma patients who received care from at least 1 service with a high proportion of physicians modeling unprofessional behavior were at an increased risk of death or complications.

Nephrectomy After High-Grade Renal Trauma is Associated With Higher Mortality: Results From the Multi-Institutional Genitourinary Trauma Study (MiGUTS).

OBJECTIVE: To test the hypothesis that undergoing nephrectomy after high-grade renal trauma is associated with higher mortality rates. METHODS: We gathered data from 21 Level-1 trauma centers through the Multi-institutional Genito-Urinary Trauma Study. Patients with high-grade renal trauma were included. We assessed the association between nephrectomy and mortality in all patients and in subgroups of patients after excluding those who died within 24 hours of hospital arrival and those with GCS≤8. We controlled for age, injury severity score (ISS), shock (systolic blood pressure <90 mmHg), and Glasgow Coma Scale (GCS). RESULTS: A total of 1181 high-grade renal trauma patients were included. Median age was 31 and trauma mechanism was blunt in 78%. Injuries were graded as III, IV, and V in 55%, 34%, and 11%, respectively. There were 96 (8%) mortalities and 129 (11%) nephrectomies. Mortality was higher in the nephrectomy group (21.7% vs 6.5%, P <.001). Those who died were older, had higher ISS, lower GCS, and higher rates of shock. After adjusting for patient and injury characteristics nephrectomy was still associated with higher risk of death (RR: 2.12, 95% CI: 1.26-2.55). CONCLUSION: Nephrectomy was associated with higher mortality in the acute trauma setting even when controlling for shock, overall injury severity, and head injury. These results may have implications in decision making in acute trauma management for patients not in extremis from renal hemorrhage.

A Contemporary Analysis of Delayed Diagnoses After Traumatic Injury : The Role of Operative Therapy.

BACKGROUND: Factors associated with delayed injury diagnosis (DID) have been examined, but incompletely researched. METHODS: We evaluated demographics, mechanism, and measures of mental status and injury severity among 10 years' worth of adult trauma patients at our center for association with DID in a multivariable regression model. Descriptions of DID injuries were reviewed to highlight characteristics of these injuries. RESULTS: We included 13 509 patients, 89 (0.7%) of whom had a recognized DID. In regression analysis, ISS (OR 1.04 per point, 95% CI 1.02-1.06) and number of injuries (OR 1.08 per injury, 95% CI 1.04-1.11) were associated with DID. Operative patients had twice the odds of DID (OR 2.02, 95% CI 1.18-3.44). The most common category of DID was orthopedic extremity injury (22/89). CONCLUSION: DID is associated with injury severity and operative intervention. This suggests that the presence of an injury requiring operation may distract the trauma team from additional injuries.

Beyond morbidity and mortality: The practicality of measuring patient-reported outcomes in trauma.

BACKGROUND: The 2016 Zero Preventable Deaths report highlighted the need for comprehensive injury data to include long term outcomes such as societal and workforce re-entry. Currently, postinjury quality of life is poorly understood. We hypothesized that routine measurement of patient-reported outcomes is feasible as a part of post-discharge follow-up, and that trauma patients would report that their injury had a detrimental impact on health-related quality of life (HRQoL) after discharge. METHODS: After instruction, patients self-administered the PROMIS-29 instrument in our outpatient office (11/2019-4/2020). We surveyed 7 domains: Participation in Social Roles/Activities, Anxiety, Depression, Fatigue, Pain Interference, Physical Function, and Sleep Disturbance. Results are reported as means (SD) and compared to the U.S population by t-score (mean score=50). Higher scores in negatively-worded domains (e.g. "Depression") are worse; vice versa for positively-worded domains (e.g. "Physical Function"). Repeated scores among patients returning for a second visit were analyzed using paired t-tests. RESULTS: 103 patients completed the PROMIS-29. Mean (SD) age was 42.3 (17.3) years, 75% were male, and 42% suffered a penetrating injury. Median length of stay was 3 days and median time from injury to clinic visit was 18 days. Mean scores were worse than population means in every domain. Pain Interference (mean 63.5, 95%CI [61.8-65.3]) and Physical Function (38.0 [36.2-39.8]) were particularly affected. Among patients returning for a second visit (n=10; median time between clinic visits: 17.5 days), there were no significant differences in domain scores over time. CONCLUSION: Trauma patients are at high risk for poor quality of life outcomes in the short term following injury. Our results highlight the need for early recognition and multidisciplinary treatment following injury.

Clinical and Radiographic Factors Associated With Failed Renal Angioembolization: Results From the Multi-institutional Genitourinary Trauma Study (Mi-GUTS).

OBJECTIVE: To find clinical or radiographic factors that are associated with angioembolization failure after high-grade renal trauma. MATERIAL AND METHODS: Patients were selected from the Multi-institutional Genito-Urinary Trauma Study. Included were patients who initially received renal angioembolization after high-grade renal trauma (AAST grades III-V). This cohort was dichotomized into successful or failed angioembolization. Angioembolization was considered a failure if angioembolization was followed by repeat angiography and/or an exploratory laparotomy. RESULTS: A total of 67 patients underwent management initially with angioembolization, with failure in 18 (27%) patients. Those with failed angioembolization had a larger proportion ofgrade IV (72% vs 53%) and grade V (22% vs 12%) renal injuries. A total of 53 patients underwent renal angioembolization and had initial radiographic data for review, with failure in 13 cases. The failed renal angioembolization group had larger perirenal hematoma sizes on the initial trauma scan. CONCLUSION: Angioembolization after high-grade renal trauma failed in 27% of patients. Failed angioembolization was associated with higher injury grade and a larger perirenal hematoma. Likely these characteristics are associated with high-grade renal trauma that may be less amenable to successful treatment after a single renal angioembolization.

The REBOA Dissipation Curve: Training Starts to Wane at 6 Months in the Absence of Clinical REBOA Cases.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a low-frequency, high-acuity intervention. We hypothesized that REBOA-specific knowledge and comfort deteriorate significantly within 6 months of a formal training course if REBOA is not performed in the interim. METHODS: A comprehensive REBOA course was developed including didactics and hands-on practical simulation training. Baseline knowledge and comfort were assessed with a precourse objective test and a subjective self-assessment. REBOA knowledge and comfort were then re-assessed immediately postcourse and again at 6 months and 1 year. Performance trends were measured using paired Student's t and Wilcoxon signed-rank tests. RESULTS: Thirteen participants were evaluated including trauma faculty (n = 10) and fellows (n = 3). Test scores improved significantly from precourse (72% ± 10% correct) to postcourse (88% ± 8%, p < 0.001). At 6 months, scores remained no different from postcourse (p = 0.126); at 1 year, scores decreased back to baseline (p = 0.024 from postcourse; 0.285 from precourse). Subjective comfort with femoral arterial line placement and REBOA improved with training (p = 0.044 and 0.003, respectively). Femoral arterial line comfort remained unchanged from postcourse at 6 months (p = 0.898) and 1 year (p = 0.158). However, subjective comfort with REBOA decreased relative to postcourse levels at 6 months (p = 0.009), driven primarily by participants with no clinical REBOA cases in the interim. CONCLUSIONS: A formal REBOA curriculum improves knowledge and comfort with critical aspects of this procedure. This knowledge persists at 6 months, though subjective comfort deteriorated among those without REBOA placement in the interim. REBOA refresher training should be considered at 6-month intervals in the absence of clinical REBOA cases. LEVEL OF EVIDENCE/STUDY TYPE: Level III, prognostic.

High-Performance Trauma Centers in a Single-State Trauma System : Big Saves or Marginal Gains?

BACKGROUND: Trauma centers with low observed:expected (O:E) mortality ratios are considered high performers; however, it is unknown whether improvements in this ratio are due to a small number of unexpected survivors with high mortality risk (big saves) or a larger number of unexpected survivors with moderate mortality risk (marginal gains). We hypothesized that the highest-performing centers achieve that status via larger numbers of unexpected survivors with moderate mortality risk. METHODS: We calculated O:E ratios for trauma centers in Pennsylvania for 2016 using a risk-adjusted mortality model. We identified high and low performers as centers whose 95% CIs did not cross 1. We visualized differences between these centers by plotting patient-level observed and expected mortality; we then examined differences in a subset of patients with a predicted mortality of ≥10% using the chi-squared test. RESULTS: One high performer and 1 low performer were identified. The high performer managed a population with more blunt injuries (97.2% vs 93.6%, P < .001) and a higher median Injury Severity Score (14 vs 11, P < .001). There was no difference in survival between these centers in patients with an expected mortality of <10% (98.0% vs 96.7%, P = .11) or ≥70% (23.5% vs 10.8%, P = .22), but there was a difference in the subset with an expected mortality of ≥10% (77.5% vs 43.1%, P < .001). CONCLUSIONS: Though patients with very low predicted mortality do equally well in high-performing and low-performing centers, the fact that performance seems determined by outcomes of patients with moderate predicted mortality favors a "marginal gains" theory.

Current Management of Extraperitoneal Bladder Injuries: Results from the Multi-Institutional Genito-Urinary Trauma Study (MiGUTS).

PURPOSE: We studied the current management trends for extraperitoneal bladder injuries and evaluated the use of operative repair versus catheter drainage, and the associated complications with each approach. MATERIALS AND METHODS: We prospectively collected data on bladder trauma from 20 level 1 trauma centers across the United States from 2013 to 2018. We excluded patients with intraperitoneal bladder injury and those who died within 24 hours of hospital arrival. We separated patients with extraperitoneal bladder injuries into 2 groups (catheter drainage vs operative repair) based on their initial management within the first 4 days and compared the rates of bladder injury related complications among them. Regression analyses were used to identify potential predictors of complications. RESULTS: From 323 bladder injuries we included 157 patients with extraperitoneal bladder injuries. Concomitant injuries occurred in 139 (88%) patients with pelvic fracture seen in 79%. Sixty-seven patients (43%) initially underwent operative repair for their extraperitoneal bladder injuries. The 3 most common reasons for operative repair were severity of injury or bladder neck injury (40%), injury found during laparotomy (39%) and concern for pelvic hardware contamination (28%). Significant complications were identified in 23% and 19% of the catheter drainage and operative repair groups, respectively (p=0.55). The only statistically significant predictor for complications was bladder neck or urethral injury (RR 2.69, 95% 1.21-5.97, p=0.01). CONCLUSIONS: In this large multi-institutional cohort, 43% of patients underwent surgical repair for initial management of extraperitoneal bladder injuries. We found no significant difference in complications between the initial management strategies of catheter drainage and operative repair. The most significant predictor for complications was concomitant urethral or bladder neck injury.

Readmissions After Injury: Is Fragmentation of Care Associated With Mortality?

BACKGROUND: Unplanned readmissions of surgical patients are associated with increased morbidity and mortality. "Fragmentation of care" (FOC) occurs when patients are readmitted to a different hospital than where they initially received care. FOC complicates accurate quantification of hospital readmission rates and is associated with worse outcomes in many surgical patient populations. However, few studies have evaluated the impact of FOC specifically on patients with traumatic injury. MATERIALS AND METHODS: We performed a retrospective cohort study using the 2013 National Readmissions Database. Data on demographics, diagnosis, injury severity, readmissions, complications, and outcomes were collected. Patients readmitted to hospitals within 30 d after index admission were identified, and risk factors for readmission were discerned. Patients were stratified into groups readmitted to index versus nonindex hospital. Outcomes were compared between these groups. RESULTS: A total of 333,188 patients with index admission for injury were identified; 34,197 (10.3%) were readmitted within 30 d of discharge. Of these, only 24,747 (72.4%) were readmitted to their index hospital for an FOC rate of 27.6%. There was no significant difference in outcomes between patients readmitted to index versus nonindex hospitals. Among all readmitted patients, 30-d mortality was associated only with burden of medical comorbidities and age. CONCLUSIONS: Single-institution readmission rates are not reflective of true readmission rates for trauma patients. FOC does not impact outcomes in trauma patients who are readmitted; however, age and number of comorbidities are associated with higher mortality in these patients. FOC rates are high in trauma patient populations and merit further investigation to determine potential etiologies and consequences.

Epidural catheters are associated with an increased risk of venous thromboembolism in trauma.

Little is known about the association between epidural catheters (EC) and venous thromboembolism (VTE) in trauma. We sought to study this association and hypothesized that trauma patients with EC were more likely to develop VTE. Using the Pennsylvania Trauma Outcomes Study (PTOS) registry, we identified all adult trauma patients (age ≥ 18) admitted for at least 2 days between 1/2013 and 12/2017. Baseline characteristics and outcome variables were compared between patients who underwent EC placement and those who did not. The primary outcome was development of VTE. 147,721 patients met inclusion criteria; 2247 (1.5%) developed a VTE. Patients were mostly white (85%), male (56%), with blunt trauma (94%). 776 (0.5%) had an EC placed. Patients who underwent EC placement were more likely to develop a VTE (2.8% vs. 1.5%, p = 0.003). After adjusting for covariates, patients with EC were 1.6 times more likely to develop VTE (95% CI 1.1-2.5). The overall rate of VTE was low and associated with the use of EC. Future work should focus on determining the underlying mechanisms.

The impact of interhospital transfer on mortality benchmarking at Level III and IV trauma centers: A step toward shared mortality attribution in a statewide system.

BACKGROUND: Many injured patients presenting to Level III/IV trauma centers will be transferred to Level I/II centers, but how these transfers influence benchmarking at Level III/IV centers has not been described. We hypothesized that the apparent observed to expected (O:E) mortality ratios at Level III/IV centers are influenced by the location at which mortality is measured in transferred patients. METHODS: We conducted a retrospective study of adult patients presenting to Level III/IV trauma centers in Pennsylvania from 2008 to 2017. We used probabilistic matching to match patients transferred between centers. We used a risk-adjusted mortality model to estimate predicted mortality, which we compared with observed mortality at discharge from the Level III/IV center (O) or observed mortality at discharge from the Level III/IV center for nontransferred patients and at discharge from the Level I/II center for transferred patients (O). RESULTS: In total, 9,477 patients presented to 11 Level III/IV trauma centers over the study period (90% white; 49% female; 97% blunt mechanism; median Injury Severity Score, 8; interquartile range, 4-10). Of these, 4,238 (44%) were transferred to Level I/II centers, of which 3,586 (85%) were able to be matched. Expected mortality in the overall cohort was 332 (3.8%). A total of 332 (3.8%) patients died, of which 177 (53%) died at the initial Level III/IV centers (O). Including posttransfer mortality for transferred patients in addition to observed mortality in nontransferred patients (O) resulted in worse apparent O:E ratios for all centers and significant differences in O:E ratios for the overall cohort (O:E, 0.53; 95% confidence interval, 0.45-0.61 vs. O:E, 1.00, 95% confidence interval, 0.92-1.11; p < 0.001). CONCLUSION: Apparent O:E mortality ratios at Level III/IV centers are influenced by the timing of measurement. To provide fair and accurate benchmarking and identify opportunities across the continuum of the trauma system, a system of shared attribution for outcomes of transferred patients should be devised.

Team Assessment and Decision Making Is Associated With Outcomes: A Trauma Video Review Analysis.

BACKGROUND: Teamwork is a critical element of trauma resuscitation. Assessment tools such as T-NOTECHS (Trauma NOn-TECHnical Skills) exist, but correlation with patient outcomes is unclear. Using emergency department thoracotomy (EDT), we sought to describe T-NOTECHS scores during resuscitations. We hypothesized that patients undergoing EDT whose resuscitations had better scores would be more likely to have return of spontaneous circulation (ROSC). METHODS: Continuously recording video was used to review all captured EDTs over a 24-mo period. We used a modification of the validated T-NOTECHS instrument to measure five domains on a 3-point scale (1 = best, 2 = average, 3 = worst). A total T-NOTECHS score was calculated by one of three reviewers. The primary outcome was ROSC. ROSC was defined as an organized rhythm no longer requiring internal cardiac compressions. Associations between variables and ROSC were examined using univariate regression. RESULTS: Sixty-one EDTs were captured. Nineteen patients had ROSC (31%) and 42 (69%) did not. The median T-NOTECHS score for all resuscitations was 8 [IQR 6-10]. As demographic and injury data (age, gender, mechanism, signs of life) were not associated with ROSC in univariate analysis, they were not considered for inclusion in a multivariable regression model. The association between overall T-NOTECHS score and ROSC did not reach statistical significance, but examination of the individual components of the T-NOTECHS score demonstrated that, compared to resuscitations that had "average" (2) or "worst" (3) scores on "Assessment and Decision Making," resuscitations with a "best" score were 5 times more likely to lead to ROSC. CONCLUSIONS: Although the association between overall T-NOTECHS scores and ROSC did not reach statistical significance, better scores in the domain of assessment and decision making are associated with improved rates of ROSC in patients arriving in cardiac arrest who undergo EDT. LEVEL OF EVIDENCE: Level IV Therapeutic/Care Management.

The American Association for the Surgery of Trauma renal injury grading scale: Implications of the 2018 revisions for injury reclassification and predicting bleeding interventions.

BACKGROUND: In 2018, the American Association for the Surgery of Trauma (AAST) published revisions to the renal injury grading system to reflect the increased reliance on computed tomography scans and non-operative management of high-grade renal trauma (HGRT). We aimed to evaluate how these revisions will change the grading of HGRT and if it outperforms the original 1989 grading in predicting bleeding control interventions. METHODS: Data on HGRT were collected from 14 Level-1 trauma centers from 2014 to 2017. Patients with initial computed tomography scans were included. Two radiologists reviewed the scans to regrade the injuries according to the 1989 and 2018 AAST grading systems. Descriptive statistics were used to assess grade reclassifications. Mixed-effect multivariable logistic regression was used to measure the predictive ability of each grading system. The areas under the curves were compared. RESULTS: Of the 322 injuries included, 27.0% were upgraded, 3.4% were downgraded, and 69.5% remained unchanged. Of the injuries graded as III or lower using the 1989 AAST, 33.5% were upgraded to grade IV using the 2018 AAST. Of the grade V injuries, 58.8% were downgraded using the 2018 AAST. There was no statistically significant difference in the overall areas under the curves between the 2018 and 1989 AAST grading system for predicting bleeding interventions (0.72 vs. 0.68, p = 0.34). CONCLUSION: About one third of the injuries previously classified as grade III will be upgraded to grade IV using the 2018 AAST, which adds to the heterogeneity of grade IV injuries. Although the 2018 AAST grading provides more anatomic details on injury patterns and includes important radiologic findings, it did not outperform the 1989 AAST grading in predicting bleeding interventions. LEVEL OF EVIDENCE: Prognostic and Epidemiological Study, level III.

Temporal and Geographic Variation in the Incidence of Alzheimer's Disease Diagnosis in the US between 2007 and 2014.

OBJECTIVES: Our aim was to describe the incidence of Alzheimer's disease (AD) in the United States, overall and by geographic region. DESIGN: We conducted retrospective analyses of administrative claims data for a 5% random sample of US Medicare beneficiaries aged 65 years or older. AD incidence, defined as a diagnosis for AD (International Classification of Disease, Ninth Revision, Clinical Modification code 331.0×) in a given year, with no AD diagnosis in the beneficiary's entire medical history, was estimated for each calendar year between 2007 and 2014. Beneficiaries were required to be enrolled in Medicare for the calendar year of evaluation as well as the preceding 12 months. In addition, a cross-sectional assessment of geographic variation in AD incidence was conducted for 2014. For each population area (specifically, core-based statistical area, as defined by the US Census Bureau), AD incidence was estimated overall, as well as adjusted for differences in underlying patient demographics and metrics of access to care and quality of care. Changes in AD incidence from 2007 were also estimated. SETTING: US fee-for-service Medicare. PARTICIPANTS: US Medicare beneficiaries aged 65 years or older with no history of AD. RESULTS: Overall, the diagnosed incidence of AD decreased over time, from 1.53% in 2007 to 1.09% in 2014; trends were similar for most population areas. In 2014, the rates of AD incidence ranged from 0% to more than 3% across population areas, with the highest observed incidence rates in areas of the Midwest and the South. Statistical models explain little of the geographic variation, although following adjustment, the incidence rates increased the most (in relative terms) in rural areas of western states. CONCLUSION: Our findings are consistent with previously reported estimates of incidence of AD in the United States and its recent declining trend. Additionally, the study highlights the considerable geographic variation in the incidence of AD in the United States and suggests that further research is needed to better understand the determinants of this geographic variation. J Am Geriatr Soc 68:346-353, 2020.