Selecting postoperative adjuvant systemic therapy for early-stage breast cancer: An updated assessment and systematic review of leading commercially available gene expression assays.

Gene expression assays (GEAs) can guide treatment for early-stage breast cancer. Several large prospective randomized clinical trials, and numerous additional studies, now provide new information for selecting an appropriate GEA. This systematic review builds upon prior reviews, with a focus on five widely commercialized GEAs (Breast Cancer Index®, EndoPredict®, MammaPrint®, Oncotype DX®, and Prosigna®). The comprehensive dataset available provides a contemporary opportunity to assess each GEA's utility as a prognosticator and/or predictor of adjuvant therapy benefit.

Activation and On-Scene Intervals for Severe Trauma EMS Interventions: An Analysis of the NEMSIS Database.

Objective: Time to care is a determinant of trauma patient outcomes, and timely delivery of trauma care to severely injured patients is critical in reducing mortality. Numerous studies have analyzed access to care using prehospital intervals from a Carr et al. meta-analysis of studies from 1975 to 2005. Carr et al.'s research sought to determine national mean activation and on-scene intervals for trauma patients using contemporary emergency medical services (EMS) records. Since the Carr et al. meta-analysis was published, the National Highway Traffic Safety Administration (NHTSA) created and refined the National Emergency Medical Services Information System (NEMSIS) database. We sought to perform a modern analysis of prehospital intervals to establish current standards and temporal patterns.Methods: We utilized NEMSIS to analyze EMS data of trauma patients from 2016 to 2019. The dataset comprises more than 94 million EMS records, which we filtered to select for severe trauma and stratified by type of transport and rurality to calculate mean activation and on-scene intervals. Furthermore, we explored the impact of basic life support (BLS) and advanced life support (ALS) of ground units on activation and on-scene time intervals.Results: Mean activation and on-scene intervals for ground transport were statistically different when stratified by rurality. Urban, suburban, and rural ground activation intervals were 2.60 ± 3.94, 2.88 ± 3.89, and 3.33 ± 4.58 minutes, respectively. On-scene intervals were 15.50 ± 10.46, 17.56 ± 11.27, and 18.07 ± 16.13 minutes, respectively. Mean helicopter transport activation time was 13.75 ± 7.44 minutes and on-scene time was 19.42 ± 16.09 minutes. This analysis provides an empirically defined mean for activation and on-scene times for trauma patients based on transport type and rurality. Results from this analysis proved to be significantly longer than the previous analysis, except for helicopter transport on-scene time. Shorter mean intervals were seen in ALS compared to BLS for activation intervals, however ALS on-scene intervals were marginally longer than BLS.Conclusions: With the increasing sophistication of geospatial technologies employed to analyze access to care, these intervals are the most accurate and up-to-date and should be included in access to care models.

Prevalence of germline mutations in the TP53 gene in patients with early-onset breast cancer in the Mexican population.

BACKGROUND: Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients. METHODS: We searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control. RESULTS: We identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53. CONCLUSIONS: Among Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.

Developing a National Trauma Research Action Plan: Results from the regulatory challenges Delphi survey.

BACKGROUND: In 2016, the National Academies of Sciences, Engineering, and Medicine issued a report calling for a National Trauma Research Action Plan (NTRAP) requiring a resourced, coordinated, joint approach to trauma care research. The National Academies of Sciences, Engineering, and Medicine report recommended the identification of regulatory barriers to trauma research. The NTRAP Regulatory Challenges Panel of trauma researchers and regulatory professionals was convened to identify the most challenging aspects of regulatory processes involved in conducting research. METHODS: Trauma researchers and regulatory experts were recruited to identify and rate challenging regulatory issues in 2021 to 2022. Challenge statements were developed from a comprehensive scoping review. Panelists rated the challenge level for each statement on a 9-point Likert scale. The Delphi survey was conducted over three online rounds. Consensus was defined a priori as ≥60% agreement. Results of the Delphi survey were presented to the panel during a webinar. Panel participants then participated in breakout sessions to strategize solutions, share lessons learned, and identify where more regulatory guidance is needed. RESULTS: Thirty-eight subject matter experts rated 175 regulatory challenges, of which 141 (81%) reached the consensus threshold. Of the consensus-reaching challenge statements, 42 had a challenge rating of 6 or higher. Among the highest-rated challenges were issues pertaining to conducting prehospital research, exception from informed consent, mistrust of research among various racial and ethnic groups, and issues specific to conducting pediatric trauma research. CONCLUSION: This Delphi survey rated challenges culled from a regulatory literature scoping review. The panel identified the most challenging aspects of human subjects protection while conducting trauma research and recommended strategies and best practices to address them. The findings from this study were used to develop the NTRAP Investigator Toolkit, which is available on the internet as a resource for trauma researchers. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

An executive summary of the National Trauma Research Action Plan.

ABSTRACT: The National Trauma Research Action Plan project successfully engaged multidisciplinary experts to define opportunities to advance trauma research and has fulfilled the recommendations related to trauma research from the National Academies of Sciences, Engineering and Medicine report. These panels identified more than 4,800 gaps in our knowledge regarding injury prevention and the optimal care of injured patients and laid out a priority framework and tools to support researchers to advance this field. Trauma research funding agencies and researchers can use this executive summary and supporting manuscripts to strategically address and close the highest priority research gaps. Given that this is the most significant public health threat facing our children, young adults, and military service personnel, we must do better in prioritizing these research projects for funding and providing grant support to advance this work. Through the Coalition for National Trauma Research, the trauma community is committed to a coordinated, collaborative approach to address these critical knowledge gaps and ultimately reduce the burden of morbidity and mortality faced by our patients.

Access to trauma center care: A statewide system-based approach.

BACKGROUND: Timely access to specialized trauma care is a vital element in patient outcome after severe and critical injury requiring the skills of trauma teams in levels I and II trauma centers to avoid preventable mortality. We used system-based models to estimate timely access to care. METHODS: Trauma system models consisted of ground emergency medical services, helicopter emergency medical services, and designated levels I to V trauma centers were constructed for five states. These models incorporated geographic information systems along with traffic data and census block group data to estimate population access to trauma care within the "golden hour." Trauma systems were further analyzed to identify the optimal location for an additional level I or II trauma center that would provide the greatest increase in access. RESULTS: The population of the states studied totaled 23 million people, of which 20 million (87%) had access to a level I or II trauma center within 60 minutes. Statewide-specific access ranged from 60% to 100%. Including levels III to V trauma centers, access within 60 minutes increased to 22 million (96%), ranging from 95% to 100%. The addition of a levels I and II trauma center in an optimized location in each state would provide timely access to a higher trauma capability for an additional 1.1 million, increasing total access to approximately 21.1 million people (92%). CONCLUSION: This analysis demonstrates that nearly universal access to trauma care is present in these states when including levels I to V trauma centers. However, concerning gaps remain in timely access to levels I and II trauma centers. This study provides an approach to determine more robust statewide estimates of access to care. It highlights the need for a national trauma system, one in which all components of state-managed trauma systems are assembled in a national data set to accurately identify gaps in care. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Regulatory challenges in conducting human subjects research in emergency settings: the National Trauma Research Action Plan (NTRAP) scoping review.

The complexity of the care environment, the emergent nature, and the severity of patient injury make conducting clinical trauma research challenging. These challenges hamper the ability to investigate potentially life-saving research that aims to deliver pharmacotherapeutics, test medical devices, and develop technologies that may improve patient survival and recovery. Regulations intended to protect research subjects impede scientific advancements needed to treat the critically ill and injured and balancing these regulatory priorities is challenging in the acute setting. This scoping review attempted to systematically identify what regulations are challenging in conducting trauma and emergency research. A systematic search of PubMed was performed to identify studies published between 2007 and 2020, from which 289 articles that address regulatory challenges in conducting research in emergency settings were included. Data were extracted and summarized using descriptive statistics and a narrative synthesis of the results. The review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. Most articles identified were editorial/commentary (31%) and published in the USA (49%). Regulatory factors addressed in the papers were categorized under 15 regulatory challenge areas: informed consent (78%), research ethics (65%), institutional review board (55%), human subjects protection (54%), enrollment (53%), exception from informed consent (51%), legally authorized representative (50%), patient safety (41%), community consultation (40%), waiver of informed consent (40%), recruitment challenges (39%), patient perception (30%), liability (15%), participant incentives (13%), and common rule (11%). We identified several regulatory barriers to conducting trauma and emergency research. This summary will support the development of best practices for investigators and funding agencies.

Multi-Institutional Multidisciplinary Injury Mortality Investigation in the Civilian Pre-Hospital Environment (MIMIC): a methodology for reliably measuring prehospital time and distance to definitive care.

The detailed study of prehospital injury death is critical to advancing trauma and emergency care, as circumstance and causality have significant implications for the development of mitigation strategies. Though there is no true 'Golden Hour,' the time from injury to care is a critical element in the analysis matrix, particularly in patients with severe injury. Currently, there is no standard method for the assessment of time to definitive care after injury among prehospital deaths. This article describes a methodology to estimate total prehospital time and distance for trauma patients transported via ground emergency medical services and helicopter emergency medical services using a geographic information system. Data generated using this method, along with medical examiner and field investigation reports, will be used to estimate the potential survivability of prehospital trauma deaths occurring in five US states and the District of Columbia as part of the Multi-Institutional Multidisciplinary Injury Mortality Investigation in the Civilian Pre-Hospital Environment study. One goal of this work is to develop standard metrics for the assessment of total prehospital time and distance, which can be used in the future for more complex spatial analyses to gain a deeper understanding of trauma center access. Results will be used to identify high priority areas for research and development in injury prevention, trauma system performance improvement, and public health.

The effectiveness of a pain and anxiety protocol to treat the acute pediatric burn patient.

This retrospective review of 286 acute pediatric burn survivors treated in 2001 evaluated the effectiveness of a pharmacotherapeutic protocol for pain, anxiety, and itching. Background pain, procedural pain, exercise pain, anxiety, incidence of acute stress disorder (ASD), and itch were measured with standardized instruments. When this review was compared to similar reviews done in 1993-1994 and 1998, a steady trend toward using more potent pain medications in this patient population is evident. While the use of acetaminophen alone decreased from 50.6% of patients in 1993-1994 and 26.3% in 1998 to 7.3% in 2001, the use of opiates increased from 44.8% in 1993-1994 and 66.9% in 1998 to 81.3% of patients in 2001. Likewise, the use of benzodiazepines for anxiety has increased from 59.8% in 1998 to 77.5% of patients in 2001. During that same period the incidence of ASD decreased from 12.1% in 1993-1994 to 8.7% of patients in 2001. For effective pain and anxiety management, the average administered dose of lorazepam and morphine also increased, providing impetus to revise the pharmacotherapeutic pain protocol. Having a standard pain protocol furnishes a framework for periodic review and facilitates updating of pain and anxiety treatment practices.

Early treatment of acute stress disorder in children with major burn injury.

OBJECTIVE: This study examines retrospectively the response rate of pediatric burn survivors with acute stress disorder to either imipramine or fluoxetine. METHODS: On retrospective chart review, 128 intensive care unit patients (85 boys, 43 girls) with 52%+/- 20% total body surface area burn, length of stay of 32.8+/- 25.2 days, mean age of 9.1+/- 4.7 yrs, and age range of 13 months to 19 yrs met criteria for acute stress disorder after >or=2 days of symptoms and were treated with either imipramine or fluoxetine. If significant improvement did not occur within 7 days, the medication was either increased or switched to the other class. RESULTS: Initially, 104 patients were treated with imipramine and 24 with fluoxetine. A total of 84 patients responded to imipramine: seven of these patients required a higher dose. A total of 18 patients responded to initial fluoxetine treatment. Of 26 nonresponders to the initial medication, 13 imipramine failures and one fluoxetine failure refused further treatment. The other 12 responded to the second medication. Therefore, 114 of 128 treated patients (89%) responded to either fluoxetine (mean dose, 0.30+/- 0.14 mg/kg) or imipramine (mean dose, 1.30+/- 0.55 mg/kg). Response was independent of sex and age but was less for those with burns of >60% total body surface area. The side effects of each medication were not significant. Most patients continued treatment for >or=3 months; some required 6 months of treatment before successful discontinuation. CONCLUSIONS: Early treatment of acute stress disorder with either imipramine or fluoxetine is often able to reduce its symptoms. This is a review of a single hospital's experience in managing psychiatric distress in this very high-risk group of burned children. Additional clinical studies are needed before generalizing these findings.

A double-blind study of the analgesic efficacy of oral transmucosal fentanyl citrate and oral morphine in pediatric patients undergoing burn dressing change and tubbing.

Burn wound care is extremely painful. The pain leads to added anxiety and therefore a distressing treatment that can negatively impact healing. Pain and anxiety management with oral transmucosal fentanyl citrate was compared with this institution's standard procedural pain medication, morphine. With a double-blinded, reverse crossover, time-randomized, and placebo-controlled design, the efficacy of morphine and fentanyl citrate was assessed with patients undergoing two consecutive days of tubbing. Pain and anxiety was assessed before, during, and after the tubbing procedure using the Faces Pain Rating Scale (Whaley and Wong, 1987) and the Fear Thermometer (Silverman and Kurtines, 1996). Data were analyzed with repeated measures analysis of variance. Pain and anxiety appeared better managed with fentanyl citrate. Generalization is limited by small sample size, yet findings warrant additional investigation.

The use of haloperidol and associated complications in the agitated, acutely ill pediatric burn patient.

The use of haloperidol to induce sedation and control agitation in the acutely ill adult patient has been well documented. There are few reports, however, of the use of this neuroleptic agent to control the severe delirium and agitation that may occur in critically ill pediatric patients or acute pediatric patients suffering from burn wounds. We assessed the effectiveness and safety of the use of haloperidol by completing a retrospective chart review of 855 acutely ill children treated consecutively during the period from April 1999 to May 2002, during which time 26 children received haloperidol. The safe use of haloperidol was assessed by documenting any adverse effects or reactions observed after the administration of the drug. Of patients given haloperidol, 23% had adverse effects. This result suggests that the use of haloperidol to treat the acutely agitated and delirious pediatric burn patients is fraught with a number of difficulties and is not completely safe and effective.

Development and implementation of a curricular-wide electronic portfolio system in a school of pharmacy.

The Feik School of Pharmacy collaborated with a commercial software development company to create a Web-based e-portfolio system to document student achievement of curricular outcomes and performance in pharmacy practice experiences. The multi-functional system also could be used for experiential site selection and assignment and continuing pharmacy education. The pharmacy school trained students, faculty members, and pharmacist preceptors to use the e-portfolio system. All pharmacy students uploaded the required number of documents and assessments to the program as evidence of achievement of each of the school's curricular outcomes and completion of pharmacy practice experiences.

Treating thermally injured children suffering symptoms of acute stress with imipramine and fluoxetine: a randomized, double-blind study.

INTRODUCTION: For pediatric burn patients with the symptoms of acute stress disorder (ASD) a first line medication is not widely agreed upon. A prospective, randomized, placebo controlled, double-blind design was used to test the efficacy of imipramine and fluoxetine. METHOD: Patients 4-18 years of age with symptoms of ASD were randomized to 1 of 3 groups: imipramine, fluoxetine, or placebo for 1 week. Daily imipramine dose was 1mg/kg, with the maximum dose being 100mg. Daily fluoxetine dose was 5mg for children weighing >or=40 kg; 10mg for those weighing between 40 and 60 kg; 20mg for those weighing >60 kg. RESULTS: Sixty participants, 16 females and 44 males, had an average body surface area burn of 53% (S.D.=18) and average age of 11 years (S.D.=4). Imipramine subjects received an average daily dose of 1.00+/-0.29 mg/kg. Fluoxetine subjects received an average daily dose of 0.29+/-0.16 mg/kg. Between group differences were not detected. Fifty-five percent responded positively to placebo; 60% responded positively to imipramine; and 72% responded positively to fluoxetine. CONCLUSION: Within the parameters of this study design and sample, placebo was statistically as effective as either drug in treating symptoms of ASD.

Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial.

Severe burns induce pathophysiologic problems, among them catabolism of lean mass, leading to protracted hospitalization and prolonged recovery. Oxandrolone is an anabolic agent shown to decrease lean mass catabolism and improve wound healing in the severely burned patients. We enrolled 81 adult subjects with burns 20% to 60% TBSA in a multicenter trial testing the effects of oxandrolone on length of hospital stay. Subjects were randomized between oxandrolone 10 mg every 12 hours or placebo. The study was stopped halfway through projected enrollment because of a significant difference between groups found on planned interim analysis. We found that length of stay was shorter in the oxandrolone group (31.6 +/- 3.1 days) than placebo (43.3 +/- 5.3 days; P < .05). This difference strengthened when deaths were excluded and hospital stay was indexed to burn size (1.24 +/- 0.15 days/% TBSA burned vs 0.87 +/- 0.05 days/% TBSA burned, P < .05). We conclude that treatment using oxandrolone should be considered for use in the severely burned while hepatic transaminases are monitored.

Congenital thrombophilia associated to obstetric complications.

During pregnancy there are hemostatic changes that result in a hypercoagulable state and can have thrombotic consequences. This condition can be aggravated in women who are carriers of congenital thrombophilic factors. This thrombotic tendency can manifest as thrombotic lesions in the placenta with compromise of utero-placental circulation, which are common characteristics present in obstetric complications, such as preeclampsia/eclampsia, miscarriage, fetal loss, intrauterine growth retardation, and abruptio placentae. In this paper we review data concerning about the association of congenital thrombophilia in pregnancy with obstetric complications, mainly preeclampsia and fetal loss, focusing in factor V Leiden and its related activated protein C resistance, prothrombin mutation G20210A and hyperhomocysteinemia related with C677T mutation of methylenetetrahydrofolate reductase. Although factor V Leiden has been the thrombophilic factor most studied, all three thrombophilic mutations have been related with obstetric complications; however, contradictory results about the specific association of each mutation with each type of obstetric complication are described. These discrepancies could obey to the ethnic difference of the studied groups, or to the fact that some studies were performed in closed populations with few migratory movement, where the genetic pool is relatively homogeneous, as well as the different inclusion and exclusion criteria. Even though this variability is present, the significance of recognizing true associations between these thrombophilic mutations and obstetric complications is essential in order to determine the likelihood of routinely screening for these conditions in pregnant women with risk factors for thrombosis and for carrying out specific prophylactic measures.