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INTRODUCTION In trauma care, pelvic fractures contribute to morbidity and mortality. Since men and women have different pelvic structures and hormonal milieu, we studied if these gender differences affect clinical outcomes after pelvic fractures. METHODS Using the 2016 American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) database, we stratified 24,425 patients with pelvic fractures by gender. Male and female patients were analyzed for differences in comorbidities, mechanism of injury, complications, and other clinical parameters. RESULTS Female patients were older (p

Introduction Assaults inflicting penetrating head and neck trauma have potential for serious morbidity or mortality. This paper studies in-depth all cases treated at a level one trauma centre in the North East of England over 10 years. Methods All patients assaulted with sharp implements to the head and neck treated from 2010 to 2019 were identified using clinical codes. Results Retrospective data collection were as follows: 214 patients identified (189 male, 25 female). Average age was 31.5 years (range 3–80). The majority presented between 20:00 and 05:00. Knives were the commonest weapon. Fifty-two had scalp, 137 face and 69 neck injuries. Forty-eight percent had additional non-head and neck injuries. Eighty-six percent required admission, 16.6% to intensive care. Oral and maxillofacial and plastic surgeons provided most treatment. One hundred two required treatment under general and 96 local anaesthetic. Sixteen patients had significant vascular injury, 1 brachial plexus injury, 4 facial nerve injuries (of which 3 repaired) and one required parotid duct repair. Mean length of stay was 3.7 days. No mortality was recorded. Incidence significantly increased from 2010 to 2019. Conclusions Head and neck penetrating injuries occur frequently, often with other injuries and mainly in young males. Incidence of significant vascular or nerve injury was low. This study provides important data for those planning trauma services.

Genetic diseases involving overactivation of the mechanistic target of rapamycin (mTOR) pathway, so-called “mTORopathies,” often manifest with malformations of cortical development (MCDs), epilepsy, and cognitive impairment. How mTOR pathway hyperactivation results in abnormal human cortical development is poorly understood. To study the effect of mTOR hyperactivity on early stages of cortical development, we focused on Pretzel Syndrome (polyhydramnios, megalencephaly, symptomatic epilepsy; PMSE syndrome), a rare mTORopathy caused by homozygous germline mutations in the STRADA gene. We developed a human cortical organoid (hCO) model of PMSE and examined morphology and size for the first 2 weeks of organoid growth, and cell type composition at weeks 2, 8, and 12 of differentiation. In the second week, PMSE hCOs enlarged more rapidly than controls and displayed an abnormal Wnt pathway-dependent increase in neural rosette structures. PMSE hCOs also exhibited delayed neurogenesis, decreased subventricular zone progenitors, increased proliferation and cell death, and an abnormal architecture of primary cilia. At week 8, PMSE hCOs had fewer deep layer neurons. By week 12, neurogenesis recovered in PMSE organoids, but they displayed increased outer radial glia, a cell type thought to contribute to the expansion of the human cerebral cortex. Together, these findings suggest that megalencephaly in PMSE arises from the expansion of neural stem cells in early corticogenesis and potentially also from increased outer radial glial at later gestational stages. The delayed neuronal differentiation in PMSE organoids demonstrates the important role the mTOR pathway plays in the maintenance and expansion of the stem cell pool.

Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion of M1, pro-inflammatory/growth-inhibiting, to M2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization to M1 are a novel approach that harnesses the immune system to enhance therapeutic outcomes, including chemotherapy. We recently found that nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel (MSV-nab-PTX) promotes macrophage polarization towards M1 in breast cancer liver metastases (BCLM). However, it remains unclear to what extent tumor regression can be maximized based on modulation of the macrophage phenotype, especially for poorly perfused tumors such as BCLM. Here, for the first time, a CRISPR system is employed to permanently modulate macrophage polarization in a controlled in vitro setting. This enables the design of 3D co-culture experiments mimicking the BCLM hypovascularized environment with various ratios of polarized macrophages. We implement a mathematical framework to evaluate nanoparticle-mediated chemotherapy in conjunction with TAM polarization. The response is predicted to be not linearly dependent on the M1:M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety of M1:M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of both M1 and M2. Experimental results with the CRISPR system confirm this model-driven hypothesis. Altogether, this study indicates that response to nanoparticle-mediated chemotherapy targeting poorly perfused tumors may benefit from a fine-tuned M1:M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.

Background To review retrospectively the outcomes of management of Fournier’s gangrene (FG) and to assess for possible seasonal variations in clinical presentations of FG to a referral hospital in a tropical African country. Methods The medical records of patients who presented with FG from February 2012 to December 2019 were reviewed. Of interest were age of patient, vital signs at presentation, site of gangrene, duration of hospital admission, and management interventions deployed. Analysis was with SPSS® version 21. Results Twenty-three of 28 medical records could be analyzed. Median Fournier’s Gangrene Severity Index (FGSI) was 5 (IQR:3–10), the median Uludag-FGSI (UFGSI) was 7 (IQR:4–14). In 82.6%, the scrotum was the site of onset; in 8.7%, the lesion had spread beyond the pelvis. Diabetes mellitus (30.4%), HIV infection (13.0%) and nephropathy (17.4%) were identified co-morbidities. There were 2.4 ± 1.0 debridement sessions and 1.5 ± 1.3 transfused units of blood per patient. In 60.9%, the wound edges were undermined and apposed; in 17.4%, split skin grafting or fascio-cutaneous flap cover was deployed. In 17.4%, satisfactory wound closure needed more than 1 theater session. Mean duration of hospital admission was 51.4 ± 19.4 days. No mortality was recorded. Majority (91.2%) presented in hot, dry months of October through March with peak in December. No case presented in the wet months of May through September. Conclusion Meager resources notwithstanding, FG management outcomes are generally satisfactory. Furthermore, FG is observed to present mostly in the hot, dry months of the year in the 8 years under review.

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (

mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9-13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO-/-) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada-/- mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada-/- animals survived past P5. Strada-/- mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada-/- brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination.

We describe an individual with refractory epilepsy with myoclonic-atonic seizures (EMAS) and a suspected pathogenic variant in SCN1B, who had substantial improvement with phenytoin treatment. It is unknown whether SCN1B-related epilepsy improves or worsens with sodium channel blockers (SCBs), and this case demonstrates their potential benefit.

Summary: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain. : In this article, Isom, Parent, and colleagues show that the high risk of SUDEP in the developmental and epileptic encephalopathy, Dravet syndrome, may result from a predisposition to cardiac arrhythmias in addition to neuronal hyperexcitability, reflecting haploinsufficiency of SCN1A in heart and brain causing potential compensatory overexpression of other sodium-channel genes in those tissues. Keywords: epilepsy, cardiac arrhythmia, sodium channel, SUDEP, induced pluripotent stem cell (iPSC), developmental and epileptic encephalopathy

Parasomnias are common in childhood but there is no established treatment for parasomnias. The aim of this study was to (1) report on the outcome of using L-tryptophan to manage parasomnias in children and (2) examine sleep architecture and subjective psychological/sleep symptoms in children with parasomnia.A retrospective analysis was conducted of charts of children (3-18 years old) who underwent polysomnographic testing and were diagnosed with primary parasomnia. Study patients were either prescribed L-tryptophan (daily dose range: 500-4500 mg, mean dose of 2400 mg) to manage their parasomnias or administered no treatment whereby parents/guardians declined treatment. Questionnaires assessing sleep and psychosocial symptoms were administered at the initial clinical consultation and a follow-up parasomnia outcome questionnaire was administered over the phone to parents/guardians.One hundred and sixty-five children (106 boys, 59 girls) received a sleep diagnosis of primary parasomnia. A significantly (p 0.001) higher proportion (84%) of children taking L-tryptophan experienced improvements in their parasomnia symptoms compared with those (47%) who chose not to use L-tryptophan. Polysomnography revealed that children with parasomnias had an altered sleep architecture based on age-related normative values. Children with a diagnosis of parasomnia were also subjectively more fatigued and endorsed more depressive symptoms.This study finds that parasomnias in children are not benign and that treatment with L-tryptophan provides a favorable outcome. Children diagnosed with parasomnia had altered sleep architecture, were more fatigued, and endorsed depressive symptoms. This study supports the need to diagnose and treat parasomnias in children.

HIF-1 is a ubiquitous signaling molecule constantly expressed by the body, but is degraded during normoxic conditions. In hypoxic conditions, it persists and is active. Hypoxia is often associated with trauma due to interrupted blood flow, inflammation or other reasons, causing HIF-1 to be active in signaling and recovery. In this review, the function of HIF-1 is examined, as well as its clinical significance with regard to trauma and critical care. Using this information, we then identify potential points of treatment and intervention.

The mainstay of treatment of childhood epilepsy is to administer antiepileptic drugs (AEDs). This article provides an overview of the clinical approach to drug treatment of childhood epilepsy, focusing on general principles of therapy and properties of recently introduced medications. Initiation and cessation of therapy, adverse medication effects, drug interactions, indications for the various AEDs, and off-label use of AEDs are reviewed. The distinct challenges in treatment of epileptic spasms and neonatal seizures are addressed. Finally, ideas for the future of drug treatment of childhood epilepsy are presented, with particular attention to precision medicine.

The high prevalence of pediculosis capitis, commonly known as head lice (Pediculus humanus capitis) infestation, has led to the preparation of a community-based pediculicidal ointment, which is made of common household items and the extract of Tinospora crispa stem. The present study aimed to evaluate the safety, efficacy, and physicochemical characteristics of the T. crispa pediculicidal ointment. The physicochemical properties of the ointment were characterized, and safety was determined using acute dermal irritation test (OECD 404), while the efficacy was assessed using an in vitro pediculicidal assay. Furthermore, the chemical compounds present in T. crispa were identified using liquid-liquid extraction followed by ultra-performance liquid chromatography quadruple time-of-flight mass spectrometric (UPLC-qTOF/MS) analysis. The community-based ointment formulation was light yellow in color, homogeneous, smooth, with distinct aromatic odor and pH of 6.92±0.09. It has spreadability value of 15.04±0.98 g·cm/sec and has thixotropic behavior. It was also found to be non-irritant, with a primary irritation index value of 0.15. Moreover, it was comparable to the pediculicidal activity of the positive control Kwell®, a commercially available 1% permethrin shampoo (P>0.05), and was significantly different to the activity of the negative control ointment, a mixture of palm oil and candle wax (P

Cancer has traditionally been studied from a basic science perspective, focusing on the underlying biology, physiology, and biochemistry. Engineering has supplemented this effort via the development of technology, e.g., microscopy. In recent times, engineering and the physical sciences have positioned themselves as approaches on par with the traditional basic sciences to tackle the study of cancer. Mathematical modeling and computational simulation have become key elements of this engineering-focused effort, evaluating the growth of tumors and their response to therapy as problems that could benefit from a systems analysis perspective. Building upon previous work in this field, here is developed a modeling framework to help evaluate the response of tumors to the combination of chemotherapy and immunotherapy, focusing on non-small cell lung cancer (NSCLC). With system parameters set with patient tumor-specific parameters, the longer term goal of this work is to advance personalized cancer treatment.

Introduction SARS-CoV-2 changed the lives of children and their parents in 2020. To our knowledge, no studies have examined infant and toddler sleep during this pandemic. We sought to compare parent-reported sleep characteristics of infants and toddlers over successive quarters of the past year. Methods Parents of children aged 0–36 months were surveyed primarily in the Midwestern USA between 01/17/2020 and 12/07/2020. Each parent responded only once. Age was categorized as: $150,000. The year was divided into quarters. Multivariable linear regression included Total Sleep Time (TST), Sleep Onset Latency (SOL) and parental frustration with sleep (any frustration, scale of 1–5) as dependent variables and year quarter, child’s age, prematurity, child’s comorbidities, maternal age (during their child’s birth), parenting experience, household income, and room sharing as independent variables. Logistic regression included nap consistency (napping at the same time daily) as the dependent variable, and year quarter, child’s age, prematurity, comorbidity, maternal age, parenting experience, household income, and room sharing as independent variables. Results Of 594 children, mean age was 18.5±9.7 months and 52% were female. Prematurity and comorbidities were reported for 8% and 15%, respectively. Mean maternal age was 31.8±4.5 years. Neither TST (β=-0.488; p= 0.16) nor SOL (β= 0.029; p=0.23) were associated with year quarter. SOL was 3 minutes less for each increase in income category (β =-0.051; p= 0.003). TST (β = -0.994; p Conclusion Parent-estimated TST, nap consistency and sleep-related frustration did not differ significantly over the first 12 months of the pandemic. Yet, our results underscore that special attention should be given to the sleep of infants and toddlers with comorbidities, who share a room, and who have a lower household income. Support (if any) 2T32HL110952-06

Neuroblastoma, the most frequently occurring extracranial solid tumor of childhood, arises from neural crest-derived cells that are arrested at an early stage of differentiation in the developing sympathetic nervous system. There is an urgent need to identify clinically relevant biomarkers for better prognosis and treatment of this aggressive malignancy. Eyes Absent 1 (EYA1) is an essential transcriptional coactivator for neuronal developmental programs during organogenesis. Whether or not EYA1 is implicated in neuroblastoma and subcellular localization of EYA1 is relevant to clinical behaviour of neuroblastoma is not known. We studied EYA1 expression and subcellular localization by immunohistochemistry in tissue microarrays containing tumor specimens from 98 patients, 66 of which were characterized by known clinical prognostic markers of neuroblastoma. Immunostaining results were evaluated and statistically correlated with the degree of histologic differentiation and with neuroblastoma risk stratification group characteristics, including stage of disease, patient age, tumor histology and mitosis–karyorrhexis index (MKI), respectively. We found that EYA1 levels were significantly higher in neuroblastomas than in ganglioneuromas and ganglioneuroblastomas. EYA1 was more highly expressed in stage 1,2,3 or 4S tumors as compared to stage 4 tumors (P

// Allison Eberhardt 1 , Jeanne N. Hansen 1 , Jan Koster 2 , Louis T. Lotta Jr. 1 , Simeng Wang 1 , Emmett Livingstone 1 , Kun Qian 3 , Linda J. Valentijn 2 , Yujun George Zheng 3 , Nina F. Schor 1 , Xingguo Li 1 1 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA 2 Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands 3 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA Correspondence to: Nina F. Schor, email: Nina_schor@urmc.rochester.edu Xingguo Li, email: Xingguo_li@urmc.rochester.edu Keywords: neuroblastoma, MYCN, PRMT1, arginine methylation, protein stability Received: April 30, 2016 Accepted: August 13, 2016 Published: August 23, 2016 ABSTRACT Amplification or overexpression of MYCN is associated with poor prognosis of human neuroblastoma. We have recently defined a MYCN-dependent transcriptional signature, including protein arginine methyltransferase 1 (PRMT1), which identifies a subgroup of patients with high-risk disease. Here we provide several lines of evidence demonstrating PRMT1 as a novel regulator of MYCN and implicating PRMT1 as a potential therapeutic target in neuroblastoma pathogenesis. First, we observed a strong correlation between MYCN and PRMT1 protein levels in primary neuroblastoma tumors. Second, MYCN physically associates with PRMT1 by direct protein-protein interaction. Third, depletion of PRMT1 through siRNA knockdown reduced neuroblastoma cell viability and MYCN expression. Fourth, we showed that PRMT1 regulates MYCN stability and identified MYCN as a novel substrate of PRMT1. Finally, we demonstrated that mutation of putatively methylated arginine R65 to alanine decreased MYCN stability by altering phosphorylation at residues serine 62 and threonine 58. These results provide mechanistic insights into the modulation of MYCN oncoprotein by PRMT1, and suggest that targeting PRMT1 may have a therapeutic impact on MYCN-driven oncogenesis.

Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.

Bitter taste receptors (Tas2Rs) are a subfamily of G-protein coupled receptors expressed not only in the oral cavity but also in several extra-oral tissues and disease states. Several natural bitter compounds from plants, such as bitter melon extract and noscapine, have displayed anti-cancer effects against various cancer types. In this study, we examined the prevalence of Tas2R subtype expression in several epithelial ovarian or prostate cancer cell lines, and the functionality of Tas2R14 was determined. qPCR analysis of five TAS2Rs demonstrated that mRNA expression often varies greatly in cancer cells in comparison to normal tissue. Using receptor-specific siRNAs, we also demonstrated that noscapine stimulation of ovarian cancer cells increased apoptosis in ovarian cancer cells in a receptor-dependent, but ROS-independent manner. This study furthers our understanding of the function of Tas2Rs in ovarian cancer by demonstrating that their activation has an impact on cell survival.

Efficient patient transportation by ground emergency medical services (GEMS) or helicopter emergency medical services (HEMS) to a trauma center is vital for optimal care. We investigated differences between the modes of transport in terms of demographics, injury, scene location, and outcome.Morristown Medical Center (MMC), Morristown, NJ METHODS: All 903 trauma admissions in 2016 by advanced life support (ALS) to MMC, a Level I Trauma Center, were retrospectively analyzed.22% of admissions were HEMS and 78% were GEMS. HEMS patients had higher Injury Severity Scores (ISS) (p0.001); however, mortality and length of stay were not statistically different. The percentage of pediatric patients transported by HEMS that were discharged home after emergency department evaluation was greater than the older populations (p0.001). Older age and higher ISS had the largest impact on mortality (p0.001).We believe our current use of HEMS is adequate since patient outcomes between HEMS and GEMS was similar, even though HEMS patients have higher ISS. However, helicopter use in the pediatric population was over-utilized, possibly due to the scarcity of hospitals capable of managing pediatric traumas. Implementation of the Air Medical Prehospital Triage scoring system may also help correct for these unnecessary HEMS transports.

Giant cell-rich osteosarcoma by its abundance of osteoclastic giant cells and paucity of tumor osteoid, leads to its easy confusion with giant cell tumor during biopsy interpretation. In this report, we describe a unique case of upper fibular metaphyseal giant cell-rich osteosarcoma in a 12-year-old boy; the radiographic and histopathologic features of the biopsy and initial resected tumor are virtually indistinguishable from conventional giant cell tumor. The tumor rapidly recurred 7 months after resection with metastasis to the groin lymph nodes, was resistant to first-line chemotherapy and pursued an aggressive course, developing disseminated metastasis to the lung, liver, pelvis, scapula and clavicle, and resulted in the death of the patient 21 months after initial presentation. The subtle features alerting one to the possibility of giant cell-rich osteosarcoma are retrospectively evaluated in comparison with cases of metaphyseal conventional giant cell tumors, four from our records and those from literature review. We conclude that the occurrence of a giant cell-rich lesion in the metaphysis of a skeletally immature individual merits careful assessment for the presence of periosteal reaction, permeative infiltrative margins, lacelike osteoid formation, high mitotic activity or Ki67 proliferative index, and extra-tumoral lymphovascular permeation, since the possibility of an aggressive lesion notably giant cell-rich osteosarcoma probably increases with the number of such features.

Chemotherapy for non-small cell lung cancer (NSCLC) typically involves a doublet regimen for a number of cycles. For any particular patient, a course of treatment is usually chosen from a large number of combinational protocols with drugs in concomitant or sequential administration. In spite of newer drugs and protocols, half of patients with early disease will live less than five years and 95% of those with advanced disease survive for less than one year. Here, we apply mathematical modeling to simulate tumor response to multiple drug regimens, with the capability to assess maximum tolerated dose (MTD) as well as metronomic drug administration. We couple pharmacokinetic-pharmacodynamic intracellular multi-compartment models with a model of vascularized tumor growth, setting input parameters from in vitro data, and using the models to project potential response in vivo. This represents an initial step towards the development of a comprehensive virtual system to evaluate tumor response to combinatorial drug regimens, with the goal to more efficiently identify optimal course of treatment with patient tumor-specific data. We evaluate cisplatin and gemcitabine with clinically-relevant dosages, and simulate four treatment NSCLC scenarios combining MTD and metronomic therapy. This work thus establishes a framework for systematic evaluation of tumor response to combination chemotherapy. The results with the chosen parameter set indicate that although a metronomic regimen may provide advantage over MTD, the combination of these regimens may not necessarily offer improved response. Future model evaluation of chemotherapy possibilities may help to assess their potential value to obtain sustained NSCLC regression for particular patients, with the ultimate goal of optimizing multiple-drug chemotherapy regimens in clinical practice.

To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes. We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter

Neuroblastoma is a cancer of the neural crest almost exclusively seen in childhood. While children with single, small primary tumors are often cured with surgery alone, the 65% of children with neuroblastoma whose disease has metastasized have less than a 50% chance of surviving five years after diagnosis. Innovative pharmacological strategies are critically needed for these children. Efforts to identify novel targets that afford ablation of neuroblastoma with minimal toxicity to normal tissues are underway. Developing approaches to neuroblastoma include those that target the catecholamine transporter, ubiquitin E3 ligase, the ganglioside GD2, the retinoic acid receptor, the protein kinases ALK and Aurora, and protein arginine N-methyltransferases. Here, as examples of the use of chemistry to combat neuroblastoma, we describe targeting of the protein arginine N-methyltransferases and their role in prolonging the half-life of the neuroblastoma oncoprotein N-Myc, redox signaling in neuroblastoma, and developmentally regulated proteins expressed in primitive neuroblastoma cells but not in mature neural crest elements.

The generation of human induced pluripotent stem cells (iPSCs) and their differentiation into neural cells have generated great interest for modeling genetic epilepsies. The study of genetic diseases using human cell models containing the patient-specific genetic background can provide important information on pathogenic mechanisms, particularly when animal models have not been faithful in recapitulating a specific disorder. In this chapter we discuss techniques for deriving iPSCs, differentiating the iPSCs into neurons in monolayer, as well as three-dimensional (3D) cultures, and various assays to study the iPSC-derived neurons. We also review the genetic epilepsies that have been modeled to date using iPSCs. Finally, we examine the potential for iPSC-based models to aid in the development of therapies for epilepsy.

Hurricane Sandy was a particularly unusual storm with regard to both size and location of landfall. The storm landed in New Jersey, which is unusual for a tropical storm of such scale, and created hazardous conditions which caused injury to residents during the storm and in the months following. This study aims to describe differences in trauma center admissions and patterns of injury during this time period when compared to a period with no such storm. Data were collected for this study from patients who were admitted to the trauma center at Morristown Medical Center during Hurricane Sandy or the ensuing cleanup efforts (patients admitted between 29 October 2012 and 27 December 2012) as well as a control group consisting of all patients admitted to the trauma center between 29 October 2013 and 27 December 2013. Patient information was collected to compare the admissions of the trauma center during the period of the storm and cleanup to the control period. A total of 419 cases were identified in the storm and cleanup period. 427 were identified for the control. Striking injuries were more common in the storm and cleanup group by 266.7% (p = 0.0107); cuts were more common by 650.8% (p = 0.0044). Medical records indicate that many of these injuries were caused by Hurricane Sandy. Self-inflicted injuries were more common by 301.3% (p = 0.0294). There were no significant differences in the total number of patients, mortality, or injury severity score between the two cohorts. The data we have collected show that the conditions caused by Hurricane Sandy and the following cleanup had a significant effect on injury patterns, with more patients having been injured by being struck by falling or thrown objects, cut while using tools, or causing self-inflicted injuries. These changes, particularly during the cleanup period, are indicative of environmental changes following the storm which increase these risks of injury.

Polymer nanoassemblies (PNAs) with drug release fine-tuned to occur in acidic tumor regions (pH 7) while sparing normal tissues (pH = 7.4) were previously shown to hold promise as nanoparticle drug carriers to effectively suppress tumor growth with reduced systemic toxicity. However, therapeutic benefits of pH-controlled drug delivery remain elusive due to complex interactions between the drug carriers, tumor cells with varying drug sensitivity, and the tumor microenvironment.We implement a combined computational and experimental approach to evaluate the in vivo antitumor activity of acid-sensitive PNAs controlling drug release in pH 5 ~ 7.4 at different rates [PNA1 (fastest) PNA2 PNA3 (slowest)].Computational simulations projecting the transport, drug release, and antitumor activity of PNAs in primary and metastatic tumor models of colorectal cancer correspond well with experimental observations in vivo. The simulations also reveal that all PNAs could reach peak drug concentrations in tumors at 11 h post injection, while PNAs with slower drug release (PNA2 and PNA3) reduced tumor size more effectively than fast drug releasing PNA1 (24.5 and 20.3 vs 7.5%, respectively, as fraction of untreated control).A combined computational/experimental approach may help to evaluate pH-controlled drug delivery targeting aggressive tumors that have substantial acidity.

In accordance with recent terminology, it is proposed that malignant mesenchymoma should be renamed 'composite sarcoma' and defined as 'a sarcoma composed of two or more cellular types each of which is sufficiently differentiated to permit clear recognition of its histogenetic type microscopically, immunohistochemically or ultrastructurally; excluding fibrosarcomatous and high-grade pleomorphic undifferentiated sarcomatous component, dedifferentiated sarcoma and the combination of osteosarcoma and chondrosarcoma which is regarded as a single histogenetic type'. Four cases of primary osseous composite sarcoma (POCS) were identified among 928 primary bone sarcomas. Their age ranged from 10 to 87 years, peak incidence in the second decade with equal sex distribution. Most presented with pain, commonest in the knee, affecting the metaphysis, appearing radiologically as expansile infiltrative osteolytic lesions with cortical erosion, periosteal reaction, variable extent of osteoblastic areas and soft tissue extension. All contained variable amounts of conventional high-grade osteosarcoma with or without chondrosarcoma component; the other constituents were liposarcoma, rhabdomyosarcoma and leiomyosarcoma. In all cases, Ki67 proliferative index was over 35%, there was no CDK4 and MDM2 amplification. The absence of low-grade component supported the de novo origin of POCS rather than derivation from divergent dedifferentiation. The two older patients with hitherto undescribed osteoleiomyosarcoma died 2 and 10 months after operation, whereas the two younger with osteorhabdomyosarcoma and osteoliposarcoma enjoyed disease-free survival at 16 and 6 years after chemotherapy despite the latter showing lung metastasis at presentation. Identification of the different lines of differentiation together with their approximate amounts and histological grades is therefore mandatory for POCS as multi-agent chemotherapy catered for each sarcoma component might offer hope for long-term disease-free survival.

Although extensive research effort and resources have been dedicated to the development of nanotherapeutics to treat cancer, few formulations have reached clinical application. A major reason is that the large number of parameters available to tune nanotherapy characteristics coupled with the variability in tumor tissue precludes evaluation of complex interactions through experimentation alone. In order to optimize the nanotechnology design and gain further insight into these phenomena, mathematical modeling and computational simulation have been applied to complement empirical work. In this chapter, we discuss modeling work related to nanotherapy and the tumor microenvironment. We first summarize the biology underlying the dysregulated tumor microenvironment, followed by a description of major nano-scale parameters. We then present an overview of the mathematical modeling of cancer nanotherapy, including evaluation of nanotherapy in multi-dimensional tumor tissue, coupling of nanotherapy with vascular flow, modeling of nanotherapy in combination with in vivo imaging, modeling of nanoparticle transport based on in vitro data, modeling of vasculature-bound nanoparticles, evaluation of nanotherapy using pharmacokinetic modeling, and modeling of nano-based hyperthermia. We conclude that an even tighter interdisciplinary effort between biological, material, and physical scientists is needed in order to eventually overcome the tumor microenvironment barrier to successful nanotherapy.

Although Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. Although Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, whereas Notch3 was 10-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RBPjk-association molecule and transactivation domains of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3. Cancer Res; 71(3); 1115–25. ©2011 AACR.

The MYC family of transcription factors is one of the most frequently overexpressed oncogenes in human malignancies, including tumors that are derived from the nervous system. MYCN plays a causative role in neuroblastoma, a common and fatal childhood cancer of the developing sympathetic nervous system. Thus, the MYC family has been considered as a promising cancer target; however, so far, no small molecules can directly target MYC or MYCN in vivo. We have recently reported that PRMT1 functions as a key regulator of the stability and oncogenicity of MYCN. In this study, we have performed the structure-activity relationship analysis of diamidine-related PRMT1-seletive inhibitors. In correlation with their inhibition against PRMT1 in biochemical assays, these compounds showed remarkable anticancer properties both in neuroblastoma cell lines in vitro and in a preclinical mouse model of neuroblastoma in vivo. Mechanistically, these potent PRMT1 inhibitors destabilized MYCN, caused cell cycle arrest, and restored normal developmental signals of the developing sympathetic neuroblast precursors. Together, our results demonstrate that PRMT1-seletive inhibitors are promising anti-neuroblastoma agents and may represent a general strategy to target certain MYC/MYCN-driven cancers. Citation Format: Jeanne N. Hansen, Louis T. Lotta, Allison Eberhardt, Yujun George Zheng, Sen Ji, Shengyong Yang, Nina F. Schor, Xingguo Li. Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B22.

Objective The CREATE trial reported that coronary artery disease (CAD) patients suffering from a first depression derived less benefit from citalopram relative to placebo than those with a recurrent depression. The present investigation sought to determine whether the differential benefit of citalopram between those with a first depression and those with recurrent depression could be explained by indicators of vascular depression and cardiac disease severity. Methods Secondary analyses of data from CREATE, a 12-week, randomized placebo-controlled trial of 284 patients with major depressive disorder and CAD were used. Recurrence subgroups were compared on baseline characteristics reflecting vascular depression and cardiac disease severity. Outcome measures were the mean change from baseline to 12 weeks on the 24-item Hamilton Depression Rating Scale administered centrally by telephone. ANCOVA was used to assess the potential interaction of each baseline variable with citalopram/placebo treatment in predicting outcomes. Results Few baseline differences differentiated patients with a first versus recurrent depression, and none accounted for the differential treatment efficacy in these subgroups. Patients with a cardiac event in the past 6 months ( P =.02) and taking angiotensin-converting enzyme inhibitors ( P =.03) experienced less change with citalopram relative to placebo. Older age, worse functional status, taking β-blockers, presence of angina (all P P =.05) predicted smaller changes in depression, independent of treatment assignment. Conclusions There was limited evidence that the lack of improvement with citalopram relative to placebo in CAD patients with a first depression can be attributed to vascular depression.

e24120Background: The influence of tumor microenvironment characteristics on cancer progression and efficacy of chemotherapy has been the focus of intensive research. In particular, macrophages are...

Emergency departments are affected by overcrowding, which may lead to diversion and cause delays in emergency services. In the past decade, overcrowding has become a significant national problem, with critically ill patients being diverted because of a lack of space and resources. Diversion of ED patients also is problematic from an administrative perspective, as it is a loss of potential revenue for the institution. The decision for diversion is made when it is deemed that the emergency department is at capacity or the hospital does not have sufficient bed capacity. A similar decision-making process is applied to critical care diversion and is contingent on the lack of available critical care beds. Also affected by ED overcrowding and diversion are EMTs, who transport the ill and injured. EMTs are challenged with finding alternative hospitals and dealing with prolonged transport times, which is a burden for the EMTs and potentially puts patients at risk. According to a study by Begley and colleagues, there could be a correlation between diversion and death rates among the most severe trauma patients transferred from lower-level hospitals. The state of New Jersey has a 2-tiered emergency response system consisting of Basic Life Support (BLS) and Advanced Life Support (ALS). BLS care is provided by either professional providers or volunteers and conducted under the direction of the local government. ALS operates under the auspices of the New Jersey Department of Health and Senior Services and is provided by a hospital-based Mobile Intensive Care Unit; while the volunteer BLS services generally are freestanding and nonregulated. All requests for EMS receive a BLS response, and patients with critical medical conditions additionally receive an ALS response; as a result, 2 vehicles are dispatched. Within our catchment area, BLS providers are EMTs or First Responders, and ALS providers are paramedics. Word Net Book defines diversion as sending on a course or direction different from the one that was planned or intended. In New Jersey, diversion cannot be mandated by a hospital; it is only an advisory status. Therefore, ambulances with critically ill patients have the discretion to utilize a diverted emergency department (see Table 1 for descriptions and definitions of diversion). Emergency service providers can be affected dramatically by hospital diversion. The decision of which emergency department to utilize often is not clear because of geographical distance between hospitals. Available resources and prolonged transport times factor heavily in the decision making. The authority to utilize an emergency department or hospital that is on diversion may be heavily scrutinized by a hospital staff that is already stretched to capacity. This situation creates a potential source of conflict between the EMTs and the ED staff. The purpose of this study was to identify the perception of hospital diversion by EMS providers and how these perceptions affect their management. This study specifically evaluates how diversion affects comfort level of care providers, reception of ED personnel, EMS, and patients, along with barriers to the continuum of care. This issue is important, because EMS providers are critical members of the emergency service team and have Gayle Walker-Cillo, New Jersey ENA, is ED Clinician, Morristown Memorial Hospital, Morristown, NJ.

Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus and electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Herein we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than did control mice, although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-γ, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens.

Obstructive sleep apnea (OSA) is a potentially fatal disorder that affects millions of adults in the United States. By definition, apnea is a cessation of airflow at any level of the repository tract, most notably in the nasal and oral pharynx, that lasts at least 10 seconds. In The Posthumous Papers of the Pickwick Club, originally published in 1837 by Charles Dickens, there was an extremely obese boy named Joe who could not help falling asleep during the day. 119 years later the name ‘‘Pickwickian’’ came up, when, in 1956, Dr. C.S. Burwell and colleagues published a medical case report titled ‘‘Extreme Obesity Associated With Alveolar Hypoventilation, a Pickwickian Syndrome.’’ Syndromes such as this usually include obesity, hypersomnolence, periodic breathing with alveolar hyperventilation, and cor pulmonale. Since the first tracheostomy was completed by Kuhlo for the treatment of upper airway obstruction in a Pickwickian subject, more than a few key surgical advances have noticeably contributed to the comprehension and treatment of OSA. Maxillomandibular advancement (MMA) has been definitively shown to be the most effective surgical method for the management of OSA. MMA was originally advocated based on the fact that maxillofacial skeletal abnormality is a well-recognized predictor of OSA and that maxillomandibular deficiency results in reduced airway dimension (Fig. 1), which in turn leads to ultimate nocturnal obstruction. MMA achieves improvement of the pharyngeal and hypopharyngeal airway by physically expanding the skeletal structure (Fig. 2). The forward movement of the maxillomandibular complex enhances the tension and collapsibility of the suprahyoid and velopharyngeal musculature. Although MMA traditionally has been set aside for patients with unbalanced maxillofacial features, it is currently encouraged for the treatment of OSA in patients who lack such features, primarily because of recent evidence that suggests that earlier unease about MMA resulting in compromised facial aesthetics has been of no consequence in most patients surveyed. This conclusion is caused by the fact that most patients who have OSA are middle-aged adults. Many of these patients are already showing visible signs of facial aging secondary to the drooping of their soft tissue. MMA provides facial skeletal expansion and consequently augments aesthetics through increased soft tissue support.

Objective Antipsychotics are frequently used in the management of delirium, although there is limited information regarding the safety and efficacy of antipsychotics in treating delirium. The purpose of this study was to systematically evaluate the evidence for the efficacy and safety of antipsychotics in treating delirium. Sources MEDLINE (July 1980 to July 2005) and Cochrane databases were searched for English language articles using keywords. Study selection Prospective studies with standardized criteria for diagnosing delirium and evaluating its severity. Data synthesis In total, 14 studies (9 single agent studies and 5 comparison trials) met inclusion criteria. Study medications included haloperidol, chlorpromazine, olanzapine, risperidone, and quetiapine. Improvements in delirium severity were reported with all of these antipsychotic medications. No study included a placebo comparison to account for spontaneous improvements in delirium. Other methodological limitations included inadequate blinding, randomization, and handling of participant withdrawals. The improvements in delirium tended to occur soon after initiation of treatment, and most of the studies examined used relatively low doses of antipsychotic medication. Serious adverse events attributable to antipsychotic medication were uncommon in studies, although side effects were not evaluated systematically in most studies. Conclusion To date, there are no published double-blind, randomized, placebo-controlled trials to establish the efficacy or safety of any antipsychotic medication in the management of delirium. There is limited evidence from uncontrolled studies that supports the use of low-dose, short-term treatment of delirium with some antipsychotics. Further study with well-designed clinical trials is required in this area.

Fenretinide is a chemotherapeutic agent in clinical trials for the treatment of neuroblastoma, among the most common and most deadly cancers of childhood. Fenretinide induces apoptosis in neuroblastoma cells through accumulation of mitochondrial reactive oxygen species released from Complex II. The neurotrophin receptor, p75NTR, potentiates this effect. The signaling activity of p75NTR is dependent upon its cleavage to its intracellular domain, p75ICD, trafficking of p75ICD to the nucleus, and functioning of p75ICD as a transcription factor. Mitochondrial Complex II comprises 4 subunits, all of which are encoded by nuclear DNA. We therefore hypothesized that the fenretinide-potentiating effects of p75NTR are the result of transcriptional enrichment of Complex II by p75ICD. However, the present studies demonstrate that neither induced expression of p75ICD or its active fragments nor overexpression of p75NTR results in altered expression or activity of Complex II.

There is increasing evidence linking depression and cardiovascular disease. However, the authors could find no literature directly linking depression with atrial fibrillation or atrial flutter. The authors report the case of a patient with uncontrolled atrial arrhythmia who cardioverted to normal sinus rhythm after treatment of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) with venlafaxine. The authors discuss comorbidity of MDD and atrial fibrillation, and explore evidence of venlafaxine as an antiarrhythmic agent. Further research is needed to establish the clinical role of venlafaxine as a Class 1 antiarrhythmic agent and any association between atrial arrhythmias and MDD and PTSD.