An Integrated Approach Including CRISPR/Cas9-Mediated Nanopore Sequencing, Mate Pair Sequencing, and Cytogenomic Methods to Characterize Complex Structural Rearrangements in Acute Myeloid Leukemia.

Complex structural chromosome abnormalities such as chromoanagenesis have been reported in acute myeloid leukemia (AML). They are usually not well characterized by conventional genetic methods, and the characterization of chromoanagenesis structural abnormalities from short-read sequencing still presents challenges. Here, we characterized complex structural abnormalities involving chromosomes 2, 3, and 7 in an AML patient using an integrated approach including CRISPR/Cas9-mediated nanopore sequencing, mate pair sequencing (MPseq), and SNP microarray analysis along with cytogenetic methods. SNP microarray analysis revealed chromoanagenesis involving chromosomes 3 and 7, and a pseudotricentric chromosome 7 was revealed by cytogenetic methods. MPseq revealed 138 structural variants (SVs) as putative junctions of complex rearrangements involving chromosomes 2, 3, and 7, which led to 16 novel gene fusions and 33 truncated genes. Thirty CRISPR RNA (crRNA) sequences were designed to map 29 SVs, of which 27 (93.1%) were on-target based on CRISPR/Cas9 crRNA nanopore sequencing. In addition to simple SVs, complex SVs involving over two breakpoints were also revealed. Twenty-one SVs (77.8% of the on-target SVs) were also revealed by MPseq with shared SV breakpoints. Approximately three-quarters of breakpoints were located within genes, especially intronic regions, and one-quarter of breakpoints were intergenic. Alu and LINE repeat elements were frequent among breakpoints. Amplification of the chromosome 7 centromere was also detected by nanopore sequencing. Given the high amplification of the chromosome 7 centromere, extra chromosome 7 centromere sequences (tricentric), and more gains than losses of genomic material, chromoanasynthesis and chromothripsis may be responsible for forming this highly complex structural abnormality. We showed this combination approach's value in characterizing complex structural abnormalities for clinical and research applications. Characterization of these complex structural chromosome abnormalities not only will help understand the molecular mechanisms responsible for the process of chromoanagenesis, but also may identify specific molecular targets and their impact on therapy and overall survival.

Characterization of Pediatric Reports in the US Food and Drug Administration Adverse Event Reporting System from 2010-2020: A Cross-Sectional Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a database of adverse event (AE) and medication error reports for drugs and therapeutic biologics. Examining trends of reported individual case safety reports (ICSRs) provides context for evaluating safety concerns. OBJECTIVE: Characterize pediatric FAERS ICSRs and compare trends (1) to adult reports; (2) within pediatric subgroups. METHODS: This cross-sectional study examined FAERS ICSRs received between January 1, 2010, through December 31, 2020. Stratified age bands were neonates, infants, younger children, older children, adolescents, and adults. We characterized groups by patient demographic information, suspect products, AEs, and reporter type. RESULTS: From 2010 to 2020, there were 11,258,995 FAERS ICSRs; 3.1% described pediatric patients. Compared to adults, pediatric ICSRs had higher proportions of all serious outcomes except death. Within pediatric subgroups, neonates had the highest proportions of serious outcomes (96.2%) compared to infants, younger children, older children, and adolescents (79.8%, 67.9%, 59.5%, and 52.7%, respectively). Younger pediatric age groups were more likely to have weight information than older age groups but were less likely to include gender information. The most frequently reported AE was off label use for pediatrics and drug ineffective for adults. Products and AEs reported also differed among pediatric subgroups. Neonates, infants, and adolescents had entirely distinct sets of top five product-event combinations. CONCLUSION: Pediatric ICSRs represent a minority of FAERS reports but have distinctly different attributes relative to adult ICSRs. Reporting trends also vary within pediatric subgroups, which highlights the need for unique considerations for pediatric safety surveillance.

Evaluating Opioid Dispensing Rates among Pediatrics and Young Adults based on CURES Data Reporting in California from 2015-2019.

BACKGROUND: Receipt of opioid prescriptions in pediatric and young adult patients may be a risk factor for future opioid misuse. Data from prescription drug monitoring programs provide insight on outpatient opioid use. In our study, we analyzed the opioid dispensing rates for pediatrics and young adults in California. METHODS: A secondary analysis was performed from 2015-2019 using Controlled Utilization Review and Evaluation System data. This database provides dispensing data of controlled substances in California. Patients younger than 25 years who were prescribed opiates were analyzed by county. We further divided them into two groups (children: ≤14 years; adolescents and young adult: 15-24 years). Descriptive statistics and heat maps were used to illustrate the trends in opioid usage among different age groups. RESULTS: The overall percentages for the number of opioids being dispensed to patients aged <25 years have decreased over the past four years. In 2015, 6 out of 58 counties in California were considered "high-rate" with >2.9% of opioids dispensed to patients younger than 25 years old; in 2019, this number reduced to zero. Patients 25 and older received a higher proportion of opioids compared to younger populations; in 2019, 35.91% of opioids were dispensed to patients 45-64, and 8.92% to patients younger than 25. CONCLUSION: Pediatric opioid prescriptions have declined over the recent years. However, a high degree of variability of prescription rates between demographic counties was noted. More studies are warranted in order to understand this discrepancy in opioid prescribing among pediatric and young adult patients.

One swab, two tests: Validation of dual SARS-CoV-2 testing on the Abbott ID NOW™.

BACKGROUND: Point-of-care tests (POCT) are promising tools to detect SARS-CoV-2 in specific settings. Initial reports suggest the ID NOW™ COVID-19 assay (Abbott Diagnostics Inc, USA) is less sensitive than standard real-time reverse transcription polymerase chain reaction (rRT-PCR) assays. This has raised concern over false negatives in SARS-CoV-2 POCT. OBJECTIVES: We compared the performance of the ID NOW™ COVID-19 assay to our in-house rRT-PCR assay to assess whether dry swabs used in ID NOW™ testing could be stored in transport media and be re-tested by rRT-PCR for redundancy and to provide material for further investigation. METHODS: Paired respiratory swabs collected from patients at three acute care hospitals were used. One swab in transport media (McMaster Molecular Media (MMM)) was tested for SARS-CoV-2 by a laboratory-developed two-target rRT-PCR assay. The second was stored dry in a sterile container and tested by the ID NOW™ COVID-19 assay. Following ID NOW™ testing, dry swabs were stored in MMM for up to 48 h and re-tested by rRT-PCR. Serially diluted SARS-CoV-2 particles were used to assess the impact of heat inactivation and storage time. RESULTS: Respiratory swabs (n = 343) from 179 individuals were included. Using rRT-PCR results as the comparator, the ID NOW™ COVID-19 assay had positive (PPA) and negative (NPA) percent agreements of 87.0% (95% CI:0.74-0.94) and 99.7% (95% CI:0.98-0.99). Re-tested swabs placed in MMM following ID NOW testing had PPA and NPA of 88.8% (95% CI:0.76-0.95) and 99.7% (95% CI:0.98-0.99), respectively. CONCLUSIONS: Storing spent dry swabs in transport media for redundancy rRT-PCR testing is a potential approach to address possible false negatives with the ID NOW™ COVID-19 assay.

Melanoma With an Unknown Primary in an Asymptomatic Elderly Male With Unilateral Lymphadenopathy.

Melanoma with an unknown primary (MUP) is an uncommon metastatic melanoma without an obvious primary site. MUP has a higher prevalence in men in their fifth decade of life. The pathogenesis of MUP is still unknown but several hypotheses have been proposed including the predominant regression theory, occult cutaneous, or visceral location, or by the presence of ectopic melanocytes. Proper physical examination, imaging, and histopathological review are needed to diagnose MUP. Patients with MUP must be aggressively treated and monitored for recurrence. We present a case of MUP occurring in an asymptomatic 61-year-old male with axillary lymphadenopathy. We hope to raise awareness that melanoma of unknown primary can present in lymph nodes without external structural changes.

Application of a computational model in simulating an endovascular clot retrieval service system within regional Australia.

INTRODUCTION: The global demand for endovascular clot retrieval (ECR) has grown rapidly in recent years creating challenges to healthcare system planning and resource allocation. This study aims to apply our established computational model to predict and optimise the performance and resource allocation of ECR services within regional Australia, and applying data from the state of South Australia as a modelling exercise. METHOD: Local geographic information obtained using the Google Maps application program interface and real-world data was input into the discrete event simulation model we previously developed. The results were obtained after the simulation was run over 5 years. We modelled and compared a single-centre and two-centre ECR service delivery system. RESULTS: Based on the input data, this model was able to simulate the ECR delivery system in the state of South Australia from the moment when emergency services were notified of a potential stroke patient to potential delivery of ECR treatment. In the model, ECR delivery improved using a two-centre system compared to a one-centre system, as the percentage of stroke patients requiring ECR was increased. When 15% of patients required ECR, the proportion of 'failure to receive ECR' cases for a single-centre system was 17.35%, compared to 3.71% for a two-centre system. CONCLUSIONS: Geolocation and resource utilisation within the ECR delivery system are crucial in optimising service delivery and patient outcome. Under the model assumptions, as the number of stroke cases requiring ECR increased, a two-centre ECR system resulted in increased timely ECR delivery, compared to a single-centre system. This study demonstrated the flexibility and the potential application of our DES model in simulating the stroke service within any location worldwide.

Racial and ethnic disparities in opioid use for adolescents at US emergency departments.

BACKGROUND: Racial/ethnic disparities in the use of opioids to treat pain disorders have been previously reported in the emergency department (ED). Further research is needed to better evaluate the impact race/ethnicity may have on the use of opioids in adolescents for the management of pain disorders in the ED. METHODS: This was a cross-sectional study using data from the National Hospital Ambulatory Medical Care Survey from 2006 to 2016. Multivariate models were used to evaluate the role of race/ethnicity in the receipt of opioid agonists while in the ED. All ED visits with patients aged 11-21 years old were analyzed. Races/ethnicities were stratified as non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. In addition to race, statistical analysis included the following covariates: pain score, pain diagnosis, age, region, sex, and payment method. RESULTS: There was a weighted total of 189,256,419 ED visits. Those visits involved 109,826,315 (58%) non-Hispanic Whites, 46,314,977 (24%) non-Hispanic Blacks, and 33,115,127 (18%) Hispanics, with 21.6% (95% CI, 21.1%-22.1), 15.2% (95% CI, 14.6-15.9%), and 17.4% (95% CI, 16.5-18.2%) of those visits reporting use of opioids, respectively. Regardless of age, sex, and region, non-Hispanic Whites received opioids at a higher rate than non-Hispanic Blacks and Hispanics. Based on diagnosis, non-Hispanic Whites received opioids at a higher rate in multiple pain diagnoses. Additionally, non-Hispanic Blacks and Hispanics were less likely to receive an opioid when reporting moderate pain (aOR = 0.738, 95% CI 0.601-0.906, aOR = 0.739, 95% CI 0.578-0.945, respectively) and severe pain (aOR = 0.580, 95% CI 0.500-0.672, aOR = 0.807, 95% CI 0.685-0.951, respectively) compared to non-Hispanic Whites. CONCLUSIONS: Differences in the receipt of opioid agonists in EDs among the races/ethnicities exist, with more non-Hispanic Whites receiving opioids than their minority counterparts. Non-Hispanic Black women may be an especially marginalized population. Further investigation into sex-based and regional differences are needed.

PKCα-mediated phosphorylation of the diacylglycerol kinase ζ MARCKS domain switches cell migration modes by regulating interactions with Rac1 and RhoA.

Cells can switch between Rac1 (lamellipodia-based) and RhoA (blebbing-based) migration modes, but the molecular mechanisms regulating this shift are not fully understood. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, forms independent complexes with Rac1 and RhoA, selectively dissociating each from their common inhibitor RhoGDI. DGKζ catalytic activity is required for Rac1 dissociation but is dispensable for RhoA dissociation; instead, DGKζ stimulates RhoA release via a kinase-independent scaffolding mechanism. The molecular determinants that mediate the selective targeting of DGKζ to Rac1 or RhoA signaling complexes are unknown. Here, we show that protein kinase Cα (PKCα)-mediated phosphorylation of the DGKζ MARCKS domain increased DGKζ association with RhoA and decreased its interaction with Rac1. The same modification also enhanced DGKζ interaction with the scaffold protein syntrophin. Expression of a phosphomimetic DGKζ mutant stimulated membrane blebbing in mouse embryonic fibroblasts and C2C12 myoblasts, which was augmented by inhibition of endogenous Rac1. DGKζ expression in differentiated C2 myotubes, which have low endogenous Rac1 levels, also induced substantial membrane blebbing via the RhoA-ROCK pathway. These events were independent of DGKζ catalytic activity, but dependent upon a functional C-terminal PDZ-binding motif. Rescue of RhoA activity in DGKζ-null cells also required the PDZ-binding motif, suggesting that syntrophin interaction is necessary for optimal RhoA activation. Collectively, our results define a switch-like mechanism whereby DGKζ phosphorylation by PKCα plays a role in the interconversion between Rac1 and RhoA signaling pathways that underlie different cellular migration modes.

Anxiety and Mood Disorders Impacting Physician Opioid Prescribing in the Pediatric Hospital Setting.

This research examined whether pediatric inpatients without an anxiety/mood disorder are more likely to receive opioids in response to pain compared to patients diagnosed with a mental health condition. Research questions were tested using cross-sectional inpatient electronic medical record data. Propensity score matching was used to match patients with a disorder with patients without the disorder (anxiety analyses: N = 2892; mood analyses: N = 1042). Although patients with anxiety and mood disorders experienced greater pain, physicians were less likely to order opioids for these patients. Analyses also disclosed an interaction of anxiety with pain-the pain-opioid relation was stronger for patients without an anxiety disorder than for patients with an anxiety diagnosis. Instead, physicians were more likely to place non-opioid analgesic orders to manage the pain of patients with anxiety disorders. Findings imply that pain management decisions might be influenced by patient's mental health.

Evaluating risk factors for acute graft versus host disease in pediatric hematopoietic stem cell transplant patients receiving tacrolimus.

To identify the clinical and pharmacological risk factors associated with tacrolimus pharmacodynamics for acute graft-versus-host disease (aGVHD) in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. A retrospective cohort single center chart review study was conducted with pediatric patients who received tacrolimus prophylaxis after allogeneic HSCT between January 1, 2017, and December 31, 2019. Potential risk factors were tested separately between aGVHD and non-aGVHD cohorts and were further analyzed in a logistic regression model with backward elimination and a partial least squares discriminant analysis. Thirty-three patient cases were included in our study and 52% (17/33) developed aGVHD while on tacrolimus prophylaxis. When tested independently, donor age and sibling versus parent donor/recipient relation were shown to be statistically significant between aGVHD and non-aGVHD patients (p < 0.005). Pharmacological factors associated with tacrolimus treatment failed to demonstrate a significant impact on patient's risk of aGVHD. Using a best fit logistic regression model that tested all the variables together, donor age was the only significant variable predicting patient's risk of aGVHD (p < 0.01). Donor relationship and donor age were unable to be evaluated separately and are therefore confounding variables. Among pediatric patients receiving allogeneic HSCT, aGVHD risk is significantly decreased by either sibling donor and/or younger donors. Although no conclusions were drawn on the effect of tacrolimus therapy (p = 0.08), results warrant additional research with a larger sample size to evaluate the accuracy of monitoring tacrolimus serum trough levels.

Parental Psychosocial Factors Moderate Opioid Administration Following Children's Surgery.

BACKGROUND: This investigation aimed to examine the impact of parental psychosocial variables on the administration of opioids to young children experiencing postoperative pain. METHODS: Participants in this longitudinal analysis were children ages 2-12 undergoing tonsillectomy with or without adenoidectomy and their parents. Parents completed validated instruments assessing trait anxiety, perceived stress, and coping style before surgery, and children and parents completed instruments assessing pain and administration of opioids and acetaminophen on days 1, 2, 3, and 7 at home after surgery. The structure of the data was such that parents and children completed multiple data assessments making the data multilevel (ie, days of data within dyads). To address this issue of data structure, multilevel modeling was used to analyze the dataset. RESULTS: Participants included 173 parent-child dyads (mean child age = 5.99 ± 2.51) recruited between 2012 and 2017. We found that parent-related psychosocial variables, such as trait anxiety, stress, and coping style, moderated the relationship between the child's pain and postoperative medication administration. Specifically, when predicting hydrocodone, the interactions between anxiety and pain and stress and pain were significant; when child pain was high, high-anxiety and high-stressed parents gave their children 19% and 12% more hydrocodone, respectively, compared to low-anxiety and low-stressed parents. When predicting acetaminophen, the interactions between anxiety and pain, a blunting coping style and pain, and a monitoring coping style and pain were significant. CONCLUSIONS: These results suggest the need to identify parents who experience high levels of perceived stress and trait anxiety and use appropriate interventions to manage stress and anxiety. This may ensure children receive optimal amounts of pain medication following surgery.

Evaluating the 0-10 Point Pain Scale on Adolescent Opioid Use in US Emergency Departments.

OBJECTIVE: To evaluate trends in national emergency department (ED) adolescent opioid use in relation to reported pain scores. METHODS: A retrospective, cross-sectional analysis on National Hospital Ambulatory Medical Care Survey (NHAMCS) data was conducted on ED visits involving patients aged 11-21 from 2008-2017. Crude observational counts were extrapolated to weighted estimates matching total population counts. Multivariate models were used to evaluate the role of a pain score in the reported use of opioids. Anchors for pain scores were 0 (no pain) and 10 (worst pain imaginable). RESULTS: 31,355 observations were captured, which were extrapolated by the NHAMCS to represent 162,515,943 visits nationwide. Overall, patients with a score of 10 were 1.35 times more likely to receive an opioid than patients scoring a 9, 41.7% (CI95 39.7-43.8%) and 31.0% (CI95 28.8-33.3%), respectively. Opioid use was significantly different between traditional pain score cutoffs of mild (1-3) and moderate pain (4-6), where scores of 4 were 1.76 times more likely to receive an opioid than scores of 3, 15.5% (CI95 13.7-17.3%) and 8.8% (CI95 7.1-10.6%), respectively. Scores of 7 were 1.33 times more likely to receive opioids than scores of 6, 24.7% (CI95 23.0-26.3%) and 18.5% (CI95 16.9-20.0%), respectively. Fractures had the highest likelihood of receiving an opioid, as 49.2% of adolescents with a fracture received an opioid (CI95 46.4-51.9%). Within this subgroup, only adolescents reporting a fracture pain score of 10 had significantly higher opioid use than adjacent pain scores, where fracture patients scoring a 10 were 1.4 times more likely to use opioids than those scoring 9, 82.2% (CI95 76.1-88.4%) and 59.8% (CI95 49.0-70.5%), respectively. CONCLUSIONS: While some guidelines in the adult population have revised cut-offs and groupings of the traditional tiers on a 0-10 point pain scale, the adolescent population may also require further examination to potentially warrant a similar adjustment.

Race, Ethnicity, and Insurance: the Association with Opioid Use in a Pediatric Hospital Setting.

BACKGROUND: This study examined the association between race/ethnicity and health insurance payer type with pediatric opioid and non-opioid ordering in an inpatient hospital setting. METHODS: Cross-sectional inpatient encounter data from June 2013 to June 2018 was retrieved from a pediatric children's hospital in Southern California (N = 55,944), and statistical analyses were performed to determine associations with opioid ordering. RESULTS: There was a significant main effect of race/ethnicity on opioid and non-opioid orders. Physicians ordered significantly fewer opioid medications, but a greater number of non-opioid medications, for non-Hispanic African American children than non-Hispanic Asian, Hispanic/Latinx, and non-Hispanic White pediatric patients. There was also a main effect of health insurance payer type on non-opioid orders. Patients with government-sponsored plans (e.g., Medi-Cal, Medicare) received fewer non-opioid prescriptions compared with patients with both HMO and PPO coverage. Additionally, there was a significant race/ethnicity by insurance interaction on opioid orders. Non-Hispanic White patients with "other" insurance coverage received the greatest number of opioid orders. In non-Hispanic African American patients, children with PPO coverage received fewer opioids than those with government-sponsored and HMO insurance. For non-Hispanic Asian patients, children with PPO were prescribed more opioids than those with government-sponsored and HMO coverage. CONCLUSION: Findings suggest that the relationship between race/ethnicity, insurance type, and physician decisions opioid prescribing is complex and multifaceted. Given that consistency in opioid prescribing should be seen regardless of patient background characteristics, future studies should continue to assess and monitor unequitable differences in care.

A community effort for automatic detection of postictal generalized EEG suppression in epilepsy.

Applying machine learning to healthcare sheds light on evidence-based decision making and has shown promises to improve healthcare by combining clinical knowledge and biomedical data. However, medicine and data science are not synchronized. Oftentimes, researchers with a strong data science background do not understand the clinical challenges, while on the other hand, physicians do not know the capacity and limitation of state-of-the-art machine learning methods. The difficulty boils down to the lack of a common interface between two highly intelligent communities due to the privacy concerns and the disciplinary gap. The School of Biomedical Informatics (SBMI) at UTHealth is a pilot in connecting both worlds to promote interdisciplinary research. Recently, the Center for Secure Artificial Intelligence For hEalthcare (SAFE) at SBMI is organizing a series of machine learning healthcare hackathons for real-world clinical challenges. We hosted our first Hackathon themed centered around Sudden Unexpected Death in Epilepsy and finding ways to recognize the warning signs. This community effort demonstrated that interdisciplinary discussion and productive competition has significantly increased the accuracy of warning sign detection compared to the previous work, and ultimately showing a potential of this hackathon as a platform to connect the two communities of data science and medicine.

Parent responses to pediatric pain: The differential effects of ethnicity on opioid consumption.

OBJECTIVE: Within the context of the United States opioid epidemic, some parents often fear the use of opioids to help manage their children's postoperative pain. As a possible consequence, parents often do not dispense optimal analgesic medications to their children after surgery, putting their children at risk of suffering from postsurgical pain. The objective of this research was to assess ethnicity as a predictor of both pain and opioid consumption, and to examine how Hispanic/Latinx and Non-Hispanic White parents alter their child's opioid consumption in response to significant postsurgical pain. METHODS: Participants were 254 children undergoing outpatient tonsillectomy and/or adenoidectomy surgery and their parents. Longitudinal multilevel modeling examined changes in both parent-reported pain and hydrocodone/APAP consumption (mg/kg) on days 1 to 7 after surgery. RESULTS: Parent reports of postoperative pain were higher in Hispanic/Latinx patients compared to their Non-Hispanic White counterparts (ß = -0.15; 95% CI: -0.28, -0.01). There was also a significant interaction of ethnicity and pain on opioid consumption (ß = 0.07; 95% CI: 0.01, 0.13). The relationship between parent perceived pain and opioid use was stronger for Non-Hispanic White children, suggesting that this group was more likely to consume opioids to help manage clinically significant postsurgical pain. CONCLUSIONS: Hispanic/Latinx children might be at risk for undertreatment of surgical pain. Findings highlight the importance of assessing parent background and cultural beliefs as predictors of at home pain management and the potential effectiveness of tailored interventions that educate parents about monitoring and treating child postoperative pain.

Dermal Hemorrhage: A Clue to Lichen Sclerosus et Atrophicus.

Lichen sclerosus et atrophicus (LSA) may present in a rare bullous and hemorrhagic form that is often difficult to recognize both clinically and histopathologically. Clinically, the lesions may be characterized by atrophic and ivory-white sclerotic plaques in both genital and extragenital regions. Histologically, fully developed lesions of LSA are characterized by a thinned, effaced epidermis with interface change, a wide band of hyalinization in the upper dermis, and a lymphohistiocytic infiltrate below the hyalinized area. Extensive vacuolar degeneration weakens the integrity of the dermoepidermal junction, which contributes to the development of marked edema in the papillary dermis and subepidermal vesiculation. With increased fragility of dermal capillaries, hemorrhage can accumulate within the bullae. Recognizing prominent upper dermal hemorrhage as a secondary change may lead to a prompt diagnosis of LSA. We present a case of extragenital LSA that mimics a dermal hemorrhage clinically and histologically in a 71-year-old Caucasian woman.

Geographic Service Delivery for Endovascular Clot Retrieval: Using Discrete Event Simulation to Optimize Resources.

BACKGROUND: Endovascular clot retrieval (ECR) is the standard of care for acute ischemic stroke caused by large vessel occlusion. Reducing stroke symptom onset to reperfusion time is associated with improved functional outcomes. This study aims to develop a computational model to predict and identify time-related outcomes of community stroke calls within a geographic area based on variable parameters to support planning and coordination of ECR services. METHODS: A discrete event simulation (DES) model to simulate and predict ECR service was designed using SimPy, a process-based DES framework written in Python. Geolocation data defined by the user, as well as that used by the model, were sourced using the Google Maps application programming interface. Variables were customized by the user on the basis of their local environment to provide more accurate prediction. RESULTS: A DES model can estimate the delay between the time that emergency services are notified of a potential stroke and potential cerebral reperfusion using ECR at a capable hospital. Variables can be adjusted to observe the effect of modifying each parameter input. By varying the percentage of stroke patients receiving ECR, we were able to define the levels at which our existing service begins to fail in service delivery and assess the effect of adding centers. CONCLUSIONS: This novel computational DES model can aid the optimization of delivery of a stroke service within a city, state, or country. By varying geographic, population, and other user-defined inputs, the model can be applied to any location worldwide.

Children's cancer pain in a world of the opioid epidemic: Challenges and opportunities.

The opioid crisis in the United States has grown at an alarming rate. Children with cancer are at high risk for pain, and opioids are a first-line treatment in this population. Accordingly, there is an urgent need to optimize pain management in children with cancer without contributing to the opioid crisis. This report details opportunities for this optimization, including clinical practice guidelines, comprehensive approaches to pain management, mobile health, and telemedicine. It is vital to balance appropriate use of analgesics with efforts to prevent misuse in order to reduce unnecessary suffering and minimize unintended harms.