Impact of the Unstirred Water Layer on the Permeation of Small-Molecule Drugs.

Over the last two decades, numerous molecular dynamics (MD) simulation-based investigations have attempted to predict the membrane permeability to small-molecule drugs as indicators of their bioavailability, a majority of which utilize the inhomogeneous solubility diffusion (ISD) model. However, MD-based membrane permeability is routinely 3-4 orders of magnitude larger than the values measured with the intestinal perfusion technique. There have been contentious discussions on the sources of the large discrepancies, and the two indisputable, potentially dominant ones are the fixed protonation state of the permeant and the neglect of the unstirred water layer (UWL). Employing six small-molecule drugs of different biopharmaceutical classification system classes, the current MD study relies on the ISD model but introduces the (de)protonation of the permeant by characterizing the permeation free energy of both neutral and charged states. In addition, the role of the UWL as a potential resistance against permeation is explored. The new MD protocol closely mimics the nature of small-molecule permeation and yields estimates that agree well with in vivo intestinal permeability.

The initial sticking of high velocity water onto graphite under non-equilibrium supersonic flow conditions.

In this paper, we present a combined experimental and theoretical study that explored the initial sticking of water on cooled surfaces. Specifically, these ultra-high vacuum gas-surface scattering experiments utilized supersonic molecular beam techniques in conjunction with a cryogenically cooled highly oriented pyrolytic graphite crystal, giving control over incident kinematic conditions. The D2O translational energy spanning 300-750 meV, the relative D2O flux, and the incident angle could all be varied independently. Three different experimental measurements were made. One involved measuring the total amount of D2O scattering as a function of surface temperature to determine the onset of sticking under non-equilibrium gas-surface collision conditions. Another measurement used He specular scattering to assess structural and coverage information for the interface during D2O adsorption. Finally, we used time-of-flight (TOF) measurements of the scattered D2O to determine how energy is exchanged with the graphite surface at surface temperatures above and near the conditions needed for gaseous condensation. For comparison and elaboration of the roles that internal degrees of freedom play in this process, we also did similar TOF measurements using another mass 20 incident particle, atomic neon. Enriching this study are precise molecular dynamics simulations that elaborate on gas-surface energy transfer and the roles of molecular degrees of freedom in gas-surface collisional energy exchange processes. This study furthers our fundamental understanding of energy exchange and the onset of sticking and ultimately gaseous condensation for gas-surface encounters occurring under high-velocity flows.

Biophysical properties of tear film lipid layer II. Polymorphism of FAHFA.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of endogenous lipids that consist of two acyl chains connected through a single ester bond. Being a unique species of FAHFAs, (O-acyl)-ω-hydroxy fatty acids (OAHFAs) differ from other FAHFAs in that their hydroxy fatty acid backbones are ultralong and their hydroxy esterification is believed to be solely at the terminal (ω-) position. Only in recent years with technological advances in lipidomics have OAHFAs been identified as an important component of the tear film lipid layer (TFLL). It was found that OAHFAs account for approximately 4 mol% of the total lipids and 20 mol% of the polar lipids in the TFLL. However, their biophysical function and contribution to the TFLL is still poorly understood. Here we studied the molecular biophysical mechanisms of OAHFAs using palmitic-acid-9-hydroxy-stearic-acid (PAHSA) as a model. PAHSA and OAHFAs share key structural similarities that could result in comparable biophysical properties and molecular mechanisms. With combined biophysical experiments, atomic force microscopy observations, and all-atom molecular dynamics simulations, we found that the biophysical properties of a dynamic PAHSA monolayer under physiologically relevant conditions depend on a balance between kinetics and thermal relaxation. PAHSA molecules at the air-water surface demonstrate unique polymorphic behaviors, which can be explained by configurational transitions of the molecules under various lateral pressures. These findings could have novel implications in understanding biophysical functions that FAHFAs, in general, or OAHFAs, specifically, play in the TFLL.

Menthol in electronic cigarettes causes biophysical inhibition of pulmonary surfactant.

With an increasing prevalence of electronic cigarette (e-cigarette) use, especially among youth, there is an urgent need to better understand the biological risks and pathophysiology of health conditions related to e-cigarettes. A majority of e-cigarette aerosols are in the submicron size and would deposit in the alveolar region of the lung, where they must first interact with the endogenous pulmonary surfactant. To date, little is known whether e-cigarette aerosols have an adverse impact on the pulmonary surfactant. We have systematically studied the effect of individual e-cigarette ingredients on an animal-derived clinical surfactant preparation, bovine lipid extract surfactant, using a combination of biophysical and analytical techniques, including in vitro biophysical simulations using constrained drop surfactometry, molecular imaging with atomic force microscopy, chemical assays using carbon nuclear magnetic resonance and circular dichroism, and in silico molecular dynamics simulations. All data collectively suggest that flavorings used in e-cigarettes, especially menthol, play a predominant role in inhibiting the biophysical function of the surfactant. The mechanism of biophysical inhibition appears to involve menthol interactions with both phospholipids and hydrophobic proteins of the natural surfactant. These results provide novel insights into the understanding of the health impact of e-cigarettes and may contribute to better regulation of e-cigarette products.

The potential energy profile of the decomposition of 1,1-diamino-2,2-dinitroethylene (FOX-7) in the gas phase.

1,1-Diamino-2,2-dinitroethene (FOX-7) is an energetic material with low sensitivity and high detonation performance, thus it has been considered as a potential replacement for traditional nitro-based energetic materials. In a recent publication (J. Phys. Chem. A, 2022, 126, 4747), the initial decomposition steps of FOX-7 were studied using reflectron time-of-flight mass spectrometry and infrared spectroscopy. The experimental study was complemented with quantum chemistry calculations, which demonstrated the gas phase potential energy surface to be indicative of the reaction process in the condensed phase. The computation in J. Phys. Chem. A, 2022, 126, 4747 focuses on the primary decomposition - but in this manuscript, the full decomposition pathway on the singlet surface, consisting of 54 intermediates and 37 transition states, is characterized at an unprecedented detail. The calculations show that the nitro group, instead of the amine group, is primarily responsible for the sensitivity and endothermicity of FOX-7 decomposition. This result sheds light on how to critically optimize the performance of FOX-7 and design the next generation of nitro-based energetic materials. A comprehensive roadmap, initiated from FOX-7, covers the chemical space of the entire decomposition thus providing a holistic demonstration of various key decomposition pathways leading to various small, gas phase products such as NO, NO2, NH2, CO2, and CO.

Cardiopulmonary resuscitation and skill retention in emergency physicians.

STUDY OBJECTIVES: The American Heart Association (AHA) recently established the Resuscitation Quality Improvement (RQI) program, which requires physicians to perform quarterly cardiopulmonary resuscitation (CPR) skill checks. The aim of this study was to determine if timing of last training impacted skill performance of emergency physicians. METHODS: A convenience sample of emergency medicine (EM) physicians was asked to complete a Basic Life Support (BLS) scenario on a manikin. Participants passed the scenario if they successfully performed high-quality CPR. Participants completed a survey to assess clinical experience and timing of prior BLS training. Outcomes were comparisons of skills check pass rates for physicians recently trained in BLS (≤90 days) and those trained >90 days ago and those trained >2 years ago. RESULTS: A total of 113 individuals were included in the study: 87 attending physicians and 26 residents. Overall 92.9% correctly performed CPR with the proper assessment, compression rate, compression depth and rescue breaths. There was no difference between success rates in EM physicians who had BLS training within 90 days (91.7%) and physicians who had not had BLS within 90 days, (93.1%). (p = 1.00) There was no difference in the pass rate of those trained within 90 days (91.7%) to those trained >2 years ago (90.9%) (95CI 0.088, 0.096). CONCLUSION: There was no difference between delivery of high-quality CPR in EM physicians who had recent BLS training and those who did not.

Control of Magnetic Bearings for Rotor Unbalance With Plug-In Time-Varying Resonators.

Rotor unbalance, common phenomenon of rotational systems, manifests itself as a periodic disturbance synchronized with the rotor's angular velocity. In active magnetic bearing (AMB) systems, feedback control is required to stabilize the open-loop unstable electromagnetic levitation. Further, feedback action can be added to suppress the repeatable runout but maintain closed-loop stability. In this paper, a plug-in time-varying resonator is designed by inverting cascaded notch filters. This formulation allows flexibility in designing the internal model for appropriate disturbance rejection. The plug-in structure ensures that stability can be maintained for varying rotor speeds. Experimental results of an AMB-rotor system are presented.

Ebola virus outbreak 2014: clinical review for emergency physicians.

The 2014 Ebola outbreak in West Africa is the largest in history. Ebola viral disease is a severe and fatal illness characterized by a nonspecific viral syndrome followed by fulminant septic shock and coagulopathy. Despite ongoing efforts directed at experimental treatments and vaccine development, current medical management of Ebola viral disease is largely limited to supportive therapy, thus making early case identification and immediate implementation of appropriate control measures critical. Because a case of Ebola viral disease was confirmed in the United States on September 30, 2014, emergency medicine providers should be knowledgeable about it for a number of reasons: we are being called on to answer questions about Ebola and allay public fears, we are likely to be first to encounter an infected patient, and there are increasing numbers of US emergency physicians working in Africa who risk coming in direct contact with the disease. This article seeks to provide emergency physicians with the essential and up-to-date information required to identify, evaluate, and manage Ebola viral disease and to join global efforts to contain the current outbreak.

Atomistic Insight into the Lipid Nanodomains of Synaptic Vesicles.

Membrane curvature, once regarded as a passive consequence of membrane composition and cellular architecture, has been shown to actively modulate various properties of the cellular membrane. These changes could also lead to segregation of the constituents of the membrane, generating nanodomains with precise biological properties. Proteins often linked with neurodegeneration (e.g., tau, alpha-synuclein) exhibit an unintuitive affinity for synaptic vesicles in neurons, which are reported to lack distinct, ordered nanodomains based on their composition. In this study, all-atom molecular dynamics simulations are used to study a full-scale synaptic vesicle of realistic Gaussian curvature and its effect on the membrane dynamics and lipid nanodomain organization. Compelling indicators of nanodomain formation, from the perspective of composition, surface areas per lipid, order parameter, and domain lifetime, are identified in the vesicle membrane, which are absent in a flat bilayer of the same lipid composition. Therefore, our study supports the idea that curvature may induce phase separation in an otherwise fluid, disordered membrane.

Interaction between Permeation Enhancers and Lipid Bilayers.

Permeation enhancers (PEs) are a class of molecules that interact with the epithelial membrane and transiently increase its transcellular permeability. Although there have been few clinical trials of PE coformulated drugs, the mechanism of action of PEs remains elusive. In this paper, the interaction between two archetypes of PEs [salcaprozate sodium (SNAC) and sodium caprate (C10)] and membranes is investigated with extensive all-atom molecular dynamics simulations. The simulations show that (1) the association between the neutral PEs and membranes is favored in free energy, (2) the propensity of neutral PE aggregation is larger in aqueous solution than in lipid bilayers, (3) the equilibrium distribution of neutral PEs in membranes is fast, e.g., accessible with unbiased MD simulations, and (4) the micelle of neutral PEs formed in aqueous solution does not rupture the membranes (e.g., not forming pores or breaking up the membrane) under simulation conditions. All results combined, this study indicates that PEs insert into the membranes in an equilibrium or near equilibrium process. This study lays the foundation for future investigations of how PEs impact the free energy of permeation for small molecules.

Differential expression of cytochrome P450 omega-hydroxylase isoforms and their association with clinicopathological features in pancreatic ductal adenocarcinoma.

BACKGROUND: The cytochrome P450 (CYP) superfamily consists of enzymes that catalyze the oxidation of lipids, steroids, and drugs. In particular, the CYP4 family plays an essential role in lipid metabolism by the ω-hydroxylation of terminal ends of fatty acids. Disturbance of this system has been associated with increased angiogenesis, proliferation, and metastasis of several cancers. This study aimed to detect the expression of CYP4 isoforms (CYP4A11, CYP4F2, CYP4F3) in pancreatic ductal adenocarcinoma (PDA) and their association with clinicopathological features. METHODS: Pancreatic specimens were collected from 73 patients who underwent surgical resection at the Thomas Jefferson University Hospital. Quantitative polymerase chain reaction was used to examine the cytochrome P450 isoforms in PDA (n = 62), adjacent-normal (n = 30), and benign tissues (n = 11). Logistic regression models were used to analyze gene expression among tissue types. Spearman rank correlations were calculated for isoform expression and for age. Differences in expression by gender were assessed via t test. Other clinicopathological variables (diabetes, smoking, obesity, T stage, perineural invasion, nodal status) were analyzed by Wilcoxon rank sum. RESULTS: CYP4 expression for isoforms was significantly higher in PDA tissues versus matched-adjacent tissues (p < 0.01). PDA tumors expressed significantly higher levels of CYP4F2 and CYP4F3 when compared to benign lesions (p < 0.01). Significant associations were found between low levels of CYP4F2 and CYP4F3 and increased age of PDA patients. Interestingly, all isoforms were expressed at higher levels in male patients. CONCLUSIONS: Transcriptional upregulation of cytochrome P450 ω-hydroxylase suggests that these enzymes have the potential to be used as distinguishing markers in pancreatic pathology.

Hantavirus infection in North America: a clinical review.

The recent outbreak of hantavirus in Yosemite National Park has attracted national attention, with 10 confirmed cases of hantavirus cardiopulmonary syndrome and thousands of more people exposed. This article will review the epidemiology, presentation, workup, and treatment for this rare but potentially lethal illness. The possibility of infection with hantavirus deserves consideration in patients with severe respiratory symptoms with rodent exposure or rural/wilderness travel. Accurate diagnosis requires a high index of suspicion. Hantavirus cardiopulmonary syndrome presents as a vague prodrome of fever, cough, myalgias, chills, and nausea followed by a rapidly worsening respiratory phase. Presumptive diagnosis can be made based on pulmonary interstitial edema on chest radiographs in association with leukocytosis, thrombocytopenia, and hemoconcentration. Suspected cases should be confirmed with a reference laboratory and reported to the appropriate public health authorities. Although treatment is primarily supportive, aggressive fluid administration should be avoided due to the risk of pulmonary edema. The cardiopulmonary phase of the disease can progress rapidly with catastrophic decompensation in as little as a few hours. Patients require rapid intensive care unit admission for monitoring, mechanical ventilation, vasoactive agents, and possibly extracorporeal mechanical ventilation. Emergency physicians should be aware of outbreaks and vigilant for hantavirus exposures, especially during the summer and early fall months.

Emergency physician evaluation of a novel surgical cricothyroidotomy tool in simulated combat and clinical environments.

We sought to investigate the performance of a novel cricothyroidotomy CRIC device compared to the traditional surgical in both simulated combat environments and the emergency department (ED) setting. Twenty U.S. Army staff and resident emergency medicine physicians were randomized to device and simulated setting order and performed cricothyroidotomies in the standard manner and with the CRIC device via the TraumaMan surgical simulator in three simulated settings: the ED, a day combat environment, and a night combat environment. Differences in procedural completion for the two methods in different settings were compared by two-tailed paired t-tests. The occurrence of major and minor procedural complications and questions presented as 5-point Likert scales to describe participants' preferences of cricothyroidotomy methods were compared by chi2 analysis. Time to incision, time to procedural completion, and rate of major and minor complications were not significantly different between the standard surgical method and the CRIC device (p > 0.05). In the simulated ED setting, 60% of participants preferred the standard surgical method (95% confidence interval: 38.5-81.5), whereas in the simulated combat settings, 50% of participants preferred each device (95% confidence interval: 28.1-71.9). In our population, we observed similar operator performance characteristics and physician preferences between the 2 methods in all simulated cricothyroidotomy settings.

Measles: Contemporary considerations for the emergency physician.

Measles, or rubeola, is a highly contagious acute febrile viral illness. Despite the availability of an effective vaccine since 1963, measles outbreaks continue worldwide. This article seeks to provide emergency physicians with the contemporary knowledge required to rapidly diagnose potential measles cases and bolster public health measures to reduce ongoing transmission.

Optimized light-matter interaction and defect hole placement in photonic crystal cavity sensors.

Photonic crystal slab cavities were investigated for increased light-matter interaction based on selective placement of sublattice hole sized defect holes inside L3 cavities. A multiple-hole defect (MHD) consisting of three defect holes placed in the regions of highest cavity mode field intensity were demonstrated through finite-difference time-domain simulations and experiments to exhibit the strongest light-matter interaction without introducing significant scattering losses. Compared to an L3 cavity without defect holes, these strategically designed three-hole MHD cavities presented higher quality factor and more than double the resonance wavelength shift upon exposure to a thin oxide and two small chemical molecules.

Procedural sedation with propofol: a retrospective review of the experiences of an emergency medicine residency program 2005 to 2010.

OBJECTIVES: The objective of this study is to evaluate the types and rates of adverse events associated with the use of propofol for procedural sedation by physicians from our emergency medicine residency program and compare those adverse event rates with those rates already published for all moderate and deep sedatives for procedural sedation, including propofol. METHODS: This study was a retrospective chart review of all 215 procedural sedations performed with propofol in our emergency department (ED) from June 2005 to December 2010. The mean patient age was 29 years (SD, 22.1 years; range, 1-91 years). Adverse events were compiled and examined from chart data and compared with similar published studies on adverse event rates using propofol. RESULTS: Of the 215 patients, 10 (4.65%) experienced adverse events related to procedural sedation with propofol. Our frequency of adverse events was not statistically different from the published rate for all moderate and deep sedatives (P = .407). Of all the adverse events, hypotension was the most common, occurring in 5 (2.33%) of the 215 patients. Of the 215 patients, 3 (1.40%) experienced brief hypoxia, with 2 (0.93%) of 3 patients requiring jaw thrust airway repositioning. Two (0.93%) of the 215 patients developed brief apnea that required brief bag valve mask-assisted ventilation. No patient required any advanced airway management. All 215 patients recovered completely from the procedural sedation and were discharged from the ED in stable and improved condition. CONCLUSIONS: The adverse event rates from our study correlate with those of numerous earlier as well as recently published studies of moderate and deep sedatives, including propofol. The disciplined use of propofol by emergency physicians should continue to provide ED patients with the best available management options and care while additional focused and larger scale research is conducted to definitively confirm the premise that emergency physicians can continue to safely perform procedural sedation with propofol.

Optimized Quantum Phase Estimation for Simulating Electronic States in Various Energy Regimes.

While quantum algorithms for simulations exhibit better asymptotic scaling than their classical counterparts, they currently cannot be accurately implemented on real-world devices. Instead, chemists and computer scientists rely on costly classical simulations of these quantum algorithms. In particular, the quantum phase estimation (QPE) algorithm is among several approaches that has attracted much attention in recent years due to its genuine quantum character. However, it is memory-intensive to simulate and intractable for moderate system sizes. This paper discusses the performance and applicability of QPESIM, a new simulation of the QPE algorithm designed to take advantage of modest computational resources. In particular, we demonstrate the versatility of QPESIM in simulating various electronic states by examining the ground and core-level states of H2O. For these states, we also discuss the effect of the active-space size on the quality of the calculated energies. For the high-energy core-level states, we demonstrate that new QPE simulations for active spaces defined by 15 active orbitals significantly reduce the errors in core-level excitation energies compared to earlier QPE simulations using smaller active spaces.

Charles Bonnet Syndrome With Superimposed Delirium.

Charles Bonnet Syndrome (CBS) is diagnosed when a patient who is psychiatrically intact experiences visual hallucinations in the setting of significant visual acuity or field loss. The exact pathophysiology of the CBS hallucinations remains largely unknown. The main theories include the deafferentation theory and perceptual release theory. There are suspected neurotransmitters involved, including acetylcholine and dopamine. There is no defined treatment protocol with medication for CBS, but various psychotropic medications have been used with varying degrees of remission of symptoms. This case report describes a 64-year-old male with Charles Bonnet Syndrome in the setting of superimposed delirium. We note the different medications that were trialed to reduce his CBS symptoms and decrease episodes of behavioral disturbances. Clinical features of this rare syndrome with superimposed delirium are summarized in hopes of providing directions for management and future study.

Assessing the Intestinal Permeability of Small Molecule Drugs via Diffusion Motion on a Multidimensional Free Energy Surface.

A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The in silico method reported in this manuscript also reproduces the permeability measured from the intestinal assay (in vivo) better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization.

Developing a National Trauma Research Action Plan: Results from the Neurotrauma Research Panel Delphi Survey.

BACKGROUND: In 2016, the National Academies of Science, Engineering and Medicine called for the development of a National Trauma Research Action Plan. The Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. Given the public health burden of injuries to the central nervous system, neurotrauma was one of 11 panels formed to address this recommendation with a gap analysis and generation of high-priority research questions. METHODS: We recruited interdisciplinary experts to identify gaps in the neurotrauma literature, generate research questions, and prioritize those questions using a consensus-driven Delphi survey approach. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the importance of the questions on a 9-point Likert scale. Consensus was defined as 60% or greater of panelists agreeing on the priority category. We then coded research questions using an National Trauma Research Action Plan taxonomy of 118 research concepts, which were consistent across all 11 panels. RESULTS: Twenty-eight neurotrauma experts generated 675 research questions. Of these, 364 (53.9%) reached consensus, and 56 were determined to be high priority (15.4%), 303 were deemed to be medium priority (83.2%), and 5 were low priority (1.4%). The research topics were stratified into three groups-severe traumatic brain injury (TBI), mild TBI (mTBI), and spinal cord injury. The number of high-priority questions for each subtopic was 46 for severe TBI (19.7%), 3 for mTBI (4.3%) and 7 for SCI (11.7%). CONCLUSION: This Delphi gap analysis of neurotrauma research identified 56 high-priority research questions. There are clear areas of focus for severe TBI, mTBI, and spinal cord injury that will help guide investigators in future neurotrauma research. Funding agencies should consider these gaps when they prioritize future research. LEVEL OF EVIDENCE: Diagnostic Test or Criteria, Level IV.