A novel case of recurrent cylindroma of the orbit.

Cylindroma is a rare benign tumour of eccrine origin that has not been previously reported within the orbit. We report a case of a recurrent orbital cylindroma following incomplete excision. A 75-year-old female presented with a recurrent left inferomedial orbital mass. Seven years prior a mass of the same location was excised and on histology at the time resembled a cylindroma. The patient had a history of lung adenocarcinoma. Magnetic resonance imaging (MRI) found the recurrent mass to be a well-circumscribed lesion anterior to the inferior oblique. The mass was subsequently excised. Histological analysis found a well-circumscribed neoplasm with a characteristic jigsaw pattern of nested cells, consistent with cylindroma. This case demonstrates the possibility for cylindromas to occur within the orbit and their ability to reoccur if incompletely excised.

Levetiracetam dosing for seizure prophylaxis in neurocritical care patients.

BACKGROUND/OBJECTIVE: Levetiracetam is used for seizure prophylaxis in patients presenting with subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI). We aim to characterize the optimal levetiracetam dosage for seizure prophylaxis. METHODS: This retrospective cohort study included adult patients at an academic tertiary hospital presenting with SAH or TBI who received levetiracetam at a total daily dose (TDD) equivalent to or greater than 1000 mg. The primary outcome was combined seizure incidence, including clinical and subclinical seizures. RESULTS: We identified 139 patients (49.6% male, mean age 53 years) for inclusion. For patients receiving a 1000-mg TDD, the administration was 500 mg twice daily. For patients receiving >1000-mg TDD, 77/78 patients received 1000 mg twice daily and one patient received 750 mg twice daily. Patients receiving 1000-mg TDD had a higher seizure incidence than those receiving >1000-mg TDD (p = 0.01), despite no difference in examined confounders, including history of alcoholism (p = 0.49), benzodiazepine use (p = 0.28), or propofol use (p = 0.17). No difference in adverse effects was observed (anemia, p = 0.44; leukopenia, p = 0.60; thrombocytopenia, p = 0.86). CONCLUSIONS: Patients may experience a reduced incidence of clinical and electroencephalographic seizures with levetiracetam dosing >1000-mg TDD.

An Audit and Comparison of pH, Measured Concentration, and Particulate Matter in Mannitol and Hypertonic Saline Solutions.

Background: The preferred hyperosmolar therapy remains controversial. Differences in physical properties such as pH and osmolality may be important considerations in hyperosmolar agent selection. We aimed to characterize important physical properties of commercially available hyperosmolar solutions. Methods: We measured pH and concentration in 37 commonly-used hyperosmolar solutions, including 20 and 25% mannitol and 3, 5, 14.6, and 23.4% hypertonic saline. pH was determined digitally and with litmus paper. Concentration was determined by freezing point and vapor pressure osmometry. Salinity/specific gravity was measured with portable refractometry. Particulate matter was analyzed with filtration and light microscopy and with dynamic light scattering nephelometry. Results: pH of all solutions was below physiological range (measured range 4.13-6.80); there was no correlation between pH and solution concentration (R 2 = 0.005, p = 0.60). Mannitol (mean 5.65, sd 0.94) was less acidic than hypertonic saline (5.16, 0.60). 14/59 (24%) pH measurements and 85/111 concentration measurements were outside manufacturer standards. All 36/36 mannitol concentration measurements were outside standards vs. 48/72 (67%) hypertonic saline (p < 0.0001). All solutions examined on light microscopy contained crystalline and/or non-crystalline particulate matter up to several hundred microns in diameter. From nephelometry, particulate matter was detected in 20/22 (91%) solutions. Conclusion: We present a novel characterization of mannitol and hypertonic saline. Further research should be undertaken, including research examining development of acidosis following hyperosmolar therapy, the relevance of our findings for dose-response, and the clinical relevance of particulate matter in solution.

Mechanisms, mediators, and surrogate estimation of crash modification factors.

In road safety, a commonly-used measure of treatment effectiveness is the crash modification factor, usually defined as a ratio of the expected crash frequency with the treatment to the expected frequency without. This paper explores the possibility of using surrogates to estimate crash modification factors. As in other situations where observational data are used to estimate causal effects, it is necessary to leverage background causal knowledge with the observational results. When the background knowledge is such that a crash-generating mechanism can be represented with a directed acyclic graph, the connectivity structure of the graph can be used to identify candidate surrogates. The modification factor associated with a safety-related improvement can then, in principle, be estimated from knowledge of how the improvement affects the surrogates, together with information on how the surrogates are distributed in the population of crashes. After developing this relationship between surrogates and crash modification factors, its potential usefulness is illustrated with two simulation studies, where estimates of CMFs using surrogates are compared to estimates computed from crash frequencies.

Inactivated Four-Factor Prothrombin Complex Concentrate Dosing Practices for Reversal of Warfarin-Related Intracranial Hemorrhage.

BACKGROUND/OBJECTIVE: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra®) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH). METHODS: This is a multicenter retrospective pragmatic registry study of adult patients admitted at a participating study site between January 1, 2014, and December 31, 2015, who received I4F-PCC for reversal of warfarin-related ICH. Practices around warfarin-related ICH reversal in context of I4F-PCC utilization are described, including repeat I4F-PCC dosing, adjunctive reversal agents, and dose rounding policies (i.e., rounding doses to nearest vial size vs preparing exact/unrounded doses). All research was approved by local human investigation committees at each institution. RESULTS: Seventeen institutions contributed data on 528 patients to this registry. These institutions were primarily urban centers (74%), located in the southeast USA (47%), with Level 1 Trauma designation (79%), and with Comprehensive Stroke Center designation (74%). Most patients included in the study had sustained a non-traumatic ICH (68%), had a median admission GCS of 14 (IQR 7-15), and were receiving warfarin for atrial fibrillation (57.4%). There was substantial time latency between baseline INR and I4F-PCC (median 2.4 h, IQR 1.4-4.5 h). Most patients received adjunctive reversal agents, including vitamin K (89.5%) and fresh frozen plasma (FFP) (31.9%). A smaller proportion (6.0%) of patients received repeat I4F-PCC dosing. The median ICU length of stay (LOS) was 3 days (IQR 2-7 days), median hospital LOS was 6 days (IQR 3-12 days), and overall mortality rate was 28.8%. For institutions rounding doses to the nearest vial size, the first post-I4F-PCC dose INR was statistically but not clinically significantly lower than for institutions without vial size dose rounding, with comparable degrees of INR reduction from baseline. No differences were observed between dose rounding cohorts in adverse effects, ICU or hospital LOS, modified Rankin score at discharge, or mortality rates. CONCLUSIONS: Most patients received single doses of I4F-PCC, with adjunctive reversal agents and rounding doses to vial size. The time difference from baseline INR to factor product administration is a potential opportunity for process improvement in the management of warfarin-related ICH.

In Vivo Morphology of Nasolacrimal Duct Opening into the Inferior Meatus.

PURPOSE: To study the in vivo morphology of nasolacrimal duct (NLD) openings into the inferior meatus. METHODS: Patients undergoing endoscopic dacryocystorhinostomy and lacrimal intubation had endoscopic real-time examination of the NLD opening. Morphology of NLD openings (size, shape, mucosal folds), and their location from the axilla of the inferior turbinate were assessed. RESULTS: Forty-three lacrimal systems of 39 adult patients (11 males, 28 females) with a mean age of 61 years were studied. Thirty-five patients had unilateral involvement, and 74% had anatomical NLD obstruction. Of 43 lacrimal systems, 41 had a visible NLD opening. The majority was sulci shaped (63%, 26/41) followed by fissure type (34%), and 2% had wide-open round morphology. The majority of the openings (93%) were oriented vertically, and 67% (14/21) of the sulci shaped openings continued into gutter like channels along the lateral nasal wall. Mucosal folds were present in 7% (3/41) of the openings along the edges. The mean distance between the opening and the axilla of the inferior turbinate was 3.7± 2.1 mm (median, 3.6; range, 0-7.2). CONCLUSION: Sulci shaped NLD openings were the most common morphology, and mucosal folds were less commonly observed compared with cadaveric studies.

In Vivo Morphological Study of Common Canalicular Orifice and Its Impact on Lacrimal Probing.

PURPOSE: To study the in vivo morphology of common canalicular/lacrimal sac mucosal folds (CLS-MFs) and their relationship with probing findings. METHODS: Consecutive cases undergoing endoscopic dacryocystorhinostomy had endoscopic examination of the internal canalicular orifice (ICO). Details of CLS-MFs folds, probing findings, and outcomes of dacryocystorhinostomy were analyzed. RESULTS: Thirty-six lacrimal systems of 34 patients (mean age, 58 years; 7 males, 27 females) were examined. All 36 lacrimal systems had a single common canalicular orifice entering the lacrimal sac (100%). Overall, 61.1% (22/36) had visible CLS-MFs, out of which only 13.6% (3/22) were overhanging the ICO requiring manipulation of the probe to enter the lacrimal sac. The orientation of folds was superior 180° in 2, posterosuperior in 2, posterior in 6, inferior 180° in 6, and inferior 270° (excluding 10-2'o clock quadrant) in 6 systems. Two cases preoperatively labeled as having common canalicular obstruction, based on lacrimal syringing, had CLS-MFs impacting against the ICO without any anatomical obstruction. One of 5 cases with lacrimal sac mucocele had CLS-MFs located along the posterosuperior edge extending for 270°, which resulted in a soft stop on preoperative lacrimal syringing findings. Only 1 case had a true membrane (2.7%) overlying the ICO, which required excision. No differences in outcomes of dacryocystorhinostomy were observed between cases with CLS-MFs versus without any folds. CONCLUSION: CLS-MFs display a wide variation in terms of morphological location and extent along the ICO. They might be responsible for the false soft stop observed in some cases on preoperative syringing and do not require excision.

A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity.

Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with the clinical target MIF (MIF-1), but the precise contribution of MIF-2 to immune physiology or pathology is unclear. Like MIF-1, MIF-2 has intrinsic keto-enol tautomerase activity and mediates biological functions by engaging the cognate, common MIF family receptor CD74. Evidence that the catalytic site of MIF family cytokines has a structural role in receptor binding has prompted exploration of tautomerase inhibitors as potential biological antagonists and therapeutic agents, although few catalytic inhibitors inhibit receptor activation. Here we describe the discovery and biochemical characterization of a selective small-molecule inhibitor of MIF-2. An in silico screen of 1.6 million compounds targeting the MIF-2 tautomerase site yielded several hits for potential catalytic inhibitors of MIF-2 and identified 4-(3-carboxyphenyl)-2,5-pyridinedicarboxylic acid (4-CPPC) as the most functionally potent compound. We found that 4-CPPC has an enzymatic IC50 of 27 µm and 17-fold selectivity for MIF-2 versus MIF-1. An in vitro binding assay for MIF-1/MIF-2 to the CD74 ectodomain (sCD74) indicated that 4-CPPC inhibits MIF-2-CD74 binding in a dose-dependent manner (0.01-10 µm) without influencing MIF-1-CD74 binding. Notably, 4-CPPC inhibited MIF-2-mediated activation of CD74 and reduced CD74-dependent signal transduction. These results open opportunities for development of more potent and pharmacologically auspicious MIF-2 inhibitors to investigate the distinct functions of this MIF family member in vivo.

Explaining crash modification factors: Why it's needed and how it might be done.

Although the Highway Safety Manual (HSM) now provides empirical tools for predicting the safety consequences of highway engineering decisions, these tools represent the driver and vehicle conditions prevailing in the United States during the last few decades. As automated vehicles improve in capability and increase in market share these conditions will change, possibly reducing the accuracy of HSM predictions. Assessing the transferability of a crash modification factor to new situations almost certainly requires an explanation of how the modification achieves its effect, but at present there is little guidance on how such explanations might be posed and tested. This paper describes the use of micro-simulation to develop an explanation of how pedestrian hybrid beacons (PHB) modify pedestrian crash likelihood. Since the literature indicated that PHBs can affect both pedestrian and driver behavior it was necessary to include both possibilities in the model. To simulate injury severity distributions similar to those recorded in a crash database it was necessary to propose that almost all simulated drivers attempt to brake in pedestrian/vehicle encounters. Then changing the simulated fraction of careful pedestrians from between 0% and 30% to between 80% and 90% gave simulated crash modification factors similar to estimates reported in the literature. The resulting working hypothesis then is that PHBs achieve their crash reduction effect in large part by modifying pedestrian behavior. This is not so much a direct observation as it is an inference to the best explanation. That is, the support for the hypothesis comes from its ability to explain the data at hand. This hypothesis should be tested further, and additional tests are proposed.

Using naturalistic driving study data to investigate the impact of driver distraction on driver's brake reaction time in freeway rear-end events in car-following situation.

INTRODUCTION: The rear-end crash is one of the most common freeway crash types, and driver distraction is often cited as a leading cause of rear-end crashes. Previous research indicates that driver distraction could have negative effects on driving performance, but the specific association between driver distraction and crash risk is still not fully revealed. This study sought to understand the mechanism by which driver distraction, defined as secondary task distraction, could influence crash risk, as indicated by a driver's reaction time, in freeway car-following situations. METHOD: A statistical analysis, exploring the causal model structure regarding drivers' distraction impacts on reaction times, was conducted. Distraction duration, distraction scenario, and secondary task type were chosen as distraction-related factors. Besides, exogenous factors including weather, visual obstruction, lighting condition, traffic density, and intersection presence and endogenous factors including driver age and gender were considered. RESULTS: There was an association between driver distraction and reaction time in the sample freeway rear-end events from SHRP 2 NDS database. Distraction duration, the distracted status when a leader braked, and secondary task type were related to reaction time, while all other factors showed no significant effect on reaction time. CONCLUSIONS: The analysis showed that driver distraction duration is the primary direct cause of the increase in reaction time, with other factors having indirect effects mediated by distraction duration. Longer distraction duration, the distracted status when a leader braked, and engaging in auditory-visual-manual secondary task tended to result in longer reaction times. PRACTICAL APPLICATIONS: Given drivers will be distracted occasionally, countermeasures which shorten distraction duration or avoid distraction presence while a leader vehicle brakes are worth considering. This study helps better understand the mechanism of freeway rear-end events in car-following situations, and provides a methodology that can be adopted to study the association between driver behavior and driving features.

A case of traumatic infraorbital neuroma.

A 53-year-old Afghan man presented with a 12-month history of left proptosis, diplopia and facial swelling 20 years after a bomb blast injury. Magnetic resonance and computed tomography imaging revealed a well-circumscribed lesion centred within the left inferior orbit/superior maxillary sinus along with left orbital fracture. Histopathology and immunostaining of the debulked lesion were consistent with traumatic neuroma of the infraorbital nerve. Infraorbital neuromas have developed following orbital decompression surgeries but have not been reported previously following non-surgical trauma.

Safety of peripheral administration of phenylephrine in a neurologic intensive care unit: A pilot study.

Integral to the management of the neurocritically injured patient are the prevention and treatment of hypotension, maintenance of cerebral perfusion pressure, and occasionally blood pressure augmentation. When adequate volume resuscitation fails to meet perfusion needs, vasopressors are often used to restore end-organ perfusion. This has historically necessitated central venous access given well-documented incidence of extravasation injuries associated with peripheral administration of vasopressors. In this pilot study, we report our 6-month experience with peripheral administration of low-concentration phenylephrine (40 µg/mL) in our neurocritical care unit. We were able to administer peripheral phenylephrine, up to a dose of 2 µg/(kg min), for an average of 14.29hours (1-54.3) in 20 patients with only 1 possible minor complication and no major complications. This was achieved by adding additional safety measures in our computerized physician order entry system and additional nurse-driven safety protocols. Thus, with careful monitoring and safety precautions, peripheral administration of phenylephrine at an optimized concentration appears to have an acceptable safety profile for use in the neurocritical care unit up to a mean infusion time of 14hours.

Splenic rupture associated with primary CMV infection, AMSAN, and IVIG.

Splenic rupture is a rare complication of primary cytomegalovirus infection, but has not been reported after administration of intravenous immunoglobulin or in the setting of the Guillain-Barré syndrome and its many variants, which often lead to treatment with intravenous immunoglobulin. There is strong evidence that intravenous immunoglobulin causes sequestration of erythrocytes in the spleen and extravascular hemolytic anemia. This may result in a two-hit scenario that clinicians should be aware of, where a patient who is at risk for splenic rupture due to primary cytomegalovirus infection receives intravenous immunoglobulin as treatment for the cytomegalovirus-associated Guillain-Barré syndrome, further increasing their risk of rupture.

Impact of birth cohort screening for hepatitis C.

Hepatitis C (HCV) is a leading cause of liver-related complications, and the burden of liver disease is expected to increase. Given the over-representation of HCV-related liver disease in persons born between 1945 and 1965, and the failure of risk-based screening to identify many infected persons, birth cohort screening has been advocated and endorsed by both the Centers for Disease Control and United States Preventive Services Task Force, regardless of the presence of risk factors. Birth cohort testing is more cost-effective than risk-based screening especially when those with more advanced disease are given priority for treatment. Several barriers exist at the patient and provider level that need to be overcome to fully realize the potential benefit of birth cohort screening in reducing HCV-related morbidity and mortality.

Crash reconstruction and crash modification factors.

This paper addresses the following question: Under what conditions can reconstructed road crashes be used to estimate the effect of a safety-related countermeasure? Results developed by Pearl and his associates are used to draw two main conclusions. First, when one can (1) identify a structural equation describing a type of crash, (2) identify an additional structural equation describing the countermeasure's impact, and (3) estimate the initiating conditions for a set of reconstructed crashes, then a lower bound for a crash modification factor can be estimated by simulating whether or not each of the reconstructed crashes would still have occurred had the countermeasure been present. If the countermeasure's effect is monotonic this bound becomes tight. Second, in situations where it is not possible to reliably identify the structural equations needed for simulation, but where one can (1) identify a set of crash inputs which, when given, make the crash outcome conditionally independent of the countermeasure, and (2) predict how the distribution of these inputs will change in response to the countermeasure, then nonparametric estimation of the countermeasure's crash modification factor is possible. When it is not possible to predict the countermeasure's effect on the conditioning variables it may still be possible to identify constraints or specifications which the countermeasure should satisfy in order to realize a target crash modification.

Effective treatment of refractory intracranial hypertension after traumatic brain injury with repeated boluses of 14.6% hypertonic saline.

OBJECT: Normal intracranial pressure (ICP) and cerebral perfusion pressure (CPP) have been identified as favorable prognostic factors in the outcome of patients with traumatic brain injuries (TBIs). Osmotic diuretics and hypertonic saline (HTS) are commonly used to treat elevated ICP in patients with TBI; however, sustained effects of repeated high-concentration HTS boluses for severely refractory ICP elevation have not been studied. The authors' goal in this study was to determine whether repeated 14.6% HTS boluses were efficacious in treating severely refractory intracranial hypertension in patients with TBI. METHODS: In a prospective cohort study in a neurocritical care unit, adult TBI patients with sustained ICP > 30 mm Hg for more than 30 minutes after exhaustive medical and/or surgical therapy received repeated 15-minute boluses of 14.6% HTS over 12 hours through central venous access. RESULTS: Response to treatment was evaluated in 11 patients. Within 5 minutes of bolus administration, mean ICP decreased from 40 to 33 mm Hg (30% reduction, p < 0.05). Intracranial pressure-lowering effects were sustained for 12 hours (41% reduction, p < 0.05) with multiple boluses (mean number of boluses 7 ± 5.5). The mean CPP increased 22% and 32% from baseline at 15 and 30 minutes, respectively (p < 0.05). The mean serum sodium level (SNa) at baseline was 155 ± 7.1 mEq/L, and after multiple boluses of 14.6% HTS, S(Na) at 12 hours was 154 ± 7.1 mEq/L. The mean heart rate, systolic blood pressure, blood urea nitrogen, and creatinine demonstrated no significant change throughout the study. CONCLUSIONS: The subset of TBI patients with intracranial hypertension that is completely refractory to all other medical therapies can be treated effectively and safely with repeated boluses of 14.6% HTS rather than a one-time dose.