Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A.

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for the treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5-capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-γ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A.

INTRODUCTION: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation. AIM: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec. METHODS: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion. RESULTS: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals. CONCLUSION: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.

Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.

INTRODUCTION: Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection. AIM: To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment. METHODS: In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported. RESULTS: No new treatment-related safety signals emerged. During year 6, a participant in the 6 × 1013  vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10-5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints. CONCLUSIONS: Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.

The Use of Parenteral Nutrition and Disparities in Its Allocation Following Traumatic Injury.

INTRODUCTION: Severe traumatic injury requires rapid and extensive deployment of resources to save the lives of the critically injured. The sequelae of traumatic injuries frequently require extensive intervention obligating patients to a complicated recovery process devoid of meaningful nutrition. In this setting, parenteral nutrition (PN) is key in enabling appropriate wound healing, recovery, and rehabilitation. We sought to examine the use of PN in adult trauma management and to highlight any disparities in the utilization of PN in adult trauma patients. METHODS: We queried the 2017-2019 Trauma Quality Improvement Program (TQIP) for adult patients (aged > 18 y) who sustained blunt or penetrating traumatic injuries and received PN as part of their hospitalization. We compared time to PN administration based on demographics. We then used a multivariable logistic regression model to identify factors associated with the use of PN. We hypothesized that PN would be less commonly employed in the uninsured and minority groups. RESULTS: We identified 2,449,498 patients with sufficient data for analysis. Of these, 1831 patients were treated with PN. On univariate analysis, PN patients were more commonly male (74.7% PN versus 60.2% non-PN; P < 0.001). PN use was more frequent in the Black population (24.3% PN versus 15.5% non-PN; P < 0.001) and less frequent in the White population (72.7% PN versus 81.2% non-PN; P < 0.001). PN use was also much more common among patients covered by Medicaid. Penetrating trauma was over twice as common among PN recipients relative to non-PN patients (% PN versus % non-PN). PN patients had higher injury severity scores (ISSs), more intensive care unit days, longer hospitalizations, and increased mortality compared to non-PN patients. PN patients were half as likely to discharge home and twice as likely to discharge to a long-term care facility. Multivariable analysis including age, race, trauma mechanism, primary payer, and ISS, demonstrated an association of PN use with increasing age (OR 1.01, P < 0.001), cases of penetrating trauma (odds ratio [OR], 2.47; P < 0.001), and patients with high ISS (OR, 0.1.06; P < 0.001). There was decreased use in Uninsured patient (OR, 0.54; P < 0.001). CONCLUSIONS: PN use following traumatic injury is rarely required. Patients treated with PN typically have a resource-intense hospital course. More severe injuries, penetrating trauma, and increased age are more likely to result in PN use. Variations in PN use are apparent based on insurance payer, further examination into allocation of hospital and intensive care resources, as it pertains to patient socioeconomic status, is warranted in light of these findings.

Firearm Ownership: A Key Factor to Consider in Firearm Suicide Deaths in Children, Despite State Gun Laws.

INTRODUCTION: Firearm-related suicides among children present a significant public health concern and a tragic loss of young lives. This study explores the relationship between firearm-related suicides, gun ownership, and state-specific gun laws. METHODS: This retrospective cohort study collected data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research on children under 18 who died by firearm-related suicides between 2009 and 2016 in all 50 states and D.C. It also utilized data from the RAND State-Level Estimates of Household Firearm Ownership. The study focused on the rate of child firearm suicide deaths per 100,000 individuals. The key variable of interest was the percentage of guns owned per household in each state. Univariable analysis was conducted to examine the association between individual gun laws and child firearm suicide mortalities, while multivariable regression, adjusting for household gun ownership and significant firearm legislation, was employed to assess connection to child firearm suicide mortality. RESULTS: From 2009 to 2016, 3903 children died from firearm-related suicides in the United States. In our analysis, 15 out of 44 firearm laws were found to be associated with reducing the rates of firearm suicides among children (P < 0.05). However, multivariable regression showed that higher state gun ownership rates were the primary predictor of increased child fatalities from firearms, with children in such states being 325% more likely to die when analyzing handgun laws and 337% more likely when analyzing long gun laws, as indicated by coefficients of 4.25 and 4.37, respectively. No state laws alone notably improved death rates. CONCLUSIONS: Gun ownership has a stronger association with child suicide rates than state-specific gun laws. Given the weight of gun ownership, future research should prioritize comprehensive public health initiatives to prevent child firearm-related suicides.

Factors Associated with Discharge to Skilled Nursing Facility Following Gunshot Wounds.

INTRODUCTION: Firearm injury is a public health crisis. Most victims are minorities in underserved neighborhoods. Measuring firearm injury by mortality underestimates its impact, as most victims survive to discharge. This study was done to determine if race and insurance status are associated with discharge disposition for gunshot wound (GSW)-related trauma. METHODS: Using the 2019 Trauma Quality Improvement Program database, we identified GSW patients with Abbreviated Injury Scale (AIS) = 1-3. Exclusion criteria included patients who died in hospital and routine home discharge. We compared discharge patterns of patients based on demographics (age, gender, race, ethnicity, payor, AIS, hospital designation, and length of stay [LOS]) and injury severity. Multivariable logistic regression models identified factors associated with discharge disposition. RESULTS: Our sample included 2437 patients with GSWs. On univariable analysis, Black patients were more likely to discharge to home with home health (64.1% Black versus 34.7% White; P < 0.001). White patients were more likely to discharge to skilled nursing facility (SNF) (51.4% White versus 44.6% Black; P < 0.001). Controlling for age, race, Latin ethnicity, primary payor, LOS, AIS severity, and injury severity score factors independently associated with discharge to SNF included age (0.0462, P < 0.001), Medicaid (1.136, P < 0.0003), Medicare (1.452, P < 0.001), and LOS (0.03745, P < 0.001). CONCLUSIONS: Postacute care following traumatic injuries is essential to recovery. Black GSW victims are more likely to be discharged to home health than White patients, who are more likely to be discharged to SNF. Targeted programs to reduce barriers to appropriate aftercare are necessary to eliminate this bias and improve the care of underserved populations.

Systematic Literature Review of Health-Related Quality-of-Life Measures for Caregivers of Older Adult Trauma Patients.

INTRODUCTION: As the older adult population increases, hospitals treat more older adults with injuries. After leaving, these patients suffer from decreased mobility and independence, relying on care from others. Family members often assume this responsibility, mostly informally and unpaid. Caregivers of other older adult populations have increased stress and decreased caregiver-related quality of life (CRQoL). Validated CRQoL measures are essential to capture their unique experiences. Our objective was to review existing CRQoL measures and their validity in caregivers of older adult trauma patients. METHODS: A professional librarian searched published literature from the inception of databases through August 12, 2022 in MEDLINE (via PubMed), Embase (via Elsevier), and CINAHL Complete (via EBSCO). We identified 1063 unique studies of CRQoL in caregivers for adults with injury and performed a systematic review following COnsensus-based Standards for the selection of health Measurement Instruments guidelines for CRQoL measures. RESULTS: From the 66 studies included, we identified 54 health-related quality-of-life measures and 60 domains capturing caregiver-centered concerns. The majority (83%) of measures included six or fewer CRQoL content domains. Six measures were used in caregivers of older adults with single-system injuries. There were no validated CRQoL measures among caregivers of older adult trauma patients with multisystem injuries. CONCLUSIONS: While many measures exist to assess healthcare-related quality of life, few, if any, adequately assess concerns among caregivers of older adult trauma patients. We found that CRQoL domains, including mental health, emotional health, social functioning, and relationships, are most commonly assessed among caregivers. Future measures should focus on reliability and validity in this specific population to guide interventions.

Outcomes by time-to-OR for penetrating abdominal trauma patients.

INTRODUCTION: Time-To-OR is a critical process measure for trauma performance. However, this measure has not consistently demonstrated improvement in outcome. STUDY DESIGN: Using TQIP, we identified facilities by 75th percentile time-to-OR to categorize slow, average, and fast hospitals. Using a GEE model, we calculated odds of mortality for all penetrating abdominal trauma patients, firearm injuries only, and patients with major complication by facility speed. We additionally estimated odds of mortality at the patient level. RESULTS: Odds of mortality for patients at slow facilities was 1.095; 95% CI: 0.746, 1.608; p = 0.64 compared to average. Fast facility OR = 0.941; 95% CI: 0.780, 1.133; p = 0.52. At the patient-level each additional minute of time-to-OR was associated with 1.5% decreased odds of in-hospital mortality (OR 0.985; 95% CI:0.981, 0.989; p < 0.001). For firearm-only patients, facility speed was not associated with odds of in-hospital mortality (p-value = 0.61). Person-level time-to-OR was associated with 1.8% decreased odds of in-hospital mortality (OR 0.982; 95% CI: 0.977, 0.987; p < 0.001) with each additional minute of time-to-OR. Similarly, failure-to-rescue analysis showed no difference in in-hospital mortality at the patient level (p = 0.62) and 0.4% decreased odds of in-hospital mortality with each additional minute of time-to-OR at the patient level (OR 0.996; 95% CI: 0.993, 0.999; p = 0.004). CONCLUSION: Despite the use of time-to-OR as a metric of trauma performance, there is little evidence for improvement in mortality or complication rate with improved time-to-OR at the facility or patient level. Performance metrics for trauma should be developed that more appropriately approximate patient outcome.

A National Comparison of Volume and Acuity for Adult and Pediatric Trauma: A Trauma Quality Improvement Program Cohort Study.

INTRODUCTION: Most injured children receive trauma care outside of a pediatric trauma center. Differences in physiology, dosing, and injury pattern limit extrapolation of adult trauma principles to pediatrics. We compare US trauma center experience with pediatric and adult trauma resuscitation. MATERIALS AND METHODS: We queried the 2019 Trauma Quality Improvement Program to describe the experience of US trauma centers with pediatric (<15 y) and adult trauma. We quantified blunt, penetrating, burn, and unspecified traumas and compared minor, moderate, severe, and critical traumas (ISS 1-8 Minor, ISS 9-14 Moderate, ISS 15-24 Severe, ISS 25+ Critical). We estimated center-level volumes for adults and children. Institutional identifiers were generated based on unique center specific factors including hospital teaching status, hospital type, verification level, pediatric verification level, state designation, state pediatric designation, and bed size. RESULTS: A total of 755,420 adult and 76,449 pediatric patients were treated for traumatic injuries. There were 21 times as many critical or major injuries in adults compared to children, 17 times more moderate injuries, and 6 times more minor injuries. Children and adults presented with similar rates of blunt trauma, but penetrating injuries were more common in adults and burn injuries were more common in children. Comparing center-level data, adult trauma exceeded pediatric for every severity and mechanism. CONCLUSIONS: There is relatively limited exposure to high-acuity pediatric trauma at US centers. Investigation into pediatric trauma resuscitation education and simulation may promote pediatric readiness and lead to improved outcomes.

Factors Associated With Triage Decisions in Older Adult Trauma Patients: Impact on Mortality and Morbidity.

INTRODUCTION: As medical advances have significantly increased the life expectancy among older adults, the number of older patients requiring trauma care has risen proportionately. Nevertheless, it is unclear among this growing population which sociodemographic and economic factors are associated with decisions to triage and transfer to level I/II centers. This study aims to assess for any association between patient sociodemographic characteristics, triage decisions, and outcomes during acute trauma care presentations. METHODS: The National Trauma Data Bank was queried for patients aged 65 and older with an injury severity score > 15 between the years 2007 to 2017. Factors associated with subsequent levels of triage on presentation were assessed using multivariate logistic regression, and associations of levels of triage with outcomes of mortality, morbidity, and hospital length of stay are examined using logistic and linear regression models. RESULTS: Triage of 210,310 older adult trauma patients showed significant findings. American Indian patients had higher odds of being transferred to level I/II centers, while Asian, Black, and Native Hawaiian patients had lower odds of being transferred to level I/II centers when compared to Caucasian patients (P < 0.001). Regarding insurance, self-pay (uninsured) patients were less likely to be transferred to a higher level of care; however, this was also demonstrated in private insurance holders (P < 0.001). Caucasian patients had significantly higher odds of mortality, with Black patients (odds ratio [OR] 0.80 [0.75, 0.85]) and American Indian patients (OR 0.87 [0.72, 1.04]) having significantly lower odds (P < 0.001). Compared to government insurance, private insurance holders (OR 0.82 [0.80, 0.85]) also had significantly lower odds of mortality, while higher odds among self-pay were observed (OR 1.75 [1.62, 1.90]), (P < 0.001). CONCLUSIONS: Access to insurance is associated with triage decisions involving older adults sustaining trauma, with lower access increasing mortality risk. Factors such as race and gender were less likely to be associated with triage decisions. However, due to this study's retrospective design, further prospective analysis is necessary to fully assess the decisions that influence trauma triage decisions in this patient population.

Development of a prospective biliary dashboard to compare performance and surgical cost.

BACKGROUND: Transparency around surgeon level data may align healthcare delivery with quality care for patients. Biliary surgery includes numerous procedures performed by both general surgeons and subspecialists alike. Cholecystectomy is a common surgical procedure and an optimal cohort to measure quality outcomes within a healthcare system. METHODS: Data were collected for 5084 biliary operations performed by 68 surgeons in 11 surgical divisions in a health system including a tertiary academic hospital, two regional community hospitals, and two ambulatory surgery centers. A privacy protected dashboard was developed to compare surgeon performance and cost between July 2018 and June 2022. A sample cohort of patients ≥ 18 years who underwent cholecystectomy were compared by operative time, cost, and 30-day outcomes. RESULTS: Over 4 years, 4568 cholecystectomy procedures were performed by 57 surgeons. Operations were done by 57 surgeons in four divisions and included 3846 (84.2%) laparoscopic cholecystectomies, 601 (13.2%) laparoscopic cholecystectomies with cholangiogram, and 121 (2.6%) open cholecystectomies. Patients were admitted from the emergency room in 2179 (47.7%) cases while 2389 (52.3%) cases were performed in the ambulatory setting. Individual surgeons were compared to peers for volume, intraoperative data, cost, and outcomes. Cost was lowest at ambulatory surgery centers, yet only 4.2% of elective procedures were performed at these facilities. Prepackaged kits with indocyanine green were more expensive than cholangiograms that used iodinated contrast. The rate of emergency department visits was lowest when cases were performed at ambulatory surgery centers. CONCLUSION: Data generated from clinical dashboards can inform surgeons as to how they compare to peers regarding quality metrics such as cost, time, and complications. In turn, this may guide strategies to standardize care, optimize efficiency, provide cost savings, and improve outcomes for cholecystectomy procedures. Future application of clinical dashboards can assist surgeons and administrators to define value-based care.

Trends in Assault Mortalities Among Asian Americans, 2009-2018.

INTRODUCTION: As of yet, few studies have described the prevalence or rates of assault mortalities involving Asian victims on a national level. This study aimed to describe yearly trends and regional differences in assault mortalities among Asians. METHODS: This repeat cross-sectional study from 2009 to 2018 used data from the Mortality Multiple Cause-of-Death Public Use Record from the National Center for Health Statistics and the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research. Total and proportion of assault mortalities involving Asians or Pacific Islanders were calculated by year. Total and rates (per 100,000 Asians or Pacific Islanders) of assault mortalities among Asians or Pacific Islanders were stratified by state and county classification where deaths occurred. RESULTS: In 2009, 344 assault mortalities among Asians or Pacific Islanders accounted for 2.07% of assault-related deaths. In 2018, 366 assault mortalities among Asians or Pacific Islanders accounted for 1.96% of assault-related deaths. Furthermore, there were more assault mortalities from 2009 to 2018 among Asians or Pacific Islanders in California (n = 1116) and large central metropolitan counties (n = 1707). However, the highest rates of assault mortalities were in Alaska and Mississippi (7.1 and 6.8 per 100,000, respectively) and noncore nonmetropolitan counties (2.9 per 100,000). CONCLUSIONS: These findings emphasize the importance of studying and addressing violence toward Asians in rural regions and Southern states. Future studies should use these results as a baseline to analyze mortality data from 2019 to 2021, when available, to examine the coronavirus disease 2019 pandemic's impact on assault mortalities among Asian.

Racial Differences in Firearms Used and Autopsies Following Gun Deaths Exist.

INTRODUCTION: Disparities in gun violence across race are well documented. Studying these disparities is essential to reduce preventable gun deaths. This study evaluates the relationship between sociodemographic factors and firearms used in gun deaths. MATERIALS AND METHODS: This retrospective cohort study of firearm mortalities from 2009 to 2018 used the Mortality Multiple Cause-of-Death Public Use Record from the National Center for Health Statistics. The primary outcome was the type of firearm used and the secondary outcome was autopsy status. Factors of interest include race, ethnicity, gender, marital status, age, education, and place of death. Factors significantly associated with outcomes in univariate analyses were included in separate multivariate logistic regression models for assaults, intentional self-harm, and accidents. RESULTS: A total of 276,127 firearm deaths from 2009 to 2018 were analyzed. Compared to White victims, Black victims were less likely to die from handguns (accident: odds ratio [OR] = 0.70, P < 0.05; self-harm: OR = 0.84, P < 0.001; assault: OR = 0.58, P < 0.001) and rifles, shotguns, or large firearms (accident: OR = 0.30, P < 0.001; self-harm: OR = 0.37, P < 0.001; assault: OR = 0.28, P < 0.001). Black decedents were more likely to undergo autopsy than White decedents (accident: OR = 2.14, P < 0.001; intentional self-harm: OR = 2.02, P < 0.001; assault: OR = 2.02, P < 0.001). Ethnicity, gender, marital status, age, education, and other racial identities were also associated with firearms used and autopsy rates (P < 0.05). CONCLUSIONS: Differences in firearms used and autopsy rates following gun deaths exist by race, ethnicity, gender, marital status, age, and education. Future studies should investigate the relationship between sociodemographic factors and firearms used and autopsy status following gun deaths.

Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy.

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.

Race and Insurance Status as Predictors of Bicycle Trauma Outcome in Adults.

BACKGROUND: Race and insurance status have been shown to predict outcomes in pediatric bicycle traumas. It is unknown how these factors influence outcomes in adult bicycle traumas. This study aims to evaluate the association, if any, between race and insurance status with mortality in adults. METHODS: This retrospective cohort study used the National Trauma Data Bank Research Data Set for the years 2013-2015. Multivariate logistic regression models were used to determine the independent association between patient race and insurance status on helmet use and on outcomes after hospitalization for bicycle-related injury. These models adjusted for demographic factors and comorbid variables. When examining the association between race and insurance status with outcomes after hospitalization, injury characteristics were also included. RESULTS: A study population of 45,063 met the inclusion and exclusion criteria. Multivariate regression demonstrated that black adults and Hispanic adults were significantly less likely to be helmeted at the time of injury than white adults [adjusted odds ratio of helmet use for blacks 0.25 (95% CI 0.22-0.28) and for Hispanics 0.33 (95% CI 0.30-0.36) versus whites]. Helmet usage was also independently associated with insurance status, with Medicare-insured patients [AOR 0.51 (95% CI 0.47-0.56) versus private-insured patients], Medicaid-insured patients [AOR 0.18 (95% CI 0.17-0.20)], and uninsured patients [AOR 0.29 (95% CI 0.27-0.32)] being significantly less likely to be wearing a helmet at the time of injury compared with private-insured patients. Although patient race was not independently associated with hospital mortality among adult bicyclists, we found that uninsured patients had significantly higher odds of mortality [AOR 2.02 (AOR 1.31-3.12)] compared with private-insured patients. CONCLUSIONS: Minorities and underinsured patients are significantly less likely to be helmeted at the time of bicycle-related trauma when compared with white patients and those with private insurance. Public health efforts to improve the utilization of helmets during bicycling should target these subpopulations.

The Impact of Nonsteroidal Anti-inflammatory Drugs on Older Adult Trauma Patients With Hip Fractures.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use is frequently recommended for multimodal analgesia to reduce opioid use. We hypothesized that increased NSAID utilization will decrease opioid requirements without leading to significant complications in older adult trauma patients undergoing hip fracture repair. METHODS: An observational cross-sectional cohort study of 190,057 adult trauma patients over a 6-y period (2008-2014) in the national Premier Healthcare Database was performed. Patients aged 65 or older undergoing femur repair and hip arthroplasty following fractures due to falls were analyzed. Primary outcome was opioid use, and secondary outcomes included transfusion requirements, length of stay (LOS), and organ system dysfunction. Continuous outcomes were analyzed using mixed-effect linear regression models to assess the effect of NSAIDs on the day of surgery. Fixed effects were included for patient and hospital characteristics, comorbidities, co-treatments, and surgery. Random intercepts for each hospital were included to control for clustering. Categorical outcomes were similarly analyzed using mixed-effect logistic regression models. RESULTS: NSAIDs decreased opioids prescribed (12.01 versus 11.43 morphine milligram equivalents) (odds ratio [OR], -0.23; confidence interval [CI] = -0.41, -0.06) without overall increased bleeding (40.83% versus 43.18%; OR, 1.02; CI = 0.99, 1.05). NSAIDs were associated with reduced LOS (5.61 versus 5.96 d; CI = -0.24, -0.12), intensive care unit admissions (9.73% versus 10.59%; OR, 0.91; CI = 0.86, 0.96), and pulmonary complications (OR, 0.88; CI = 0.83, 0.93). Additionally, there was a 21% prescribing variability based solely on hospital. CONCLUSIONS: NSAIDs were associated with decreased opioid requirements, hospital LOS, and intensive care unit admissions in older adult trauma patients without overall increase in bleeding. NSAIDs should be considered in multimodal pain regimens, moreover, given prescribing variability guidelines are needed. LEVEL OF EVIDENCE: Level III, Prognostic.

"I'm Leaving": Factors That Impact Against Medical Advice Disposition Post-Trauma.

BACKGROUND: Discharge against medical advice (AMA) is an important, yet understudied, aspect of health care-particularly in trauma populations. AMA discharges result in increased mortality, increased readmission rates, and higher health care costs. OBJECTIVE: The goal of this analysis was to determine what factors impact a patient's odds of leaving the hospital prior to treatment. METHODS: We performed a retrospective analysis of the National Trauma Data Bank on adult trauma patients (older than 14 years) from 2013 to 2015. Of the 1,770,570 patients with known disposition, excluding mortality, 24,191 patients (1.4%) left AMA. We ascertained patient characteristics including age, sex, race, ethnicity, insurance status, ETOH, drug use, geographic location, Injury Severity Score (ISS), injury mechanism, and anatomic injury location. Multivariate logistic regression models were used to determine which patient factors were associated with AMA status. RESULTS: Uninsured (odds ratio [OR] 2.72; 95% confidence interval [CI] 2.58-2.86) or Medicaid-insured (OR 2.50; 95% CI 2.37-2.63) trauma patients were significantly more likely to leave AMA than patients with private insurance. Compared to white patients, African-American patients (OR 1.06; 95% CI 1.02-1.11) were more likely, and Native-American (OR 0.62; 95% CI 0.52-0.75), Asian (OR 0.59; 95% CI 0.49-0.69), and Hispanic (OR 0.80; 95% CI 0.75-0.85) patients were less likely, to leave AMA when controlling for age, sex, ISS, and type of injury. CONCLUSIONS: Insurance status, race, and ethnicity are associated with a patient's decision to leave AMA. Uninsured and Medicaid patients have more than twice the odds of leaving AMA. These findings demonstrate that racial and socioeconomic disparities are important targets for future efforts to reduce AMA rates and improve outcomes from blunt and penetrating trauma.

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.

Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure-response analysis.

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

What's in a Name? Provider Perception of Injured John Doe Patients.

BACKGROUND: We previously demonstrated that unidentified aliased patients, John Doe's (DOEs), are one of the highest risk and most medically fragile populations of injured patients. Aliasing can result in misplaced information and confusion that must be overcome by health care professionals. DOE alias use is institutionally dependent and not uniform, which may lead to significant variation in perception of confusion and error. We sought to determine if health care practitioners experience confusion that may result in compromised care when caring for injured DOE patients. METHODS: After obtaining institutional review board approval, we surveyed critical care nurses, nurse practitioners, resident physicians, and surgeons who care for DOE patients at two academic level I trauma centers with separate DOE alias practices. Surveys asked whether caring for DOE patients created possible or actual confusion and possible or actual patient care errors. In one institution (Selective DOE), only unidentified patients were given an alias that was reconciled when information became available. At the other institution (All DOE), all trauma patients were admitted with an alias that was reconciled within 24 h. Respondents were invited to complete an anonymous questionnaire regarding the care for DOE patients. Results were analyzed with Wilcoxon rank-sum tests, and significance was assessed at a level of 0.05. RESULTS: Of 176 total respondents, 120 (68.2%) reported from Selective DOE and 56 (31.8%) from All DOE. Overall 53.1% reported that DOE use can cause serious confusion. Specifically, 31.3% reported experiencing actual confusion, although only 4% reported actual errors. Nurses had significantly higher perceived risk of confusion in the system of All DOE versus Selective DOE assignment (17.9% versus 4.2%, P < 0.01). Resident physicians reported significantly more frequent actual mistakes within the All DOE versus Selective DOE (24.1% versus 6.6%, P < 0.01), despite finding no significant difference in resident perception of confusion (21.4% versus 12.5%, respectively, P = 0.18). CONCLUSIONS: Our study sheds light on clinical consequences of EMR use and aliases for end users. We show that nurses perceive that there are greater potential complications associated with DOE aliases use, and this varies depending on the system used for managing unidentified patients. Minimizing DOE alias use may help to minimize provider confusion, risk for error, and patient safety.