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Competing Interests: Competing interests: KM has consulting relationships with Intuitive Surgical and AcuMed.

Background/objectives: Surgical populations and particularly injury survivors often present with complex trauma that elevates their risk for prolonged opioid use and misuse. Changes in opioid prescribing guidelines during the past several years have yielded mixed results for pain management after trauma, with a limiting factor being the heterogeneity of clinical populations and treatment needs in individuals receiving opioids. The present analysis illuminates this gap between clinical guidelines and clinical practice through qualitative feedback from hospital trauma providers and unit staff members regarding current opioid prescribing guidelines and practices in the setting of traumatic injury., Methods: The parent study aimed to implement a pilot screening tool for opioid misuse in four level I and II trauma hospitals throughout Wisconsin. As part of the parent study, focus groups were conducted at each study site to explore the facilitators and barriers of implementing a novel screening tool, as well as to examine the current opioid prescribing guidelines, trainings, and resources available for trauma and acute care providers. Focus group transcripts were independently coded and analyzed using a modified grounded theory approach to identify themes related to the facilitators and barriers of opioid prescribing guidelines in trauma and acute care., Results: Three major themes were identified as impactful to opioid-related prescribing and care provided in the setting of traumatic injury; these include (1) acute treatment strategies; (2) patient interactions surrounding pain management; and (3) the multifactorial nature of trauma on pain management approaches., Conclusion: Providers and staff at four Wisconsin trauma centers called for trauma-specific opioid prescribing guidelines in the setting of trauma and acute care. The ubiquitous prescription of opioids and challenges in long-term pain management in these settings necessitate additional community-integrated research to inform development of federal guidelines., Level of Evidence: Therapeutic/care management, level V., Competing Interests: Competing interests: The authors alone are responsible for the content and writing of this paper. TSACO Disclosure forms have been supplied for each author and are available upon request., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chest wall injury in older adults is a significant cause of morbidity and mortality. Optimal nonsurgical management strategies for these patients have not been fully defined regarding level of care, incentive spirometry (IS), noninvasive positive pressure ventilation (NIPPV), and the use of ketamine, epidural, and other locoregional approaches to analgesia., Methods: Relevant questions regarding older patients with significant chest wall injury with patient population(s), intervention(s), comparison(s), and appropriate selected outcomes were chosen. These focused on intensive care unit (ICU) admission, IS, NIPPV, and analgesia including ketamine, epidural analgesia, and locoregional nerve blocks. A systematic literature search and review were conducted, our data were analyzed qualitatively and quantitatively, and the quality of evidence was assessed per the Grading of Recommendations Assessment, Development, and Evaluation methodology. No funding was used., Results: Our literature review (PROSPERO 2020-CRD42020201241, MEDLINE, EMBASE, Cochrane, Web of Science, January 15, 2020) resulted in 151 studies. Intensive care unit admission was qualitatively not superior for any defined cohort other than by clinical assessment. Poor IS performance was associated with prolonged hospital length of stay, pulmonary complications, and unplanned ICU admission. Noninvasive positive pressure ventilation was associated with 85% reduction in odds of pneumonia ( p < 0.0001) and 81% reduction in odds of mortality ( p = 0.03) in suitable patients without risk of airway loss. Ketamine use demonstrated no significant reduction in pain score but a trend toward reduced opioid use. Epidural and other locoregional analgesia techniques did not affect pneumonia, length of mechanical ventilation, hospital length of stay, or mortality., Conclusion: We do not recommend for or against routine ICU admission. We recommend use of IS to inform ICU status and conditionally recommend use of NIPPV in patients without risk of airway loss. We offer no recommendation for or against ketamine, epidural, or other locoregional analgesia., Level of Evidence: Systematic Review/Meta-analysis; Level IV., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Antibiotic prophylaxis is routinely administered for most operative procedures, but their utility for certain bedside procedures remains controversial. We performed a systematic review and meta-analysis and developed evidence-based recommendations on whether trauma patients receiving tube thoracostomy (TT) for traumatic hemothorax or pneumothorax should receive antibiotic prophylaxis., Methods: Published literature was searched through MEDLINE (via PubMed), Embase (via Elsevier), Cochrane Central Register of Controlled Trials (via Wiley), Web of Science and ClinicalTrials.gov databases by a professional librarian. The date ranges for our literature search were January 1900 to March 2020. A systematic review and meta-analysis of currently available evidence were performed using the Grading of Recommendations Assessment, Development and Evaluation methodology., Results: Fourteen relevant studies were identified and analyzed. All but one were prospective, with eight being prospective randomized control studies. Antibiotic prophylaxis protocols ranged from a single dose at insertion to 48 hours post-TT removal. The pooled data showed that patients who received antibiotic prophylaxis were significantly less likely to develop empyema (OR 0.47, 95% CI 0.25 to 0.86, p=0.01). The benefit was greater in patients with penetrating injuries (penetrating OR 0.25, 95% CI 0.10 to 0.59, p=0.002, vs blunt OR 0.25, 95% CI 0.06 to 1.12, p=0.07). Administration of antibiotic prophylaxis did not significantly affect pneumonia incidence or mortality., Discussion: In adult trauma patients who require TT insertion, we conditionally recommend antibiotic prophylaxis be given at the time of insertion to reduce incidence of empyema., Prospero Registration Number: CRD42018088759., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Grading systems for acute cholecystitis are essential to compare outcomes, improve quality, and advance research. The American Association for the Surgery of Trauma (AAST) grading system for acute cholecystitis was only moderately discriminant when predicting multiple outcomes and underperformed the Tokyo guidelines and Parkland grade. We hypothesized that through additional expert consensus, the predictive capacity of the AAST anatomic grading system could be improved., Methods: A modified Delphi approach was used to revise the AAST grading system. Changes were made to improve distribution of patients across grades, and additional key clinical variables were introduced. The revised version was assessed using prospectively collected data from an AAST multicenter study. Patient distribution across grades was assessed, and the revised grading system was evaluated based on predictive capacity using area under receiver operating characteristic curves for conversion from laparoscopic to an open procedure, use of a surgical "bail-out" procedure, bile leak, major complications, and discharge home. A preoperative AAST grade was defined based on preoperative, clinical, and radiologic data, and the Parkland grade was also substituted for the operative component of the AAST grade., Results: Using prospectively collected data on 861 patients with acute cholecystitis the revised version of the AAST grade has an improved distribution across all grades, both the overall grade and across each subscale. A higher AAST grade predicted each of the outcomes assessed (all p ≤ 0.01). The revised AAST grade outperformed the original AAST grade for predicting operative outcomes and discharge disposition. Despite this improvement, the AAST grade did not outperform the Parkland grade or the Emergency Surgery Score., Conclusion: The revised AAST grade and the preoperative AAST grade demonstrated improved discrimination; however, a purely anatomic grade based on chart review is unlikely to predict outcomes without addition of physiologic variables. Follow-up validation will be necessary., Level of Evidence: Diagnostic Test or Criteria, Level IV., (Copyright © 2021 American Association for the Surgery of Trauma.)

A new methodology has been developed for analyzing heat and mass transfer to predict wax deposition in crude oil pipelines using the law of the wall dimensionless parameters. A set of physically meaningful dimensionless groups and parameters has laid a strong foundation behind the proposed methodology. The paper presents a discussion regarding the development of scale-up correlations from laboratory scale to field scale, considering the combination of both analytical groups and empirical correlations. Data from previous literature studies were employed for determining realistic values for the developed parameters and scale-up correlations. The utilization of new dimensionless scale-up parameters indicated that the wax deposition in crude oil pipelines is independent of the Reynolds number and the inner diameter of the pipeline. It further indicates that wax deposition in crude oil pipelines is mainly dependent on the heat transfer process and not on the shear reduction process. The dimensionless technique developed here can be utilized for determining the optimum pipe size and pigging frequencies to reduce and mitigate the effect of the wax deposition process., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: Because preoperative risk factor modification is generally not possible in the emergency setting, complication prevention represents an important focus for quality improvement in emergency general surgery (EGS). The objective of our study was to determine the overall impact that specific postoperative complications have in this patient population., Study Design: Our study sample consisted of patients from the 2012-2013 ACS-NSQIP database who underwent an EGS procedure. We used population attributable fractions (PAFs) to estimate the overall impact that each of 8 specific complications had on 30-day physiologic and resource use outcomes in our study population. The PAF represents the percentage reduction in a given outcome that would be anticipated if a complication were able to be completely prevented in our study population. Both unadjusted and risk-adjusted PAFs were calculated., Results: There were 79,183 patients included for analysis. The most common complications in these patients were bleeding (6.2%), incisional surgical site infection (SSI) (3.4%), pneumonia (2.7%), and organ/space SSI (2.6%). Bleeding was the complication with the greatest overall impact on mortality and end-organ dysfunction, demonstrating an adjusted PAF of 10.7% (95% CI 8.2%,13.1%, p < 0.001) and 15.9% (95% CI 13.9%, 16.7%, p < 0.001) for these respective outcomes. The only other complication with a sizeable impact on these outcomes was pneumonia (adjusted PAF of 7.9% for mortality and 13.2% for pneumonia). In contrast, complications such as urinary tract infection, venous thromboembolism, myocardial infarction, and incisional SSI had negligible impacts on these outcomes., Conclusions: Our study provides a framework for the development of high-value quality initiatives in EGS., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The American Association for the Surgery of Trauma (AAST) recently established a grading system for uniform reporting of anatomic severity of several emergency general surgery (EGS) diseases. There are five grades of severity for each disease, ranging from I (lowest severity) to V (highest severity). However, the grading process requires manual chart review. We sought to evaluate whether International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD-9-CM, ICD-10-CM) codes might allow estimation of AAST grades for EGS diseases. The Patient Assessment and Outcomes Committee of the AAST reviewed all available ICD-9-CM and ICD-10-CM diagnosis codes relevant to 16 EGS diseases with available AAST grades. We then matched grades for each EGS disease with one or more ICD codes. We used the Official Coding Guidelines for ICD-9-CM and ICD-10-CM and the American Hospital Association's "Coding Clinic for ICD-9-CM" for coding guidance. The ICD codes did not allow for matching all five AAST grades of severity for each of the 16 diseases. With ICD-9-CM, six diseases mapped into four categories of severity (instead of five), another six diseases into three categories of severity, and four diseases into only two categories of severity. With ICD-10-CM, five diseases mapped into four categories of severity, seven diseases into three categories, and four diseases into two categories. Two diseases mapped into discontinuous categories of grades (two in ICD-9-CM and one in ICD-10-CM). Although resolution is limited, ICD-9-CM and ICD-10-CM diagnosis codes might have some utility in roughly approximating the severity of the AAST grades in the absence of more precise information. These ICD mappings should be validated and refined before widespread use to characterize EGS disease severity. In the long-term, it may be desirable to develop alternatives to ICD-9-CM and ICD-10-CM codes for routine collection of disease severity characteristics.

The Hedgehog (Hh) signaling pathway is aberrantly activated in a wide variety of human cancers, and recent clinical studies have demonstrated that pathway inhibitors are effective in advanced basal cell carcinoma (BCC). The majority of these agents have been designed to target SMOOTHENED (SMO), a transmembrane regulator of Hh signaling, but subsequent mutations in SMO have been found to generate drug resistance. In other cancers, oncogenic events that bypass SMO may activate canonical Hh signaling, and SMO antagonists have not demonstrated significant activity in several diseases. Therefore, alternative strategies targeting the Hh pathway downstream of SMO may have clinical utility. Liver X receptors (LXR) regulate cholesterol and fatty acid homeostasis, and LXR activation can inhibit the Hh pathway in normal mouse embryonic fibroblasts. We examined the effects of LXR activation on Hh signaling in human multiple myeloma cells and found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. LXR activation also inhibited putative multiple myeloma cancer stem cells in vivo leading to the loss of tumor initiating and self-renewal potential. Finally, Hh signaling was inhibited downstream of SMO, suggesting that LXR agonists may represent a novel strategy to target pathogenic Hh signaling as well as treat multiple myeloma., (©2014 American Association for Cancer Research.)

Significance: Mechanosignaling is vital for maintaining the structural integrity of bone under physiologic conditions. These signals activate and suppress multiple signaling cascades regulating bone formation and resorption. Understanding these pathways is of prime importance to exploit their therapeutic potential in disorders associated with bone loss due to disuse, trauma, or disruption of homeostatic mechanisms., Recent Advances: In the case of cells of the bone, an impressive amount of data has been generated that provides evidence of a complex mechanism by which mechanical signals can maintain or disrupt cellular homeostasis by driving transcriptional regulation of growth factors, matrix proteins and inflammatory mediators in health and inflammation. Mechanical signals act on cells in a magnitude dependent manner to induce bone deposition or resorption. During health, physiological levels of these signals are essential for maintaining bone strength and architecture, whereas during inflammation, similar signals can curb inflammation by suppressing the nuclear factor kappa B (NF-κB) signaling cascade, while upregulating matrix synthesis via mothers against decapentaplegic homolog and/or Wnt signaling cascades. Contrarily, excessive mechanical forces can induce inflammation via activation of the NF-κB signaling cascade., Critical Issues: Given the osteogenic potential of mechanical signals, it is imperative to exploit their therapeutic efficacy for the treatment of bone disorders. Here we review select signaling pathways and mediators stimulated by mechanical signals to modulate the strength and integrity of the bone., Future Directions: Understanding the mechanisms of mechanotransduction and its effects on bone lay the groundwork for development of nonpharmacologic mechanostimulatory approaches for osteodegenerative diseases and optimal bone health.

Transfection has become an everyday technique widely used for functional studies in living cells. The choice of the particular transfection method is usually determined by its efficiency and toxicity, and possible functional consequences specific to the method used are normally overlooked. We describe here that nucleofection, a method increasingly used because of its convenience and high efficiency, increases the metabolic rate of some cancer cells, which can be misleading when used as a measure of proliferation. Moreover, nucleofection can alter the subcellular expression pattern of the transfected protein. These undesired effects are independent of the transfected nucleic acid, but depend on the particular cell line used. Therefore, the interpretation of functional data using this technology requires further controls and caution.

Despite recent advances in drug development, multiple myeloma (MM) remains incurable for the majority of patients due to relapse and disease progression. The cancer stem cell (CSC) hypothesis may provide an explanation for these clinical findings. It suggests that the long-term proliferative potential responsible for disease initiation, maintenance, and relapse is contained within specific subpopulations of biologically distinct tumor cells. Data in MM suggest that CSCs represent a rare cell population phenotypically resembling normal memory B cells. Compared to MM plasma cells, MM CSCs also appear to be relatively resistant to a wide variety of standard anti-cancer agents suggesting they may persist following treatment and mediate tumor re-growth and relapse. A unique property CSCs share with their normal counterparts is the potential for self-renewal that likely maintains the malignant clone over time. The development of therapeutic strategies targeting the signaling elements contributing to cancer cell self-renewal has been limited primarily because the cellular processes involved are poorly understood. However, it is common that the signaling pathway components regulating normal stem cell self-renewal are aberrantly activated in human cancers and may serve as potential therapeutic targets. One class of shared regulatory pathways are those active during normal embryonic patterning and organ formation such as Hedgehog (Hh), Notch and Wingless (Wnt), and emerging data suggest that these may play a role in CSCs. Here we review the identification and characterization of MM CSCs, the role of Hh in MM, and issues to be considered during the early clinical testing of CSC targeting agents.

Background: The voltage-gated potassium channel hEag1 (KV10.1) has been related to cancer biology. The physiological expression of the human channel is restricted to the brain but it is frequently and abundantly expressed in many solid tumors, thereby making it a promising target for a specific diagnosis and therapy. Because chronic lymphatic leukemia has been described not to express hEag1, it has been assumed that the channel is not expressed in hematopoietic neoplasms in general., Results: Here we show that this assumption is not correct, because the channel is up-regulated in myelodysplastic syndromes, chronic myeloid leukemia and almost half of the tested acute myeloid leukemias in a subtype-dependent fashion. Most interestingly, channel expression strongly correlated with increasing age, higher relapse rates and a significantly shorter overall survival. Multivariate Cox regression analysis revealed hEag1 expression levels in AML as an independent predictive factor for reduced disease-free and overall survival; such an association had not been reported before. As a functional correlate, specific hEag1 blockade inhibited the proliferation and migration of several AML cell lines and primary cultured AML cells in vitro., Conclusion: Our observations implicate hEag1 as novel target for diagnostic, prognostic and/or therapeutic approaches in AML.

Background: The management of severe hepatic trauma frequently involves exposing the liver to varying periods of warm ischemia. The ischemic tolerance of the liver, in the setting of hemorrhagic shock (HS) and trauma, is presently unknown. We tested the hypothesis that warm ischemic tolerance of the porcine liver will be decreased following resuscitation from HS., Materials and Methods: Twenty-three Yorkshire pigs were divided into three groups: 1) hepatic ischemia alone (HI, n = 9); 2) hemorrhagic shock alone (HS, n = 3); and 3) hemorrhagic shock plus hepatic ischemia combined (HSHI, n = 11). Following reperfusion, a liver biopsy was obtained and serial blood chemistries were sampled., Results: Post-operative day 7 mortality was increased in the HSHI group (7/11) compared to the HI (0/9) group, P = 0.038. Notably, deaths did not result from acute liver failure, but rather from intra-operative hemodynamic collapse shortly following hepatic reperfusion. In addition, the HSHI group experienced significantly elevated lactic acid, serum creatinine and liver enzyme levels. Analysis of the liver biopsy samples is consistent with a more severe liver injury in the HSHI group., Conclusions: The warm ischemic tolerance of the liver following resuscitation from HS is significantly decreased in this porcine model compared to HS or HI alone. Mortality was associated with acute intra-operative hemodynamic collapse occurring shortly after hepatic reperfusion.