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Dysphagia, commonly referred to as abnormal swallowing, affects millions of people annually. If not diagnosed expeditiously, dysphagia can lead to more severe complications, such as pneumonia, nutritional deficiency, and dehydration. Bedside screening is the first step of dysphagia characterization and is usually based on pass/fail tests in which a nurse observes the patient performing water swallows to look for dysphagia overt signs such as coughing. Though quick and convenient, bedside screening only provides low-level judgment of impairment, lacks standardization, and suffers from subjectivity. Recently, high resolution cervical auscultation (HRCA) has been investigated as a less expensive and non-invasive method to diagnose dysphagia. It has shown strong preliminary evidence of its effectiveness in penetration-aspiration detection as well as multiple swallow kinematics. HRCA signals have traditionally been collected and investigated in conjunction with videofluoroscopy exams which are performed using barium boluses including thin liquid. An HRCA-based bedside screening is highly desirable to expedite the initial dysphagia diagnosis and overcome all the drawbacks of the current pass/fail screening tests. However, all research conducted for using HRCA in dysphagia is based on thin liquid barium boluses and thus not guaranteed to provide valid results for water boluses used in bedside screening. If HRCA signals show no significant differences between water and thin liquid barium boluses, then the same algorithms developed on thin liquid barium boluses used in diagnostic imaging studies, it can be then directly used with water boluses. This study investigates the similarities and differences between HRCA signals from thin liquid barium swallows compared to those signals from water swallows. Multiple features from the time, frequency, time-frequency, and information-theoretic domain were extracted from each type of swallow and a group of linear mixed models was tested to determine the significance of differences. Machine learning classifiers were fit to the data as well to determine if the swallowed material (thin liquid barium or water) can be correctly predicted from an unlabeled set of HRCA signals. The results demonstrated that there is no systematic difference between the HRCA signals of thin liquid barium swallows and water swallows. While no systematic difference was discovered, the evidence of complete conformity between HRCA signals of both materials was inconclusive. These results must be validated further to confirm conformity between the HRCA signals of thin liquid barium swallows and water swallows.

Purpose The prevalence of dysphagia in patients with neurodegenerative diseases (ND) is alarmingly high and frequently results in morbidity and accelerated mortality due to subsequent adverse events (e.g., aspiration pneumonia). Swallowing in patients with ND should be continuously monitored due to the progressive disease nature. Access to instrumental swallow evaluations can be challenging, and limited studies have quantified changes in temporal/spatial swallow kinematic measures in patients with ND. High-resolution cervical auscultation (HRCA), a dysphagia screening method, has accurately differentiated between safe and unsafe swallows, identified swallow kinematic events (e.g., laryngeal vestibule closure [LVC]), and classified swallows between healthy adults and patients with ND. This study aimed to (a) compare temporal/spatial swallow kinematic measures between patients with ND and healthy adults and (b) investigate HRCA's ability to annotate swallow kinematic events in patients with ND. We hypothesized there would be significant differences in temporal/spatial swallow measurements between groups and that HRCA would accurately annotate swallow kinematic events in patients with ND. Method Participants underwent videofluoroscopic swallowing studies with concurrent HRCA. We used linear mixed models to compare temporal/spatial swallow measurements ( n = 170 ND patient swallows, n = 171 healthy adult swallows) and deep learning machine-learning algorithms to annotate specific temporal and spatial kinematic events in swallows from patients with ND. Results Differences ( p < .05) were found between groups for several temporal and spatial swallow kinematic measures. HRCA signal features were used as input to machine-learning algorithms and annotated upper esophageal sphincter (UES) opening, UES closure, LVC, laryngeal vestibule reopening, and hyoid bone displacement with 66.25%, 85%, 68.18%, 70.45%, and 44.6% accuracy, respectively, compared to human judges' measurements. Conclusion This study demonstrates HRCA's potential in characterizing swallow function in patients with ND and other patient populations.

Clinicians evaluate swallow kinematic events by analyzing videofluoroscopy (VF) images for dysphagia management. The duration of upper esophageal sphincter opening (DUESO) is one important temporal swallow event, because reduced DUESO can result in pharyngeal residue and penetration/aspiration. VF is frequently used for evaluating swallowing but exposes patients to radiation and is not always feasible/readily available. High resolution cervical auscultation (HRCA) is a non-invasive, sensor-based dysphagia screening method that uses signal processing and machine learning to characterize swallowing. We investigated HRCA's ability to annotate DUESO and predict Modified Barium Swallow Impairment Profile (MBSImP) scores (component #14). We hypothesized that HRCA and machine learning techniques would detect DUESO with similar accuracy as human judges. Trained judges completed temporal kinematic measurements of DUESO on 719 swallows (116 patients) and 50 swallows (15 age-matched healthy adults). An MBSImP certified clinician completed MBSImP ratings on 100 swallows. A multi-layer convolutional recurrent neural network (CRNN) using HRCA signal features for input was used to detect DUESO. Generalized estimating equations models were used to determine statistically significant HRCA signal features for predicting DUESO MBSImP scores. A support vector machine (SVM) classifier and a leave-one-out procedure was used to predict DUESO MBSImP scores. The CRNN detected UES opening within a 3-frame tolerance for 82.6% of patient and 86% of healthy swallows and UES closure for 72.3% of patient and 64% of healthy swallows. The SVM classifier predicted DUESO MBSImP scores with 85.7% accuracy. This study provides evidence of HRCA's feasibility in detecting DUESO without VF images., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

High-resolution cervical auscultation (HRCA) is an emerging method for non-invasively assessing swallowing by using acoustic signals from a contact microphone, vibratory signals from an accelerometer, and advanced signal processing and machine learning techniques. HRCA has differentiated between safe and unsafe swallows, predicted components of the Modified Barium Swallow Impairment Profile, and predicted kinematic events of swallowing such as hyoid bone displacement, laryngeal vestibular closure, and upper esophageal sphincter opening with a high degree of accuracy. However, HRCA has not been used to characterize swallow function in specific patient populations. This study investigated the ability of HRCA to differentiate between swallows from healthy people and people with neurodegenerative diseases. We hypothesized that HRCA would differentiate between swallows from healthy people and people with neurodegenerative diseases with a high degree of accuracy. We analyzed 170 swallows from 20 patients with neurodegenerative diseases and 170 swallows from 51 healthy age-matched adults who underwent concurrent video fluoroscopy with non-invasive neck sensors. We used a linear mixed model and several supervised machine learning classifiers that use HRCA signal features and a leave-one-out procedure to differentiate between swallows. Twenty-two HRCA signal features were statistically significant (p < 0.05) for predicting whether swallows were from healthy people or from patients with neurodegenerative diseases. Using the HRCA signal features alone, logistic regression and decision trees classified swallows between the two groups with 99% accuracy, 100% sensitivity, and 99% specificity. This provides preliminary research evidence that HRCA can differentiate swallow function between healthy and patient populations., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Ni based catalysts have been widely studied for H2 production due to the ability of Ni to break C-C and C-H bonds. In this work, we study inverse catalysts prepared by well-controlled sub-monolayer deposition of CeO2 nanocubes onto Ni thin films for ethanol steam reforming (ESR). Results show that controlling the coverage of CeO2 nanocubes on Ni enhances H2 production by more than an order of magnitude compared to pure Ni. Contrary to the idea that C deposits must be continuously oxidized for sustained H2 production, the surface of the most active catalysts show significant C deposition, yet no deactivation is observed. HAADF-STEM analysis reveals the formation of carbon filaments (CFILs), which propel Ni particles upward at the filament tips via a catalytic tip growth mechanism, resulting in a Ni@CFIL active phase for ESR. Near-ambient pressure XPS indicates that the Ni@CFIL active phase forms as a result of C gradients at the interface between regions of pure Ni metal and domains of closely packed CeO2 nanocubes. These results show that the mesoscale morphology of deposited CeO2 nanocubes is responsible for templating the formation of a Ni@CFIL catalyst, which resists deactivation leading to highly active and stable H2 production from ethanol.

Objective . Adequate upper esophageal sphincter (UES) opening is essential during swallowing to enable clearance of material into the digestive system, and videofluoroscopy (VF) is the most commonly deployed instrumental examination for assessment of UES opening. High-resolution cervical auscultation (HRCA) has been shown to be an effective, portable and cost-efficient screening tool for dysphagia with strong capabilities in non-invasively and accurately approximating manual measurements of VF images. In this study, we aimed to examine whether the HRCA signals are correlated to the manually measured anterior-posterior (AP) distension of maximal UES opening from VF recordings, under the hypothesis that they would be strongly associated. Approach . We developed a standardized method to spatially measure the AP distension of maximal UES opening in 203 swallows VF recording from 27 patients referred for VF due to suspected dysphagia. Statistical analysis was conducted to compare the manually measured AP distension of maximal UES opening from lateral plane VF images and features extracted from two sets of HRCA signal segments: whole swallow segments and segments excluding all events other than the duration of UES is opening. Main results . HRCA signal features were significantly associated with the normalized AP distension of the maximal UES opening in the longer whole swallowing segments and the association became much stronger when analysis was performed solely during the duration of UES opening. Significance . This preliminary feasibility study demonstrated the potential value of HRCA signals features in approximating the objective measurements of maximal UES AP distension and paves the way of developing HRCA to non-invasively and accurately predict human spatial measurement of VF kinematic events., (© 2021 Institute of Physics and Engineering in Medicine.)

Upper esophageal sphincter is an important anatomical landmark of the swallowing process commonly observed through the kinematic analysis of radiographic examinations that are vulnerable to subjectivity and clinical feasibility issues. Acting as the doorway of esophagus, upper esophageal sphincter allows the transition of ingested materials from pharyngeal into esophageal stages of swallowing and a reduced duration of opening can lead to penetration/aspiration and/or pharyngeal residue. Therefore, in this study we consider a non-invasive high resolution cervical auscultation-based screening tool to approximate the human ratings of upper esophageal sphincter opening and closure. Swallows were collected from 116 patients and a deep neural network was trained to produce a mask that demarcates the duration of upper esophageal sphincter opening. The proposed method achieved more than 90% accuracy and similar values of sensitivity and specificity when compared to human ratings even when tested over swallows from an independent clinical experiment. Moreover, the predicted opening and closure moments surprisingly fell within an inter-human comparable error of their human rated counterparts which demonstrates the clinical significance of high resolution cervical auscultation in replacing ionizing radiation-based evaluation of swallowing kinematics.

Laryngeal vestibule (LV) closure is a critical physiologic event during swallowing, since it is the first line of defense against food bolus entering the airway. Identifying the laryngeal vestibule status, including closure, reopening and closure duration, provides indispensable references for assessing the risk of dysphagia and neuromuscular function. However, commonly used radiographic examinations, known as videofluoroscopy swallowing studies, are highly constrained by their radiation exposure and cost. Here, we introduce a non-invasive sensor-based system, that acquires high-resolution cervical auscultation signals from neck and accommodates advanced deep learning techniques for the detection of LV behaviors. The deep learning algorithm, which combined convolutional and recurrent neural networks, was developed with a dataset of 588 swallows from 120 patients with suspected dysphagia and further clinically tested on 45 samples from 16 healthy participants. For classifying the LV closure and opening statuses, our method achieved 78.94% and 74.89% accuracies for these two datasets, suggesting the feasibility of implementing sensor signals for LV prediction without traditional videofluoroscopy screening methods. The sensor supported system offers a broadly applicable computational approach for clinical diagnosis and biofeedback purposes in patients with swallowing disorders without the use of radiographic examination., Competing Interests: Declaration of competing interest We declare we have no competing interests.

Purpose: Safe swallowing requires adequate protection of the airway to prevent swallowed materials from entering the trachea or lungs (i.e., aspiration). Laryngeal vestibule closure (LVC) is the first line of defense against swallowed materials entering the airway. Absent LVC or mistimed/ shortened closure duration can lead to aspiration, adverse medical consequences, and even death. LVC mechanisms can be judged commonly through the videofluoroscopic swallowing study; however, this type of instrumentation exposes patients to radiation and is not available or acceptable to all patients. There is growing interest in noninvasive methods to assess/monitor swallow physiology. In this study, we hypothesized that our noninvasive sensor- based system, which has been shown to accurately track hyoid displacement and upper esophageal sphincter opening duration during swallowing, could predict laryngeal vestibule status, including the onset of LVC and the onset of laryngeal vestibule reopening, in real time and estimate the closure duration with a comparable degree of accuracy as trained human raters., Method: The sensor-based system used in this study is high-resolution cervical auscultation (HRCA). Advanced machine learning techniques enable HRCA signal analysis through feature extraction and complex algorithms. A deep learning model was developed with a data set of 588 swallows from 120 patients with suspected dysphagia and further tested on 45 swallows from 16 healthy participants., Results: The new technique achieved an overall mean accuracy of 74.90% and 75.48% for the two data sets, respectively, in distinguishing LVC status. Closure duration ratios between automated and gold-standard human judgment of LVC duration were 1.13 for the patient data set and 0.93 for the healthy participant data set., Conclusions: This study found that HRCA signal analysis using advanced machine learning techniques can effectively predict laryngeal vestibule status (closure or opening) and further estimate LVC duration. HRCA is potentially a noninvasive tool to estimate LVC duration for diagnostic and biofeedback purposes without X-ray imaging.

High resolution cervical auscultation is a very promising noninvasive method for dysphagia screening and aspiration detection, as it does not involve the use of harmful ionizing radiation approaches. Automatic extraction of swallowing events in cervical auscultation is a key step for swallowing analysis to be clinically effective. Using time-varying spectral estimation of swallowing signals and deep feed forward neural networks, we propose an automatic segmentation algorithm for swallowing accelerometry and sounds that works directly on the raw swallowing signals in an online fashion. The algorithm was validated qualitatively and quantitatively using the swallowing data collected from 248 patients, yielding over 3000 swallows manually labeled by experienced speech language pathologists. With a detection accuracy that exceeded 95%, the algorithm has shown superior performance in comparison to the existing algorithms and demonstrated its generalizability when tested over 76 completely unseen swallows from a different population. The proposed method is not only of great importance to any subsequent swallowing signal analysis steps, but also provides an evidence that such signals can capture the physiological signature of the swallowing process.

Recent publications have suggested that high-resolution cervical auscultation (HRCA) signals may provide an alternative non-invasive option for swallowing assessment. However, the relationship between hyoid bone displacement, a key component to safe swallowing, and HRCA signals is not thoroughly understood. Therefore, in this work we investigated the hypothesis that a strong relationship exists between hyoid displacement and HRCA signals. Videofuoroscopy data was collected for 129 swallows, simultaneously with vibratory/acoustic signals. Horizontal, vertical and hypotenuse displacements of the hyoid bone were measured through manual expert analysis of videofluoroscopy images. Our results showed that the vertical displacement of both the anterior and posterior landmarks of the hyoid bone was strongly associated with the Lempel-Ziv complexity of superior-inferior and anterior-posterior vibrations from HRCA signals. Horizontal and hypotenuse displacements of the posterior aspect of the hyoid bone were strongly associated with the standard deviation of swallowing sounds. Medial-Lateral vibrations and patient characteristics such as age, sex, and history of stroke were not significantly associated with the hyoid bone displacement. The results imply that some vibratory/acoustic features extracted from HRCA recordings can provide information about the magnitude and direction of hyoid bone displacement. These results provide additional support for using HRCA as a non-invasive tool to assess physiological aspects of swallowing such as the hyoid bone displacement.

Hyoid bone movement is an important physiological event during swallowing that contributes to normal swallowing function. In order to determine the adequate hyoid bone movement, clinicians conduct an X-ray videofluoroscopic swallowing study, which even though it is the gold-standard technique, has limitations such as radiation exposure and cost. Here, we demonstrated the ability to track the hyoid bone movement using a non-invasive accelerometry sensor attached to the surface of the human neck. Specifically, deep neural networks were used to mathematically describe the relationship between hyoid bone movement and sensor signals. Training and validation of the system were conducted on a dataset of 400 swallows from 114 patients. Our experiments indicated the computer-aided hyoid bone movement prediction has a promising performance when compared with human experts' judgements, revealing that the universal pattern of the hyoid bone movement is acquirable by the highly nonlinear algorithm. Such a sensor-supported strategy offers an alternative and widely available method for online hyoid bone movement tracking without any radiation side-effects and provides a pronounced and flexible approach for identifying dysphagia and other swallowing disorders., Competing Interests: We declare we have no competing interests.

Purpose: Outcomes following total knee arthroplasty (TKA), whether clinical, radiological or survival analysis, have been well-studied. Still, there are some concerns about patient satisfaction with the outcome of the surgery and factors that might contribute to a suboptimal result. This study aims to determine if there is correlation between primary TKA malalignment and early patient-reported outcome measures (PROMs)., Materials and Methods: Sixty patients, who had primary TKA and a minimum of 2 years of follow up, were recruited for a detailed clinical and radiological examination. Knee alignment was measured in the coronal, sagittal and axial planes. Normal and the outlier measurements of the patients' knees were defined and the clinical results (PROMs) compared to see if there was a statistically significant difference., Results: Correlation between postoperative limb malalignment in the coronal and the sagittal planes and PROMs was not significant. Conversely, there was significant negative correlation between all types of malrotation and PROMs., Conclusions: Although malalignment has been linked to inferior outcome and implant survival, our results showed that coronal and sagittal limb malalignment has no significant effect on early PROMs. However, all types of component rotational malalignment significantly worsen early PROMs.

Molecular level information about thermodynamic variations (enthalpy, entropy, and free energy) of a gas molecule as it crosses a gas-liquid interface is strongly lacking from an experimental perspective under equilibrium conditions. Herein, we perform in situ measurements of water interacting with the ionic liquid (IL) 1-butyl-3-methylimidazolium acetate, [C 4 mim][Ace], using ambient pressure X-ray photoelectron spectroscopy in order to assess the interfacial uptake of water quantitatively as a function of temperature, pressure, and water mole fraction ( x w ). The surface spectroscopy results are compared to existing bulk water absorption experiments, showing that the amount of water in the interfacial region is consistently greater than that in the bulk. The enthalpy and entropy of water sorption vary significantly between the gas-liquid interface and the bulk as a function of x w , with a crossover that occurs near x w = 0.6 where the water-IL mixture converts from being homogeneous ( x w < 0.6) to nanostructured ( x w > 0.6). Free energy results reveal that water at the gas-IL interface is thermodynamically more favorable than that in the bulk, consistent with the enhanced water concentration in the interfacial region. The results herein show that the efficacy for an ionic liquid to absorb a gas phase molecule is not merely a function of bulk solvation parameters but also is significantly influenced by the thermodynamics occurring across the gas-IL interface during the mass transfer process.

Carbon nanotube-based field-effect transistors (NTFETs) are ideal sensor devices as they provide rich information regarding carbon nanotube interactions with target analytes and have potential for miniaturization in diverse applications in medical, safety, environmental, and energy sectors. Herein, we investigate chemical detection with cross-sensitive NTFETs sensor arrays comprised of metal nanoparticle-decorated single-walled carbon nanotubes (SWCNTs). By combining analysis of NTFET device characteristics with supervised machine-learning algorithms, we have successfully discriminated among five selected purine compounds, adenine, guanine, xanthine, uric acid, and caffeine. Interactions of purine compounds with metal nanoparticle-decorated SWCNTs were corroborated by density functional theory calculations. Furthermore, by testing a variety of prepared as well as commercial solutions with and without caffeine, our approach accurately discerns the presence of caffeine in 95% of the samples with 48 features using a linear discriminant analysis and in 93.4% of the samples with only 11 features when using a support vector machine analysis. We also performed recursive feature elimination and identified three NTFET parameters, transconductance, threshold voltage, and minimum conductance, as the most crucial features to analyte prediction accuracy.

Millions of people across the globe suffer from swallowing difficulties, known as dysphagia, which can lead to malnutrition, pneumonia, and even death. Swallowing cervical auscultation, which has been suggested as a noninvasive screening method for dysphagia, has not been associated yet with any physical events. In this paper, we have compared the hyoid bone displacement extracted from the videofluoroscopy images of 31 swallows to the signal features extracted from the cervical auscultation recordings captured with a tri-axial accelerometer and a microphone. First, the vertical displacement of the anterior part of the hyoid bone is related to the entropy rate of the superior-inferior swallowing vibrations and to the kurtosis of the swallowing sounds. Second, the vertical displacement of the posterior part of the hyoid bone is related to the bandwidth of the medial-lateral swallowing vibrations. Third, the horizontal displacements of the posterior and anterior parts of the hyoid bone are related to the spectral centroid of the superior-inferior swallowing vibrations and to the peak frequency of the medial-lateral swallowing vibrations, respectively. At last, the airway protection scores and the command characteristics were associated with the vertical and horizontal displacements, respectively, of the posterior part of the hyoid bone. Additional associations between the patients' characteristics and auscultations' signals were also observed. The hyoid bone maximal displacement is a cause of swallowing vibrations and sounds. High-resolution cervical auscultation may offer a noninvasive alternative for dysphagia screening and additional diagnostic information.

Introduction: Studies have shown that structured cataract surgery training curricula are beneficial for resident surgeons-in-training, yet nearly one-third of US training programs do not have one, and public dissemination of said curricula are lacking., Methods: We created a microsurgical simulation center and accompanying structured training curriculum. Weekly lectures focused on the steps of cataract surgery, variations on technique, and complications. Each didactic was followed by a 1.5- to 2-hour time block with faculty supervision in the wet lab. Finally, to demonstrate proficiency, residents submitted a recorded video illustrating their competency within 1 week of the lecture. We reviewed videos and provided written feedback via a standardized form. Curriculum effectiveness was evaluated through formative feedback on the course itself and complication rates for resident-performed cataract surgery before and after implementation of the curriculum., Results: The course was implemented in 4 consecutive academic years, allowing time for nine junior residents to participate in the course at least once before operating as a senior. The incidence of posterior capsule tears for senior residents decreased from 3.07% in the 4 years preceding curriculum implementation to 1.13% for the senior residents who completed the course at least once as juniors ( p = .0571). Supervised wet lab sessions and submitted videos allowed faculty to identify surgically struggling residents early., Discussion: Implementation of a cataract surgery training curriculum for junior ophthalmology residents provides a safe and effective environment to practice surgical techniques. Such a curriculum may decrease the complication rates of beginner surgeons., Competing Interests: None to report.

Introduction: Acetabular cup version is crucial for successful total hip arthroplasty (THA). Many methods have been described for measurement of cup version angle. The aim of this study is to assess the accuracy of five commonly used methods for measurement of acetabular cup version in plain antero-posterior views of the pelvis and hip., Material and Methods: Sixty primary THA cases were subjected postoperatively to plain A-P of the pelvis (AP-P), A-P view of the hip (AP-H), and computed tomography (CT) imaging. The acetabular cup version was measured in AP-P and AP-H by five methods (Lewinnek, Widmer, Hassan et al., Ackland et al., and Liaw et al.). These measurements were compared to the CT measurement., Results: All plain X-ray methods showed no significant differences from the CT, except those of Hassan et al. in AP-H, and Widmer and Ackland et al. in AP-P., Conclusions and Recommendations: For measurement of acetabular cup version angle, we recommend the use of Lewinnek and Liaw et al. methods both in AP-P and in AP-H, while Hassan et al.'s method is recommended in AP-P only, and Widmer and Ackland et al.'s methods in AP-H only.

The ionic liquid-gas interface of 1-hexyl-3-methyl-imidazolium chloride, [HMIM][Cl], was examined in the presence of water vapor using lab-based ambient pressure x-ray photoelectron spectroscopy (APXPS) at room temperature. The interfacial water uptake was measured quantitatively in the pressure range of high vacuum up to a maximum of 5 Torr (27% RH) and back to high vacuum in a systematic manner. Water mole fractions in the interface determined from APXPS were compared to previously published tandem differential mobility analysis results on [HMIM][Cl] nanodroplets. Our findings show that water constitutes a significantly larger mole fraction at the interface when compared to the bulk. Additionally, the reverse isotherms showed that the uptake of water at the interface of [HMIM][Cl] is a reversible process.

The interaction of water vapor with a single crystal ZnO(101̅0) surface was investigated using synchrotron-based ambient pressure X-ray photoelectron spectroscopy (APXPS). Two isobaric experiments were performed at 0.3 and 0.07 Torr water vapor pressure at sample temperatures ranging from 750 to 295 K up to a maximum of 2% relative humidity (RH). Below 10 -4  % RH the ZnO(101̅0) interface is covered with ∼0.25 monolayers of OH groups attributed to dissociation at nonstoichiometric defect sites. At ∼10 -4  % RH there is a sharp onset in increased surface hydroxylation attributed to reaction at stoichiometric terrace sites. The surface saturates with an OH monolayer ∼0.26 nm thick and occurs in the absence of any observable molecularly bound water, suggesting the formation of a 1 × 1 dissociated monolayer structure. This is in stark contrast to ultrahigh vacuum experiments and molecular simulations that show the optimum structure is a 2 × 1 partially dissociated H 2 O/OH monolayer. The sharp onset to terrace site hydroxylation at ∼10 -4  % RH for ZnO(101̅0) contrasts with APXPS observations for MgO(100) which show a sharp onset at 10 -2  % RH. A surface thermodynamic analysis reveals that this shift to lower RH for ZnO(101̅0) compared to MgO(100) is due to a more favorable Gibbs free energy for terrace site hydroxylation.

Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.

Ambient pressure X-ray photoelectron spectroscopy (APXPS) is a powerful spectroscopy tool that is inherently surface sensitive, elemental, and chemical specific, with the ability to probe sample surfaces under Torr level pressures. Herein, we describe the design of a new lab-based APXPS system with the ability to swap small volume analysis chambers. Ag 3d(5/2) analyses of a silver foil were carried out at room temperature to determine the optimal sample-to-aperture distance, x-ray photoelectron spectroscopy analysis spot size, relative peak intensities, and peak full width at half maximum of three different electrostatic lens modes: acceleration, transmission, and angular. Ag 3d(5/2) peak areas, differential pumping pressures, and pump performance were assessed under varying N2(g) analysis chamber pressures up to 20 Torr. The commissioning of this instrument allows for the investigation of molecular level interfacial processes under ambient vapor conditions in energy and environmental research.

Lemierre syndrome is an uncommon septic thrombophlebitis of the veins of the head and the neck usually occurring after a severe oropharyngeal infection. Although subsequent septic emboli most commonly affect distant sites, such as the lungs and joints, the authors present a case of Lemierre syndrome causing bilateral cavernous sinus syndrome.

Purpose: We have previously shown that non-psychotropic cannabidiol (CBD) protects retinal neurons in diabetic rats by inhibiting reactive oxygen species and blocking tyrosine nitration. Tyrosine nitration may inhibit glutamine synthetase (GS), causing glutamate accumulation and leading to further neuronal cell death. We propose to test the hypothesis that diabetes-induced glutamate accumulation in the retina is associated with tyrosine nitration of GS and that CBD treatment inhibits this process., Methods: Sprague Dawley rats were made diabetic by streptozotocin injection and received either vehicle or CBD (10 mg/kg/2 days). After eight weeks, retinal cell death, Müller cell activation, GS tyrosine nitration, and GS activity were determined., Results: Diabetes causes significant increases in retinal oxidative and nitrative stress compared with controls. These effects were associated with Müller cell activation and dysfunction as well as with impaired GS activity and tyrosine nitration of GS. Cannabidiol treatment reversed these effects. Retinal neuronal death was indicated by numerous terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL)-labeled cells in diabetic rats compared with untreated controls or CBD-treated rats., Conclusions: These results suggest that diabetes-induced tyrosine nitration impairs GS activity and that CBD preserves GS activity and retinal neurons by blocking tyrosine nitration.

Purpose: To describe the use of fluocinolone acetonide implants (Retisert) in Vogt-Koyanagi-Harada disease (VKH)., Design: Interventional case series., Methods: Retrospective review of medical records., Results: Two patients with VKH requiring high-dose systemic corticosteroid therapy to control their inflammation and bilateral serous retinal detachments received bilateral fluocinolone acetonide implants. Upon tapering of systemic corticosteroids, one patient had recurrent serous retinal detachments and the other patient's anterior chamber and vitreous inflammation returned., Conclusions: The authors' experience with fluocinolone acetonide implants in VKH has been mixed with an inability to fully taper off of systemic corticosteroids.

Diabetic retinopathy is a leading cause of blindness in the Western world. However, treatment options for diabetic retinopathy are limited and display poor efficacy with marked patient-to-patient variation in therapeutic outcomes. Discovery of new molecular entities acting on mechanistically novel biological pathways remains as one of the key research priorities in diabetic retinopathy. Moreover, given the variable success of the existing treatment modalities, a targeted and personalized drug development strategy could be more fruitful for rational and successful transition of preclinical discoveries to the clinical realm. This review is focused on cannabidiol, a non-psychoactive native cannabinoid, as an emerging and novel therapeutic modality based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy - one of the retinal diseases associated with vascular neuroinflammation. We present the postulated and preclinically documented novel mechanisms that may underlie cannabidiol mode of action in diabetic retinopathy. We discuss the interindividual variation in pharmacokinetic pathways as well as in the SLC29A1 gene, a molecular target for cannabidiol. We emphasize that the novel mode of action of cannabidiol and the previous failures with nontargeted interventions in diabetic retinopathy collectively demand a more rational and personalized clinical development strategy for compounds that have shown promise at the preclinical stage. Moreover, it is noteworthy that ophthalmology, as a medical specialty, has fewer examples (e.g., compared to oncology) of personalized medicine and biomarker applications thus far. Understanding the biological action of cannabidiol in preclinical studies is therefore a rational first step to proactively map the pertinent biomarker strategies in clinical proof of concept studies in diabetic retinopathy, and to allow advances at the hitherto neglected intersection of personalized medicine and ophthalmology.

Purpose: Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD., Methods: The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined., Results: The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosine's TNF-alpha suppression after treatment with LPS., Conclusions: These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBD's anti-inflammatory effects are linked to the inhibition of adenosine uptake.

Purpose: Degenerative retinal diseases are characterized by inflammation and microglial activation. The nonpsychoactive cannabinoid, cannabidiol (CBD), is an anti-inflammatory in models of diabetes and glaucoma. However, the cellular and molecular mechanisms are largely unknown. We tested the hypothesis that retinal inflammation and microglia activation are initiated and sustained by oxidative stress and p38 mitogen-activated protein kinase (MAPK) activation, and that CBD reduces inflammation by blocking these processes., Methods: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-alpha levels were estimated with ELISA. Nitric oxide (NO) was determined with a NO analyzer. Superoxide anion levels were determined by the chemiluminescence of luminol derivative. Reactive oxygen species (ROS) was estimated by measuring the cellular oxidation products of 2', 7'-dichlorofluorescin diacetate., Results: In retinal microglial cells, treatment with lipopolysaccharide (LPS) induced immediate NADPH oxidase-generated ROS. This was followed by p38 MAPK activation and resulted in a time-dependent increase in TNF-alpha production. At a later phase, LPS induced NO, ROS, and p38 MAPK activation that peaked at 2-6 h and was accompanied by morphological change of microglia. Treatment with 1 microM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-alpha formation, and maintained cell morphology. In addition, LPS-treated rat retinas showed an accumulation of macrophages and activated microglia, significant levels of ROS and nitrotyrosine, activation of p38 MAPK, and neuronal apoptosis. These effects were blocked by treatment with 5 mg/kg CBD., Conclusions: Retinal inflammation and degeneration in uveitis are caused by oxidative stress. CBD exerts anti-inflammatory and neuroprotective effects by a mechanism that involves blocking oxidative stress and activation of p38 MAPK and microglia.

We identified three eyes that had undergone enucleation after transscleral resection of uveal melanoma. Two enucleated eyes with microscopically positive margins of resection exhibited no evidence of residual melanoma and these patients were alive without metastasis with at least four years' follow-up. One eye with a transected melanoma contained residual melanoma and that patient died with metastatic melanoma to the liver three years after enucleation. There appear to be at least two general types of positive surgical margins of resection of uveal melanoma: microscopically positive margins and macroscopically positive (transected) margins of resection.

Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase. In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration. Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme-linked immunosorbent assay, immunohistochemistry, and/or Western blot. CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina. Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase.

The efficacy and safety of short acting buserelin and nafarelin intranasal spray were compared to long acting leuprorelin depot intramuscular or subcutaneous injection in this prospective study of 157 women undergoing controlled ovarian hyperstimulation (COH) for in-vitro fertilisation (IVF). Patients were allocated to three groups to receive buserelin 150 microg nasal spray three times daily (Group B), nafarelin nasal spray 400 microg twice daily (Group N), or leuprorelin depot 3.75 mg once by intramuscular or subcutaneous injection (Group L) for pituitary desensitisation prior to commencing COH with human menopausal gonadotrophins (hMG) according to the Centre's protocol. The mean (+/-S.D.) age (years) (32.6+/-3.8: Group B, 32.1+/-3.3: Group N versus 32.1+/-3.3: Group L); mean (+/-S.D.) total dosage of hMG (ampoules) (37.5+/-16.1: Group B, 39.8+/-14.2: Group N versus 41.9+/-12.6: Group L) and mean daily dosage of hMG (ampoules) (3.1: Group B, 2.8: Group N versus 3.0: Group L) seen were not statistically significantly different. The duration between starting the different gonadotrophin-releasing hormone (GnRHa) and the beginning of the next menstrual period was also not seen to be statistically significantly different between the three groups (Group B: 10+/-5.5, Group N: 9.1+/-4.1 versus Group L: 8.2+/-3, days). The number of abandoned cycles was higher in Group L (17% versus 11.8%: Group B and 11.3%: Group N) but this difference did not reach statistical significance. The clinical pregnancy rates per oocyte retrieval and per embryo transfer procedure were respectively, 31.1, 35% in Group B, 12.8, 14% in Group N versus 20.5, 23.7 in Group L and were not seen to be statistically significantly different even when ongoing pregnancy rates were compared. Apart from a statistically significantly greater incidence of allergic nasal reactions in the nafarelin group (P=0.001), all other side-effects were not shown to be statistically significantly different between the three groups. We conclude that a single dose of leuprorelin depot can be considered to be as an equally effective alternative to multiple doses of buserelin or nafarelin for pituitary desensitisation in women undergoing COH for IVF.

In-vitro fertilization (IVF) by intracytoplasmic sperm injection (ICSI) with spermatozoa retrieved by percutaneous epididymal sperm aspiration (PESA) is a novel, simple and effective treatment for azoospermic men. In all, 38 azoospermic men had an IVF/PESA/ICSI cycle. A total of 42 cycles were performed. The aetiology of azoospermia was classified as failed vasectomy reversal (12 patients/16 cycles), inflammatory obstruction (five patients/five cycles), partial testicular failure (five patients/five cycles) and bilateral congenital absence of vas (16 patients/16 cycles). Adequate sperm preparations for ICSI were obtained from 38 of the 42 treatment cycles (90%). The mean fertilization rate was 32.7%, and fertilization occurred in 35 cycles (92.0%). Embryo transfer was performed in 13 out of 14 cycles (93%) in men with a failed vasectomy reversal, four out of five cycles in men with an inflammatory obstruction (80%), four out of four cycles in men with a partial testicular failure (100%), and 14 out of 15 cycles in men with a bilateral congenital absence of vas (93%). The overall pregnancy rate per two or three embryos transferred was 28.6 and 26.3% per treatment cycle respectively. The sperm parameters of the final pooled sperm aspirate preparations varied widely among the four aetiological groups. These parameters were of no value in predicting the fertilization or pregnancy rates (P > 0.05), and neither was the embryo cleavage rate.

Objective: To evaluate the recovery rate of spermatozoa from the epididymis using a percutaneous aspiration technique and to examine the fertilization rate after intracytoplasmic sperm injection., Design: Prospective observational study., Setting: Private infertility clinic, London., Subjects: Twenty patients with obstructive azoospermia who each had an attempt at IVF. The sperm used for intracytoplasmic sperm injection was retrieved by percutaneous epididymal sperm aspiration in 16 patients. In one patient, microepididymal sperm aspiration was performed in addition because the quality of the sperm obtained by percutaneous epididymal sperm aspiration was not considered suitable for microinjection. In the remaining three patients, neither percutaneous epididymal sperm aspiration nor microepididymal sperm aspiration resulted in the recovery of sperm, which was obtained by testicular biopsy in one of them., Intervention: Assisted fertilization with intracytoplasmic sperm injection., Main Outcome Measures: Normal fertilization and pregnancy rates., Results: A total of 179 eggs were collected and 157 subsequently were microinjected. Normal fertilization occurred in 22 oocytes (14%) and the total number of embryos cleaved was 30. Twelve patients underwent ET in which three conceived (pregnancy rate 25% per transfer). The implantation rate was 10% and failed fertilization occurred in four cycles., Conclusion: Percutaneous epididymal sperm aspiration can be used successfully to recover sperm in men with obstructive azoospermia for use in assisted fertilization IVF cycles. The technique is simple, effective, and less traumatic compared with an open microsurgical operation.

Pregnancy rates per cycle of intra-uterine donor insemination following ovulation induction were compared retrospectively for those patients having a single, and those having repeated insemination using frozen donor semen. Single insemination was performed in 69 cycles in which 15 women became pregnant (pregnancy rate = 22%). Of 65 cycles in which repeated insemination was performed, 16 women became pregnant (pregnancy rate = 25%). This difference in pregnancy rates was not statistically significant (chi 2 = 3.6, P = 0.84). We conclude that cycle fecundity may not be increased by repeating insemination.

We report an intramural pregnancy following a difficult embryo transfer in a 31 year-old woman, having in-vitro fertilization and embryo transfer for tubal factor infertility. The creation of a 'false passage' at a previous instrumentation of the cervix may be implicated in the ectopic placement of embryos.

Objective: The aim of this study was to assess the fertilizability of unfertilized aged human oocytes from failed in vitro fertilization (IVF) cycles using SUZI and ICSI., Methods: A total of 363 oocytes which showed no fertilization after conventional IVF was subjected to assisted fertilization using SUZI or ICSI. The microinjected oocytes which were derived from 72 patients undergoing their first IVF treatment had an intact polar body and no signs of degeneration. SUZI was carried out in 265 oocytes and ICSI in the remaining 98., Results: Significantly more oocytes were damaged after ICSI (9 vs 0.3%, P < 0.01). Normal fertilization rates were higher at 24 hr in both groups and occurred more frequently after ICSI, although the difference did not reach statistical significance. Abnormal fertilization occurred significantly more often after SUZI at 48 hr (P < 0.005), but not at 24 hr. Cleavage rates were significantly higher after ICSI (94.4 vs 57.1%, P < 0.025) at 24 hr, but this was not observed at 48 hr, although the ICSI group still showed better cleavage rates (33.3 vs 19.1%). There was no difference in embryo quality in either group., Conclusions: Our results indicate that micromanipulation rather than reinsemination should be carried out on unfertilized human oocytes from failed IVF attempts. Both techniques can be used to achieve fertilization which occurs more often after ICSI. However, the trauma from the former technique on the microinjected oocytes may impair the potential of the generated embryos to achieve pregnancy compared to SUZI. Prospective randomized trials are necessary to address the problem.