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.

SIRT1 downregulation in pneumonia is associated with an immature neutrophil response and increased disease severity.

BACKGROUND: Pneumonia remains a common complication in trauma patients. Sirtuin 1 (SIRT1) is an anti-inflammatory NAD + -dependent deacetylase that has been shown to reduce the severity of ARDS in polymicrobial sepsis. The impact of SIRT1 in acute pneumonia, however, remains unknown. We hypothesized that SIRT1 deletion in pneumonia would worsen the inflammatory response and clinical severity, and that increased SIRT1 expression would be protective. METHODS: Ten- to 14-week-old male and female SIRT1 knockout (S1KO) mice, SIRT1 overexpressor (S1OE) mice, and their wildtype (WT) littermates underwent intra-tracheal inoculation with Pseudomonas aeruginosa . Rectal temperature was recorded, SIRT1 lung protein was quantified by western blotting, Sirt1 mRNA was measured by qPCR, and lung leukocyte subpopulations were analyzed by flow cytometry. Data were analyzed by one-way ANOVA using Prism software. RESULTS: Pneumonia created a functional SIRT1 knockdown in the lungs of WT mice by 4 hours, resulting in comparable SIRT1 levels and temperatures to the S1KO mice by 12 hours. Pneumonia also partially reduced SIRT1expression in S1OE mice, but S1OE mice still had improved thermoregulation 12 hours after pneumonia. In all groups, Sirt1 mRNA expression was not affected by infection. Sirtuin 1 deletion was associated with decreased neutrophil infiltration in the lung, as well as a shift toward a more immature neutrophil phenotype. SIRT1 deletion was also associated with decreased myeloperoxidase-positive neutrophils in the lungs following pneumonia, indicating decreased neutrophil activity. S1OE mice had no change in lung leukocyte subpopulations when compared to WT. CONCLUSION: Pneumonia creates a functional SIRT1 knockdown in mice. SIRT1 deletion altered the early inflammatory cell response to pneumonia, resulting in a neutrophil response that would be less favorable for bacterial clearance. Despite overexpression of SIRT1, S1OE mice also developed low SIRT1 levels and exhibited only minimal improvement. This suggests increasing SIRT1 transcription is not sufficient to overcome pneumonia-induced downregulation and has implications for future treatment options. Targeting SIRT1 through increasing protein stability may promote a more efficient inflammatory cell response to pneumonia, thereby preventing subsequent lung injury.

Sirt3 Deletion Increases Inflammation and Mortality in Polymicrobial Sepsis.

Background: Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that confers resilience to cellular stress by promoting mitochondrial activity. Mitochondrial dysfunction is a major driver of inflammation during sepsis. We hypothesize that Sirt3 expression improves survival in polymicrobial sepsis by mitigating the inflammatory response. Materials and Methods: Sirt3 knockout (S3KO) and wild-type (WT) mice underwent cecal ligation and puncture (CLP) or sham surgery. mRNA expression was quantified using quantitative polymerase chain reaction (qPCR) and protein expression was quantified using enzyme-linked immunosorbent assay (ELISA). Spectrophotometric assays were used to quantify serum markers of organ dysfunction. For in vitro studies, bone marrow-derived macrophages (BMDMs) were harvested from S3KO and WT mice and treated with lipopolysaccharide (LPS). Results: After CLP, hepatic Sirt3 levels decreased from baseline by nine hours and remained depressed at 24 hours. Peak serum interleukin-6 (IL-6) protein levels were higher in S3KO mice. In LPS-treated BMDMs, IL-6 mRNA levels peaked earlier in S3KO cells, although peak levels were comparable to WT. Although S3KO mice had decreased median survival after CLP compared with WT, there was no difference in five-day survival or organ dysfunction. Conclusions: Although S3KO mice initially had increased inflammation and mortality, this difference abated with time, and overall survival was comparable between the groups. This pattern is consistent with the timeline of sepsis-induced Sirt3 downregulation in WT mice, and suggests that Sirt3 downregulation occurring in sepsis is at least partially responsible for the initial hyperinflammatory response and subsequent mortality. Our data support upregulation of Sirt3 as a promising therapeutic strategy for further research in sepsis.

Coral assemblages at higher latitudes favor short-term potential over long-term performance.

The persistent exposure of coral assemblages to more variable abiotic regimes is assumed to augment their resilience to future climatic variability. Yet, while the determinants of coral population resilience across species remain unknown, we are unable to predict the winners and losers across reef ecosystems exposed to increasingly variable conditions. Using annual surveys of 3171 coral individuals across Australia and Japan (2016-2019), we explore spatial variation across the short- and long-term dynamics of competitive, stress-tolerant, and weedy assemblages to evaluate how abiotic variability mediates the structural composition of coral assemblages. We illustrate how, by promoting short-term potential over long-term performance, coral assemblages can reduce their vulnerability to stochastic environments. However, compared to stress-tolerant, and weedy assemblages, competitive coral taxa display a reduced capacity for elevating their short-term potential. Accordingly, future climatic shifts threaten the structural complexity of coral assemblages in variable environments, emulating the degradation expected across global tropical reefs.

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.

Fatal opioid overdoses geospatially cluster with level 1 trauma centers in Ohio.

OBJECTIVE: Ohio is consistently ranked as one of the worst states for opioid overdose deaths. Traumatic injury has been linked to opioid overdose deaths, yet the location of trauma centers has not been explored. We examined whether geospatial clustering occurred between county-level opioid overdose deaths (OODs) and trauma center levels. METHODS: We obtained 2019 county-level data from the Ohio Department of Health for fatal overdoses from prescription opioids. We obtained the total number of opioid doses prescribed in 2019 per county from the Ohio Automated Rx Reporting System and American College of Surgeons designated trauma center locations within Ohio from their website. We used geospatial analysis to assess if clustering occurred between trauma center level and prescription opioid overdose deaths at a county level. RESULTS: There were 42 trauma centers located within 21 counties: 7 counties had level 1, and 14 counties had only level 2/level 3. There was no difference in rates of opioid doses prescribed per 100,000 people between counties with level 1 trauma centers and only level 2/level 3. However, prescription OODs rates were significantly higher in counties with level 1 trauma centers (37.6 vs 20, P = .02). Geospatial clustering was observed between level 1 trauma centers and prescription opioid overdose deaths at the county level (P < .01). CONCLUSION: Geospatial clustering exists between prescription OODs and level 1 trauma center locations in Ohio. Improved at-risk patient identification and targeted community outreach represent opportunities for trauma providers to tackle the opioid epidemic.

Risk Factors for Unplanned ICU Readmission Among Trauma Patients: Age Matters.

To determine the frequency of unplanned ICU readmission (UIR) among adult (18-64) and elderly (65+) trauma patients and to compare the risk factors for UIR and its clinical impact between age groups. DESIGN: Retrospective cohort study using clinical data from a statewide trauma registry. SETTING: All accredited trauma centers in Pennsylvania. PATIENTS: Consecutive adult and elderly trauma patients requiring admission from the emergency department to the ICU between 2012 and 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 48,340 included in the analysis, 49.5% were elderly and 3.8% experienced UIR. UIR was 1.7 times more likely among elderly patients and was associated with increased hospital length of stay in both age groups. UIR was associated with an absolute increased risk of hospital mortality of 6.1% among adult patients and 16.9% among elderly patients experiencing UIR. In addition to overall injury severity and burden of preexisting medical conditions, specific risk factors for UIR were identified in each age group. In adult but not elderly patients, UIR was significantly associated with history of stroke, peptic ulcer disease, cirrhosis, diabetes, and malignancy. In elderly but not adult patients, UIR was also significantly associated with chronic kidney disease. CONCLUSIONS: UIR is associated with worse clinical outcomes in both adult and elderly trauma patients, but risk factors and the magnitude of impact differ between age groups. Interventions to mitigate the risk of UIR that take into account patients' age group and specific risk factors may improve outcomes.

Cost-Effectiveness Analysis of Inguinal Hernia Repair With Mesh Performed by Surgeons and Medical Doctors in Ghana.

OBJECTIVES: Task-sharing is the pragmatic sharing of tasks between providers with different levels of training. To our knowledge, no study has examined the cost-effectiveness of surgical task-sharing of hernia repair in a low-resource setting. This study has aimed to evaluate and compare the cost-effectiveness of mesh repair performed by Ghanaian surgeons and medical doctors (MDs) following a standardized training program. METHODS: This cost-effectiveness analysis included data for 223 operations on adult men with primary reducible inguinal hernia. Cost per surgery was calculated from the healthcare system perspective. Disability weights were calculated using pre- and postoperative pain scores and benchmarks from the Global Burden of Disease Study 2017. RESULTS: The mean cost/disability-adjusted life-year (DALY) averted in the surgeon group was 444.9 United States dollars (USD) (95% confidence interval [CI] 221.2-668.5) and 278.9 USD (95% CI 199.3-358.5) in the MD group (P = .168), indicating that the operation is very cost-effective when performed by both providers. The incremental cost/DALY averted showed that task-sharing with MDs is also very cost-effective (95% bootstrap CI -436.7 to 454.9). The analysis found that increasing provider salaries is cost-effective if productivity remains high. When only symptomatic cases were analyzed, the mean cost/DALY averted reduced to 232.0 USD (95% CI 17.1-446.8) for the surgeon group and 129.7 USD (95% CI 79.6-179.8) for the MD group (P = .348), and the incremental cost/DALY averted increased by 45% but remained robust. CONCLUSIONS: Elective inguinal hernia repair with mesh performed by Ghanaian surgeons and MDs is a low-cost procedure and very cost-effective in the context of the study. To maximize cost-effectiveness, symptomatic patients should be prioritized over asymptomatic patients and a high level of productivity should be maintained.

Broad vs Narrow Spectrum Antibiotics in Common Bile Duct Stones: A Post Hoc Analysis of an Eastern Association for the Surgery of Trauma Multicenter Study.

BACKGROUND: Antimicrobial guidance for common bile duct stones during the perioperative period is limited. We sought to examine the effect of broad-spectrum (BS) vs narrow-spectrum (NS) antibiotics on surgical site infections (SSIs) in patients with common bile duct stones undergoing same-admission cholecystectomy. STUDY DESIGN: We performed a post hoc analysis of a prospective, observational, multicenter study of patients undergoing same-admission cholecystectomy for choledocholithiasis and/or acute biliary pancreatitis between 2016 and 2019. We excluded patients with cholangitis, perforated cholecystitis, and nonbiliary infections on admission. Patients were divided based on receipt of BS or NS antibiotics. Our primary outcome was the incidence of SSIs, and secondary outcomes included hospital length of stay, acute kidney injury (AKI), and 30-day readmission for SSI. RESULTS: The cohort had 891 patients: 51.7% (n= 461) received BS antibiotics and 48.3% (n = 430) received NS antibiotics. Overall antibiotic duration was longer in the BS group than in the NS group (6 vs 4 d, p = 0.01); however, there was no difference in rates of SSI (0.9% vs 0.5%, p = 0.7) or 30-day readmission for SSI (1.1% vs 1.2%, p = 1.0). Hospital length of stay was significantly longer in the BS group (p < 0.001) as were rates of AKI (5% vs 1.4%, p = 0.001). On multivariable regression, BS antibiotic use was a risk factor for AKI (adjusted odds ratio 2.8, 95% CI 1.16 to 7.82, p = 0.02). CONCLUSION: The incidence of SSI and 30-day readmission for SSI was similar between antibiotic groups. However, BS antibiotic use was associated with a longer hospitalization and greater likelihood of AKI.

Sirtuin 1 deletion increases inflammation and mortality in sepsis.

BACKGROUND: Sepsis is a hyperinflammatory response to infection that can lead to multiorgan failure and eventually death. Often, the onset of multiorgan failure is heralded by renal dysfunction. Sirtuin 1 (SIRT1) promotes cellular stress resilience by inhibiting inflammation and promoting mitochondrial function. We hypothesize that SIRT1 plays an important role in limiting the inflammatory responses that drive organ failure in sepsis, predominantly via expression in myeloid cells. METHODS: We performed cecal ligation and puncture (CLP) on whole body SIRT1 knockout (S1KO) and myeloid cell-specific S1KO (S1KO-LysMCre) mice on a C57BL/6J background. Serum interleukin (IL)-6 was quantified by enzyme-linked immunosorbent assay. Renal mitochondrial complex activity was measured using Oxygraph-2k (Oroboros Instruments, Innsbruck, Austria). Blood urea nitrogen (BUN) was measured from serum. Survival was monitored for up to 5 days. RESULTS: Following CLP, S1KO mice had decreased renal mitochondrial complex I-dependent respiratory capacity (241.7 vs. 418.3 mmolO2/mg/min, p = 0.018) and renal mitochondrial complex II-dependent respiratory capacity (932.3 vs. 1,178.4, p = 0.027), as well as reduced rates of fatty acid oxidation (187.3 vs. 250.3, p = 0.022). Sirtuin 1 knockout mice also had increased BUN (48.0 mg/dL vs. 16.0 mg/dL, p = 0.049). Interleukin-6 levels were elevated in S1KO mice (96.5 ng/mL vs. 45.6 ng/mL, p = 0.028) and S1KO-LysMCre mice (35.8 ng/mL vs. 24.5 ng/mL, p = 0.033) compared with controls 12 hours after surgery. Five-day survival in S1KO (33.3% vs. 83.3%, p = 0.025) and S1KO-LysMCre (60% vs. 100%, p = 0.049) mice was decreased compared with controls. CONCLUSION: Sirtuin 1 deletion increases systemic inflammation in sepsis. Renal mitochondrial dysfunction, kidney injury, and mortality following CLP were all exacerbated by SIRT1 deletion. Similar effects on inflammation and survival were seen following myeloid cell-specific SIRT1 deletion, indicating that SIRT1 activity in myeloid cells may be a significant contributor for the protective effects of SIRT1 in sepsis.

Women Empowering Women: Assessing the American College of Surgeons Women in Surgery Committee Mentorship Program.

BACKGROUND: Mentorship is an important factor for career promotion and professional development. The Women in Surgery Committee developed a mentorship program that matched early career female surgeons to senior female surgeons for 1 year. We hypothesized participation in the program would empower junior surgeons by providing opportunities to network and hone skills necessary to attain their career goals. METHODS: Survey was sent 4 to 6 weeks after program completion. Statements about mentorship and value of the Women in Surgery Committee program were ranked on a 5-point Likert scale ranging from strongly disagree (1) to strongly agree (5). Participants were compared based on frequency of encounters using Student's t-test. RESULTS: A total of 105 pairs were identified; response rate was 60%. Results reported as (mean ± SD). Participants believed mentorship was essential for young surgeons (4.5 ± 1.0), and limiting the program to female surgeons added value (4.4 ± 0.6). When compared with mentees who met less than 4 times in a year, those who met 4 or more times perceived the program as beneficial (4.4 ± 0.82, p < 0.001). Mentees who met 4 or more times in a year benefitted from creating and achieving goals (4.3 ± 0.75, p < 0.001), setting expectations (4.5 ± 0.6, p < 0.001), providing networking opportunities (4.1 ± 1.1, p < 0.05), and developing professional skills (3.9 ± 0.98). CONCLUSION: The Women in Surgery Committee Mentorship Program provides an opportunity for young female surgeons; however, perceived benefit is dependent on mentee engagement.

Early Plasma Nuclear DNA, Mitochondrial DNA, and Nucleosome Concentrations Are Associated With Acute Kidney Injury in Critically Ill Trauma Patients.

Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk. DESIGN: We conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria. We determined kinetics of plasma mitochondrial DNA (mtDNA), nuclear DNA (nDNA), and nucleosome levels across time points and associations with AKI using multivariable linear mixed-effects models, adjusted for injury characteristics and blood transfusions. We evaluated the association of presentation nucleic acid damage-associated molecular patterns (DAMP) concentrations with subsequent AKI, adjusting for injury severity using multivariable logistic regression. SETTING: Academic level I trauma center. PATIENTS: Trauma patients (n = 55) requiring intensive care for greater than or equal to 24 hours after presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKI developed in 17 patients (31%), a median of 12.0 hours (interquartile range, 6.2-24.1 hr) after presentation. mtDNA demonstrated a time-varying association with AKI (p = 0.022, interaction with time point), with differences by AKI status not emerging until 24 hours (ß = 0.97 [95% CI, 0.03-1.90] log copies/uL; p = 0.043). Patients who developed AKI had higher nDNA across all time points (overall ß = 1.41 log copies/uL [0.86-1.95 log copies/uL]; p < 0.001), and presentation levels were significantly associated with subsequent AKI (odds ratio [OR], 2.55 [1.36-4.78] per log copy/uL; p = 0.003). Patients with AKI had higher nucleosome levels at presentation (ß = 0.32 [0.00-0.63] arbitrary unit; p = 0.048), a difference that was more pronounced at 24 hours (ß = 0.41 [0.06-0.76]; p = 0.021) and 48 hours (ß = 0.71 [0.35-1.08]; p < 0.001) (p = 0.075, interaction with time point). CONCLUSIONS: Plasma nucleic acid DAMPs have distinct kinetics and associations with AKI in critically ill trauma patients. nDNA at presentation predicts subsequent AKI and may be amenable to targeted therapies in this population.

Rescue Hepatectomy and Anhepatic Phase Management After Primary Nonfunction in a Liver Transplant.

Primary nonfunction is a rare but lethal complication that occurs in a small number of liver transplants. When primary nonfunction occurs, the only definite treatment is retransplant; however, another liver might not be readily available at that time. Hence, a surgeon should be aware of the various options available at hand for patient care during the time interval between the primary nonfunction and retransplant. Here, we describe the management strategy that was devised to take care of an unstable anhepatic patient in the intensive care unit, care of the patient during anhepatic phase, and successful outcome with a second liver transplant. Our index patient was a recipient of a liver donated after cardiac death. While in the operating room, after reperfusion of the liver, the patient had right heart dysfunction leading to hemodynamic instability and congestion of the liver, which culminated in primary nonfunction. Graft hepatectomy had to be done on postoperative day 1 because of deteriorating condition of the patient, and the patient was maintained in anhepatic phase in the intensive care unit for 27 hours.

Examining Violence Against Women at a Regional Level 1 Trauma Center During the COVID-19 Pandemic.

INTRODUCTION: There is a growing concern that certain public health restrictions imposed to prevent the spread of coronavirus disease 2019 (COVID-19) could result in more violence against women (VAW). We sought to determine if the rates and types of VAW changed during the COVID-19 pandemic at our level 1 trauma center (L1TC). METHODS: We performed a retrospective review of female patients who presented to our L1TC because of violence from 2019 through 2020. Patients were grouped into a pre-COVID or COVID period. The primary aim of this study was to compare rates of VAW between groups. Secondary aims sought to evaluate for any difference in traumatic mechanism between periods and to determine if a temporal relationship existed between COVID-19 and VAW rates. RESULTS: There was no difference in rates of VAW between the pre-COVID and COVID period (3.1% vs 3.6%, P = .6); however, rates of penetrating trauma were greater during the COVID period (38.2% vs 10.3%, P = .01). After controlling for patient age and race, the odds of penetrating trauma increased during the pandemic (OR 5.8, 95% CI 1.6-28.5, P < .01). From February 2020 through October 2020, there was a direct relationship between rates of COVID-19 and VAW (r2 .78, P < .01). CONCLUSION: Rates of VAW were unchanged between the pre-COVID and COVID periods, yet the odds of penetrating VAW were 5 times greater during the pandemic. Moving forward, trauma surgeons must remain vigilant for signs of violence and ensure that support services are available during future crises.

National adherence to the ASGE-SAGES guidelines for managing suspected choledocholithiasis: An EAST multicenter study.

BACKGROUND: The American Society for Gastrointestinal Endoscopy and Society of American Gastrointestinal and Endoscopic Surgeons provide guidelines for managing suspected common bile duct (CBD) stones. We sought to evaluate adherence to the guidelines among patients with choledocholithiasis and/or acute biliary pancreatitis (ABP) and to evaluate the ability of these guidelines to predict choledocholithiasis. METHODS: We prospectively identified patients undergoing same-admission cholecystectomy for choledocholithiasis and/or ABP from 2016 to 2019 at 12 United States medical centers. Predictors of suspected CBD stones were very strong (CBD stone on ultrasound; bilirubin >4 mg/dL), strong (CBD > 6 mm; bilirubin ≥1.8 to ≤4 mg/dL), or moderate (abnormal liver function tests other than bilirubin; age >55 years; ABP). Patients were grouped by probability of CBD stones: high (any very strong or both strong predictors), low (no predictors), or intermediate (any other predictor combination). The management of each probability group was compared with the recommended management in the guidelines. RESULTS: The cohort was comprised of 844 patients. High-probability patients had 64.3% (n = 238/370) deviation from guidelines, intermediate-probability patients had 29% (n = 132/455) deviation, and low-probability patients had 78.9% (n = 15/19) deviation. Acute biliary pancreatitis increased the odds of deviation for the high- (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.06-2.8; p = 0.03) and intermediate-probability groups (OR, 1.6; 95% CI, 1.07-2.42; p = 0.02). Age older than 55 years (OR, 2.19; 95% CI, 1.4-3.43; p < 0.001) also increased the odds of deviation for the intermediate group. A CBD greater than 6 mm predicted choledocholithiasis in the high (adjusted OR (aOR), 2.16; 95% CI, 1.17-3.97; p = 0.01) and intermediate group (aOR, 2.78; 95% CI, 1.59-4.86; p < 0.001). Any very strong predictor (aOR, 2.43; 95% CI, 1.76-3.37; p < 0.0001) and both strong predictors predicted choledocholithiasis (aOR, 2; 95% CI, 1.35-2.96; p < 0.001). CONCLUSION: Almost 45% of patients with suspected CBD stones were managed discordantly from the American Society for Gastrointestinal Endoscopy and Society of American Gastrointestinal and Endoscopic Surgeons guidelines. We believe these guidelines warrant revision to better reflect the ability of the clinical variables at predicting choledocholithiasis. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Cancer Care in the Incarcerated Population: Barriers to Quality Care and Opportunities for Improvement.

Importance: Cancer is the leading cause of mortality in incarcerated individuals older than 45 years and the fourth leading cause of mortality overall. Health care professionals face increasing challenges to provide high-quality care under the confines of prison regulations and procedures. Observations: Adjusted for age, race, sex, and year of diagnosis, the standardized incidence ratio for all cancers is more than 2-fold higher in incarcerated vs general populations. Among deaths occurring in state and federal prison systems, cancer is the overall leading cause of mortality with lung cancer being the leading cause of cancer-related mortality followed by liver, colon, and pancreatic cancers, respectively. Access to high-quality oncological services remains variable; however, cost of care represents about a fifth of overall annual prison expenditures. Given the enormous patient burden, coupled with the rushed discretionary screenings performed by jail and prison nursing staff, early cancer symptoms are often missed altogether or misdiagnosed as a chronic illness or as acute infections. As such, many incarcerated individuals present with more advanced cancer stage. Incarcerated individuals have limited, if any, access to the internet, social media, and other sources of information, which severely limits their ability to research treatment options. Within the prison setting, access to professionals with special skills in assisting with social and spiritual concerns is also generally limited, and less than 4% of prisons have hospice programs. There are no uniform quality-of-care monitoring standards for correctional systems and facilities, nor are there mechanisms for reporting comparable performance data to enforce quality control within correctional health care systems. Conclusions and Relevance: There is a growing trend in cancer incidence among incarcerated patients, which is multifactorial including barriers in access to care, increased burden of chronic medical conditions, and decreased screening tests. Efforts are needed to ensure quality health care outcomes for incarcerated patients with cancer.

Using State Data to Predict a Single Institution Mortality for Patients That Fall.

BACKGROUND: Falls are the most common cause of injury-related death for patients older than 45.  We hypothesized that a machine learning algorithm developed from state-level registry data could make accurate outcome predictions at a level 1 trauma hospital. METHODS: Data for all patients admitted for fall injury during 2009 - 2019 in the state of Pennsylvania were derived from the state trauma registry.  Thirteen variables that were immediately available upon patient arrival were used for prediction modeling.  Data for the test institution were withheld from model creation.  Algorithms assessed included logistic regression (LR), random forest (RF), and extreme gradient boost (XGB).  Model discrimination for mortality was assessed with area under the curve (AUC) for each algorithm at our level 1 trauma center. RESULTS: 180,284 patients met inclusion criteria.  The mean age was 69 years ± 18.5 years with a mortality rate of 4.0%.  The AUC for predicting mortality in patients that fall for LR, RF, and XGB were 0.797, 0.876, and 0.880, respectively.  The variables which contributed to the prediction in descending order of importance for XGB were respiratory rate, pulse, systolic blood pressure, ethnicity, weight, sex, age, temperature, Glasgow Coma Scale (GCS) eye, race, GCS voice, GCS motor, and blood alcohol level. CONCLUSIONS: An extreme gradient boost model developed using state-wide trauma data can accurately predict mortality after fall at a single center within the state.  This machine learning model can be implemented by local trauma systems within the state of Pennsylvania to identify patients injured by fall that require greater attention, transfer to a higher level of care, and higher resource allocation.

Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia.

OBJECTIVE: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. METHODS: We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. RESULTS: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. CONCLUSIONS: This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Longevity pathways in stress resistance: targeting NAD and sirtuins to treat the pathophysiology of hemorrhagic shock.

Stress resistance correlates with longevity and this pattern has been exploited to help identify genes that can influence lifespan. Reciprocally, genes and pharmacological agents that have been studied primarily in the context of longevity may be an untapped resource for treating acute stresses. Here we summarize the evidence that targeting SIRT1, studied primarily in the context of longevity, can improve outcomes in hemorrhagic shock and resuscitation. Hemorrhagic shock is a potentially fatal condition that occurs when blood loss is so severe that tissues no longer receive adequate oxygen. While stabilizing the blood pressure and reperfusing tissues are necessary, re-introducing oxygen to ischemic tissues generates a burst of reactive oxygen species that can cause secondary tissue damage. Reactive oxygen species not only exacerbate the inflammatory cascade but also can directly damage mitochondria, leading to bioenergetic failure in the affected tissues. Treatments with polyphenol resveratrol and with nicotinamide adenine dinucleotide (NAD) precursors have both shown promising results in rodent models of hemorrhagic shock and resuscitation. Although a number of different mechanisms may be at play in each case, a common theme is that resveratrol and NAD both enhance the activity of SIRT1. Moreover, many of the physiologic improvements observed with resveratrol and NAD precursors are consistent with modulation of known SIRT1 targets. Because small blood vessels and limited blood volume make mice very challenging for the development of hemorrhagic shock models, there is a paucity of direct genetic evidence testing the role of SIRT1. However, the development of more robust methods in mice as well as genetic modifications in rats should allow the study of SIRT1 transgenic and KO rodents in the near future. The potential therapeutic effect of SIRT1 in hemorrhagic shock may serve as an important example supporting the value of considering "longevity" pathways in the mitigation of acute stresses.