Enhancing standard of care chemotherapy efficacy using DNA-dependent protein kinase (DNA-PK) inhibition in preclinical models of Ewing sarcoma.

Disruption of DNA damage repair via impaired homologous recombination is characteristic of Ewing sarcoma (EWS) cells. We hypothesize that this disruption results in increased reliance on non-homologous end joining (NHEJ) to repair DNA damage. In this study, we investigated if pharmacological inhibition of the enzyme responsible for NHEJ, the DNA-PK holoenzyme, alters the response of EWS cells to genotoxic standard of care chemotherapy. We used analyses of cell viability and proliferation to investigate the effects of clinical DNA-PK inhibitors (DNA-PKi) in combination with six therapeutic or experimental agents for EWS. We performed calculations of synergy using the Loewe Additivity Model. Immunoblotting evaluated treatment effects on DNA-PK, DNA damage, and apoptosis. Flow cytometric analyses evaluated effects on cell cycle and fate. We used orthotopic xenograft models to interrogate tolerability, drug mechanism, and efficacy in vivo. DNA-PKi demonstrated on-target activity, reducing phosphorylated DNA-PK levels in EWS cells. DNA-PKi sensitized EWS cell lines to agents that function as topoisomerase 2 (TOP2) poisons and enhanced the DNA damage induced by TOP2 poisons. Nanomolar concentrations of single agent TOP2 poisons induced G2M arrest and little apoptotic response, while adding DNA-PKi mediated apoptosis. In vivo, the combination of AZD-7648 and etoposide had limited tolerability but resulted in enhanced DNA damage, apoptosis, and EWS tumor shrinkage. The combination of DNA-PKi with standard of care TOP2 poisons in EWS models is synergistic, enhances DNA damage and cell death, and may form the basis of a promising future therapeutic strategy for EWS.

Literature review of spinal hematoma case reports: causes and outcomes in pediatric, obstetric, neuraxial and pain medicine cases.

BACKGROUND: The risk of spinal epidural hematoma (SEH) has been described in the literature but the impact in various patient populations has not been assessed in the same study. We identified the risk factors for SEH and calculated the OR for recovery in the pediatric, adult and obstetric (OB) patients based on the degree of neurological deficit before surgery. METHODS: Adult non-OB cases were categorized whether they were on anticoagulants or not; SEH was related to neuraxial or pain procedure; or whether there was adherence to the American Society of Regional Anesthesia (ASRA) guidelines. Eligible cases were identified through PubMed and Embase searches in the English literature from 1954 to July 2022. RESULTS: A total of 940 cases were evaluated. In the pediatric cases, SEH was typically spontaneous, related to coagulopathy or athletic trauma. OB cases were spontaneous or related to neuraxial injections. Among adults on anticoagulant(s), SEH was mostly spontaneous with no related etiology or related to neuraxial procedure. SEH occurred despite adherence to the ASRA guidelines. Among non-OB adults not on anticoagulants, SEH was due to trauma, neuraxial injections, surgery or other causes. Neurological recovery was related to the degree of neurological deficit before surgery. CONCLUSIONS: Our data show a preponderance of spontaneous SEH in all patient populations. SEH developed even though the ASRA guidelines were followed, especially in patients on multiple anticoagulants. Patients with less impairment prior to surgery had a higher likelihood of complete recovery, regardless of the interval between surgery and onset of symptoms.

Pro-Con Debate: Superior Versus Inferior Triangle Needle Placement in Transforaminal Epidural Injections.

Although transforaminal epidural injections have long been used for radicular pain, there is no universal standard injection approach to the neural foramen. The intervertebral foramen and its surrounding structures comprise an anatomically sensitive area that includes bone and joint structures, the intervertebral disk, blood vessels (in particular, the radicular arteries), the epidural sheath, and the spinal nerve root. Given the relatively high risk of inadvertent injury or injection to these nearby structures, image guidance for transforaminal epidural steroid injections (TFESIs) is standard of care. However, there is a lack of consensus regarding the optimal approach to the neural foramen: from the traditional superior ("safe") triangle or from the inferior (Kambin's) triangle. In this Pro-Con commentary article, we discuss the relative advantages and disadvantages of each approach for TFESIs.

Block Time: A Multispecialty Systematic Review of Efficacy and Safety of Ultrasound-guided Upper Extremity Nerve Blocks.

INTRODUCTION: Ultrasound-guided peripheral nerve blockade is a common pain management strategy to decrease perioperative pain and opioid/general anesthetic use. In this article our goal was to systematically review publications supporting upper extremity nerve blocks distal to the brachial plexus. We assessed the efficacy and safety of median, ulnar, radial, suprascapular, and axillary nerve blocks by reviewing previous studies. METHODS: We searched MEDLINE and Embase databases to capture studies investigating these nerve blocks across all specialties. We screened titles and abstracts according to agreed-upon inclusion/exclusion criteria. We then conducted a hand search of references to identify studies not found in the initial search strategy. RESULTS: We included 20 studies with 1,273 enrolled patients in qualitative analysis. Both anesthesiology (12, 60%) and emergency medicine (5, 25%) specialties have evidence of safe and effective use of radial, ulnar, median, suprascapular, and axillary blocks for numerous clinical applications. Recently, multiple randomized controlled trials show suprascapular nerve blocks may result in lower pain scores in patients with shoulder dislocations and rotator cuff injuries, as well as in patients undergoing anesthesia for shoulder surgery. CONCLUSION: Distal upper extremity nerve blocks under ultrasound guidance may be safe, practical strategies for both acute and chronic pain in perioperative, emergent, and outpatient settings. These blocks provide accessible, opioid-sparing pain management, and their use across multiple specialties may be expanded with increased procedural education of trainees.

Daring discourse: artificial intelligence in pain medicine, opportunities and challenges.

Artificial intelligence (AI) tools are currently expanding their influence within healthcare. For pain clinics, unfettered introduction of AI may cause concern in both patients and healthcare teams. Much of the concern stems from the lack of community standards and understanding of how the tools and algorithms function. Data literacy and understanding can be challenging even for experienced healthcare providers as these topics are not incorporated into standard clinical education pathways. Another reasonable concern involves the potential for encoding bias in healthcare screening and treatment using faulty algorithms. And yet, the massive volume of data generated by healthcare encounters is increasingly challenging for healthcare teams to navigate and will require an intervention to make the medical record manageable in the future. AI approaches that lighten the workload and support clinical decision-making may provide a solution to the ever-increasing menial tasks involved in clinical care. The potential for pain providers to have higher-quality connections with their patients and manage multiple complex data sources might balance the understandable concerns around data quality and decision-making that accompany introduction of AI. As a specialty, pain medicine will need to establish thoughtful and intentionally integrated AI tools to help clinicians navigate the changing landscape of patient care.

Serratus anterior plane block as a bridge to outpatient management of severe rib fractures: a case report.

Rib fractures account for a significant number of emergency department visits each year. A patient's disposition often depends on the severity of rib fractures, comorbidities, and ability to achieve adequate analgesia. We present a 44-year-old male patient with severe pain secondary to rib fractures. The initial disposition was to admit for pain control. However, upon performing a serratus anterior plane block, patient was functionally appropriate for discharge with proper return precautions. Serratus anterior plane block is within the skillset of the emergency physician and can be used to achieve analgesia for rib fractures without the sedative and respiratory depressive effects associated with opioids.

Cannabinoids for Pain Modulation in Orthopedic Surgery.

Cannabinoid compounds are being increasingly used as an analgesic adjuvant in the orthopedic population, but little data exist to either support or oppose this practice pattern. A review of all contemporary (2000-2020) studies on the use of cannabinoids in orthopedics is presented. Physicians and patients are optimistic that cannabinoids can decrease pain scores and perhaps opioid use; however, their application in orthopedics is not well characterized. In addition to the social stigma regarding the use of cannabis, there is limited high-quality evidence of the efficacy of cannabinoids in treating orthopedic-related pain. As cannabis becomes more accessible, well-designed trials are needed to better understand cannabinoids and guide orthopedic practice. [Orthopedics. 2022;45(6):e295-e302.].

The Specifics of Non-specific Low Back Pain: Re-evaluating the Current Paradigm to Improve Patient Outcomes.

Low back pain (LBP) is the leading cause of pain and debility worldwide and the most frequent reason for work-related disability. Global expenditures related to LBP are staggering and amount to billions of dollars each year in the United States alone. Yet, despite the considerable healthcare resources consumed, the care provided to patients with LBP has regularly been cited as both ineffective and exorbitant. Among the myriad reasons for this suboptimal care, the current approach to evaluation and management of patients with LBP is a likely contributor and is hitherto un-investigated. Following the current methodology, over 90% of patients with LBP are provided with no specific diagnosis, are managed inconsistently, and receive no express preventative care. We believed that this approach added costs and promoted chronic unresolved pain and disability. This narrative review highlights problems with the current methodology, proposes a novel concept for categorizing patients with LBP, and recommends strategies for improvement. Stratifying patients according to the etiology, in lieu of the prospects for morbidity, the strategy proposed in this article may help ascertain the cause of patient's LBP early, consolidate treatments, permit timely preventative measures, and, as a result, may improve patient outcomes.

Cannabis Exposure Decreases Need for Blood Pressure Support During General Anesthesia in Orthopedic Trauma Surgery.

Introduction: As cannabis use continues to increase in popularity, it is important to investigate how it impacts public health in all sectors of the population, including patients undergoing anesthetic management. This retrospective study focuses on the orthopedic trauma population presenting through an emergency department (ED) and receiving a urine drug screen (UDS) with subsequent urgent surgical intervention. We aimed to evaluate differences in response to general anesthesia in patients with exposure to THC, a major cannabinoid, compared to controls that screened negative for THC. Materials and Methods: All ED visits at UC Irvine, a level 1 trauma center between November 4, 2017 and January 7, 2020, were evaluated in this study. Only adult patients who received a UDS and underwent urgent orthopedic trauma surgery within 48 h of ED visit were included in this study. Additional inclusion criteria required an anesthesia time greater than 1 h as well as anesthesia induction and intubation while in the operating room. Overall, we analyzed a total of 221 adult patients. Discussion: When adjusting for demographic variability, there were statistically significant differences in response to general anesthesia between these two groups. The THC-positive (THC(+)) group was less likely to receive intraoperative vasopressors, had higher mean arterial blood pressure and mean diastolic blood pressure, needed less total fluid input and had a lower overall fluid balance. Chronic exposure to THC has been shown to downregulate cannabinoid 1 receptors and cause alterations in endocannabinoid tone. These are two potential mechanisms by which the THC(+) group in our study may have become more resistant to the typically observed hypotensive effects of general anesthesia. Conclusion: The present study suggests that prior use of cannabis, objectively assessed by urinalysis, results in a decreased need for blood pressure support during general anesthesia. The physiological basis for this phenomenon is unclear, but possible causes might include the downregulation of vascular cannabinoid receptor 1 and/or altered endocannabinoid levels after exposure to cannabis.

Positive Toxicology Results Are Not Associated with Emergency Physicians' Opioid Prescribing Behavior.

INTRODUCTION: Given the general lack of literature on opioid and naloxone prescribing guidelines for patients with substance use disorder, we aimed to explore how a physician's behavior and prescribing habits are altered by knowledge of the patient's concomitant use of psychotropic compounds as evident on urine and serum toxicology screens. METHODS: We conducted a retrospective chart review study at a tertiary, academic, Level I trauma center between November 2017-October 2018 that included 358 patients who were discharged from the emergency department (ED) with a diagnosis of fracture, dislocation, or amputation and received an opioid prescription upon discharge. We extracted urine and serum toxicology results, number and amount of prescription opioids upon discharge, and the presence of a naloxone script. RESULTS: The study population was divided into five subgroups that included the following: negative urine and serum toxicology screen; depressants; stimulants; mixed; and no toxicology screens. When comparing the 103 patients in which toxicology screens were obtained to the 255 patients without toxicology screens, we found no statistically significant differences in the total prescribed morphine milligram equivalent (75.0 and 75.0, respectively) or in the number of pills prescribed (15.0 and 13.5, respectively). Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. CONCLUSION: Our study found no association between positive urine toxicology results for psychotropically active substances and the rates of opioid prescribing within a single-center, academic ED. Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. More research on the associations between illicit drug use, opioids, and naloxone prescriptions is necessary to help establish guidelines for high-risk patients.

Pain Recognition With Electrocardiographic Features in Postoperative Patients: Method Validation Study.

BACKGROUND: There is a strong demand for an accurate and objective means of assessing acute pain among hospitalized patients to help clinicians provide pain medications at a proper dosage and in a timely manner. Heart rate variability (HRV) comprises changes in the time intervals between consecutive heartbeats, which can be measured through acquisition and interpretation of electrocardiography (ECG) captured from bedside monitors or wearable devices. As increased sympathetic activity affects the HRV, an index of autonomic regulation of heart rate, ultra-short-term HRV analysis can provide a reliable source of information for acute pain monitoring. In this study, widely used HRV time and frequency domain measurements are used in acute pain assessments among postoperative patients. The existing approaches have only focused on stimulated pain in healthy subjects, whereas, to the best of our knowledge, there is no work in the literature building models using real pain data and on postoperative patients. OBJECTIVE: The objective of our study was to develop and evaluate an automatic and adaptable pain assessment algorithm based on ECG features for assessing acute pain in postoperative patients likely experiencing mild to moderate pain. METHODS: The study used a prospective observational design. The sample consisted of 25 patient participants aged 18 to 65 years. In part 1 of the study, a transcutaneous electrical nerve stimulation unit was employed to obtain baseline discomfort thresholds for the patients. In part 2, a multichannel biosignal acquisition device was used as patients were engaging in non-noxious activities. At all times, pain intensity was measured using patient self-reports based on the Numerical Rating Scale. A weak supervision framework was inherited for rapid training data creation. The collected labels were then transformed from 11 intensity levels to 5 intensity levels. Prediction models were developed using 5 different machine learning methods. Mean prediction accuracy was calculated using leave-one-out cross-validation. We compared the performance of these models with the results from a previously published research study. RESULTS: Five different machine learning algorithms were applied to perform a binary classification of baseline (BL) versus 4 distinct pain levels (PL1 through PL4). The highest validation accuracy using 3 time domain HRV features from a BioVid research paper for baseline versus any other pain level was achieved by support vector machine (SVM) with 62.72% (BL vs PL4) to 84.14% (BL vs PL2). Similar results were achieved for the top 8 features based on the Gini index using the SVM method, with an accuracy ranging from 63.86% (BL vs PL4) to 84.79% (BL vs PL2). CONCLUSIONS: We propose a novel pain assessment method for postoperative patients using ECG signal. Weak supervision applied for labeling and feature extraction improves the robustness of the approach. Our results show the viability of using a machine learning algorithm to accurately and objectively assess acute pain among hospitalized patients. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17783.

Pain Assessment Tool With Electrodermal Activity for Postoperative Patients: Method Validation Study.

BACKGROUND: Accurate, objective pain assessment is required in the health care domain and clinical settings for appropriate pain management. Automated, objective pain detection from physiological data in patients provides valuable information to hospital staff and caregivers to better manage pain, particularly for patients who are unable to self-report. Galvanic skin response (GSR) is one of the physiologic signals that refers to the changes in sweat gland activity, which can identify features of emotional states and anxiety induced by varying pain levels. This study used different statistical features extracted from GSR data collected from postoperative patients to detect their pain intensity. To the best of our knowledge, this is the first work building pain models using postoperative adult patients instead of healthy subjects. OBJECTIVE: The goal of this study was to present an automatic pain assessment tool using GSR signals to predict different pain intensities in noncommunicative, postoperative patients. METHODS: The study was designed to collect biomedical data from postoperative patients reporting moderate to high pain levels. We recruited 25 participants aged 23-89 years. First, a transcutaneous electrical nerve stimulation (TENS) unit was employed to obtain patients' baseline data. In the second part, the Empatica E4 wristband was worn by patients while they were performing low-intensity activities. Patient self-report based on the numeric rating scale (NRS) was used to record pain intensities that were correlated with objectively measured data. The labels were down-sampled from 11 pain levels to 5 different pain intensities, including the baseline. We used 2 different machine learning algorithms to construct the models. The mean decrease impurity method was used to find the top important features for pain prediction and improve the accuracy. We compared our results with a previously published research study to estimate the true performance of our models. RESULTS: Four different binary classification models were constructed using each machine learning algorithm to classify the baseline and other pain intensities (Baseline [BL] vs Pain Level [PL] 1, BL vs PL2, BL vs PL3, and BL vs PL4). Our models achieved higher accuracy for the first 3 pain models than the BioVid paper approach despite the challenges in analyzing real patient data. For BL vs PL1, BL vs PL2, and BL vs PL4, the highest prediction accuracies were achieved when using a random forest classifier (86.0, 70.0, and 61.5, respectively). For BL vs PL3, we achieved an accuracy of 72.1 using a k-nearest-neighbor classifier. CONCLUSIONS: We are the first to propose and validate a pain assessment tool to predict different pain levels in real postoperative adult patients using GSR signals. We also exploited feature selection algorithms to find the top important features related to different pain intensities. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17783.

Knowledge and Opinion on Cannabinoids Among Orthopaedic Traumatologists.

INTRODUCTION: Cannabinoids are an increasingly popular therapy among orthopaedic patients for musculoskeletal conditions. A paucity of evidence to support their use in orthopaedics exists, likely because of the incongruence of federal and state legalization and the stigma surrounding cannabis. The purpose of this study is to elucidate sentiments and knowledge base of the orthopaedic trauma community with regard to cannabinoid-containing compounds. METHODS: A 21-question online survey was distributed to the members of the Orthopaedic Trauma Association with a response window of 3 months. RESULTS: We evaluated 251 responses. Most (88%) of the respondents did not believe that they were knowledgeable about the mechanism of action of cannabis/cannabidiol (CBD) but did feel that cannabis or CBD products play a role in managing postoperative pain (73%). Most respondents did not believe that they would be stigmatized if they suggested CBD (83%) or cannabis (67%) to patients. Despite this, fewer respondents have suggested CBD (38%) or cannabis (29%) to their patients. CONCLUSIONS: Sentiment toward cannabinoids among orthopaedic traumatologists is remarkably favorable; however, in-depth understanding is admittedly poor and routine use is uncommon. More clinical research for cannabinoids is needed to help orthopaedic traumatologists provide guidance for patients seeking advice for this recently popular therapeutic.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Choosing Between a Rock and the Pot Place.

In the evolving field of medicinal cannabis, there are many questions and concerns broached by patients to which health care providers cannot respond with anything other than anecdotal evidence. Many simple knowledge gaps persist due to barriers to high-quality research at the institutional and state levels: barriers that, in turn, stem from the federal designation of cannabis as an illegal substance. These perspectives of a California-based pain physician on the approach to the cannabis-curious pain patient highlight the necessity of a change in the classification of cannabis to streamline research as to the benefits and risks of this now ubiquitous substance.

Central venous catheter placement leading to an emergent paramedian sternotomy: a case report.

Perioperative cardiac tamponade during central venous catheter placement is rare. We present a case of tamponade from pulmonary artery injury during dialysis catheter placement resulting in complicated sternotomy and hospital course. A 52-year-old female experienced intraoperative hypotension, rapidly identified as tamponade, that was treated with an emergent paramedian sternotomy. Patient experienced postdischarge dehiscence and osteomyelitis requiring multiple reoperations. This case is the first report of a deviated paramedian sternotomy performed mainly through ribs. The complications experienced outline the importance of effective multidisciplinary knowledge of best practices to stabilize tamponade pathology, mitigating morbidity and mortality.

Prospective Study Evaluating a Pain Assessment Tool in a Postoperative Environment: Protocol for Algorithm Testing and Enhancement.

BACKGROUND: Assessment of pain is critical to its optimal treatment. There is a high demand for accurate objective pain assessment for effectively optimizing pain management interventions. However, pain is a multivalent, dynamic, and ambiguous phenomenon that is difficult to quantify, particularly when the patient's ability to communicate is limited. The criterion standard of pain intensity assessment is self-reporting. However, this unidimensional model is disparaged for its oversimplification and limited applicability in several vulnerable patient populations. Researchers have attempted to develop objective pain assessment tools through analysis of physiological pain indicators, such as electrocardiography, electromyography, photoplethysmography, and electrodermal activity. However, pain assessment by using only these signals can be unreliable, as various other factors alter these vital signs and the adaptation of vital signs to pain stimulation varies from person to person. Objective pain assessment using behavioral signs such as facial expressions has recently gained attention. OBJECTIVE: Our objective is to further the development and research of a pain assessment tool for use with patients who are likely experiencing mild to moderate pain. We will collect observational data through wearable technologies, measuring facial electromyography, electrocardiography, photoplethysmography, and electrodermal activity. METHODS: This protocol focuses on the second phase of a larger study of multimodal signal acquisition through facial muscle electrical activity, cardiac electrical activity, and electrodermal activity as indicators of pain and for building predictive models. We used state-of-the-art standard sensors to measure bioelectrical electromyographic signals and changes in heart rate, respiratory rate, and oxygen saturation. Based on the results, we further developed the pain assessment tool and reconstituted it with modern wearable sensors, devices, and algorithms. In this second phase, we will test the smart pain assessment tool in communicative patients after elective surgery in the recovery room. RESULTS: Our human research protections application for institutional review board review was approved for this part of the study. We expect to have the pain assessment tool developed and available for further research in early 2021. Preliminary results will be ready for publication during fall 2020. CONCLUSIONS: This study will help to further the development of and research on an objective pain assessment tool for monitoring patients likely experiencing mild to moderate pain. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17783.