Development of a compounded propofol nanoemulsion using multiple non-invasive process analytical technologies.

Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak of the COVID-19 pandemic, regular supply chains could not keep up with the sudden increase in global demand, causing drug shortages. Propofol is formulated as an oil-in-water emulsion which is administered intravenously. This study explores the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment to temporally alleviate such shortages. A commercially available lipid emulsion (IVLE, SMOFlipid 20 %), intended for parenteral nutrition, was used to create a propofol loaded nanoemulsion via addition of liquid propofol drug substance and subsequent mixing. Critical quality attributes such as mean droplet size and the volume-weighted percentage of large-diameter (>5µm) droplets were studied. The evolution of droplet size and propofol distribution was monitored in situ and non-destructively, maintaining sterility, using Spatially Resolved Dynamic Light Scattering and Near Infrared Spectroscopy, respectively. Using response surface methodology, an optimum was found for a 4 % w/v propofol formulation with a ∼15 min mixing time in a flask shaker at a 40° shaking angle. This study shows that extemporaneous compounding is a viable option for emergency supply of propofol drug product during global drug shortages.

New unique PAT method and instrument for real-time inline size characterization of concentrated, flowing nanosuspensions.

With the rise of nanotherapeutics -and nano based products in general-, there has been an increasing need for better understanding and control of nano-particle (NP) synthesis and formulation processes. Size characteristics are often primary, if not critical, quality attributes of nanodispersions. Process Analytical Technology (PAT) tools for inline size characterization during dispersion processing are therefore highly desired. Traditional methods for NP sizing -based on Dynamic Light Scattering (DLS) - are typically ill-suited for direct inline application: (i) typical dispersion turbidities in process conditions often exceed by far the application limits for DLS (ii) agitation/flow typical for process conditions is incompatible with standard DLS and (iii) direct and convenient inline application requires a non-invasive PAT tool giving measurements on process relevant time scales. In this article we describe a new non-invasive PAT instrument - the NanoFlowSizer (patent pending)- which provides continuous, real-time, inline size and PSD characterization of concentrated and/or flowing nanodispersions in process environments. The instrument employs Fourier Domain low coherence interferometry, yielding path length resolved dynamic light scattering data of nanodispersions. Particle size characteristics can be analyzed from these data while effects of flow and/or multiple scattering are simultaneously characterized and accounted for. As first application examples we describe (i) real-time monitoring of NP size characteristics by remote measurement of mono and bi-disperse suspensions at different turbidities in a stirred beaker (ii) real-time monitoring of NP size characteristics using an online sampling loop with a micro-flow cell and (iii) real-time inline monitoring of size characteristics of a pharmaceutical nanoemulsion during industrial pilot scale nano-emulsification and for a pharmaceutical NP suspension during circulation, at flowrates ranging up to ~l/min.

Abnormal Blood Oxygen Level-Dependent Fluctuations in Focal Cortical Dysplasia and the Perilesional Zone: Initial Findings.

BACKGROUND AND PURPOSE: Focal cortical dysplasia is a common cause of intractable epilepsy for which neurosurgery is an option. Delineations of a focal cortical dysplasia lesion on structural brain images may not necessarily reflect the functional borders of normal tissue. Our objective was to determine whether abnormalities in spontaneous blood oxygen level-dependent fluctuations arise in focal cortical dysplasia lesions and proximal regions. MATERIALS AND METHODS: Fourteen patients with focal cortical dysplasia-related epilepsy and 16 healthy controls underwent structural and resting-state functional MR imaging. Three known blood oxygen level-dependent measures were determined, including the fractional amplitude of low-frequency fluctuations, regional homogeneity, and wavelet entropy. These measures were evaluated in the lesion and perilesional zone and normalized to the contralateral cortex of patients with focal cortical dysplasia and healthy controls. RESULTS: Patients showed significantly decreased fractional amplitude of low-frequency fluctuations and increased wavelet entropy in the focal cortical dysplasia lesion and the perilesional zone (≤2 cm) relative to the contralateral homotopic cortex and the same regions in healthy controls. Regional homogeneity was significantly increased in the focal cortical dysplasia lesion compared with the contralateral homotopic cortex and healthy controls. CONCLUSIONS: Abnormalities in spontaneous blood oxygen level-dependent fluctuations were seen up to 2 cm distant from the radiologically visible boundary. It was demonstrated that functional boundaries go beyond structural boundaries of focal cortical dysplasia lesions. Validation is required to reveal whether this information is valuable for surgical planning and outcome evaluation of focal cortical dysplasia lesions and comparing current results with electrophysiologic analysis.

Cognitive deterioration in adult epilepsy: clinical characteristics of "Accelerated Cognitive Ageing".

OBJECTIVES: "Epileptic dementia" is reported in adults with childhood-onset refractory epilepsy. Cognitive deterioration can also occur in a "second-hit model". MATERIALS AND METHODS: We studied the clinical and neuropsychological characteristics of patients with cognitive deterioration (≥1 SD discrepancy between current IQ and premorbid IQ). Memory function, reaction time and processing speed were also evaluated. Analyses were performed to investigate which clinical characteristics correlated with cognitive deterioration. RESULTS: Twenty-seven patients were included with a mean age of 55.7 years old, an average age at epilepsy onset of 33.9 years and a mean duration of 21.8 years. Over 40% had experienced at least one status epilepticus. About 77.8% had at least one comorbid disease (most of (cardio)vascular origin). Cognitive deterioration scores were significant for both Performance IQ and Full Scale IQ, but not for Verbal IQ. Impairments in fluid functions primarily affected the IQ-scores. Memory was not impaired. Epilepsy factors explained 7% of the variance in deterioration, whereas 38% was explained by relatively low premorbid IQ and educational level, high age at seizure onset and older age. CONCLUSIONS: A subgroup of patients with localization-related epilepsy exhibits cognitive decline characterized by deterioration in PIQ and FSIQ, but with preserved higher order functions (VIQ and memory). Patients typically have epilepsia tarda, comorbid pathology, relatively low educational level and older age. These are factors known to increase the vulnerability of the brain by diminishing cognitive reserve. Cognitive deterioration may develop according to a stepwise "second-hit model", affecting and accelerating the cognitive ageing process.

Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols.

Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice.

Cognitive deterioration in adult epilepsy: Does accelerated cognitive ageing exist?

A long-standing concern has been whether epilepsy contributes to cognitive decline or so-called 'epileptic dementia'. Although global cognitive decline is generally reported in the context of chronic refractory epilepsy, it is largely unknown what percentage of patients is at risk for decline. This review is focused on the identification of risk factors and characterization of aberrant cognitive trajectories in epilepsy. Evidence is found that the cognitive trajectory of patients with epilepsy over time differs from processes of cognitive ageing in healthy people, especially in adulthood-onset epilepsy. Cognitive deterioration in these patients seems to develop in a 'second hit model' and occurs when epilepsy hits on a brain that is already vulnerable or vice versa when comorbid problems develop in a person with epilepsy. Processes of ageing may be accelerated due to loss of brain plasticity and cognitive reserve capacity for which we coin the term 'accelerated cognitive ageing'. We believe that the concept of accelerated cognitive ageing can be helpful in providing a framework understanding global cognitive deterioration in epilepsy.

Switching of Swimming Modes in Magnetospirillium gryphiswaldense.

The microaerophilic magnetotactic bacterium Magnetospirillum gryphiswaldense swims along magnetic field lines using a single flagellum at each cell pole. It is believed that this magnetotactic behavior enables cells to seek optimal oxygen concentration with maximal efficiency. We analyze the trajectories of swimming M. gryphiswaldense cells in external magnetic fields larger than the earth's field, and show that each cell can switch very rapidly (in <0.2 s) between a fast and a slow swimming mode. Close to a glass surface, a variety of trajectories were observed, from straight swimming that systematically deviates from field lines to various helices. A model in which fast (slow) swimming is solely due to the rotation of the trailing (leading) flagellum can account for these observations. We determined the magnetic moment of this bacterium using a to our knowledge new method, and obtained a value of (2.0±0.6) × 10(-16) A · m(2). This value is found to be consistent with parameters emerging from quantitative fitting of trajectories to our model.

Dilatancy in the flow and fracture of stretched colloidal suspensions.

Concentrated particulate suspensions, commonplace in the pharmaceutical, cosmetic and food industries, display intriguing rheology. In particular, the dramatic increase in viscosity with strain rate (shear thickening and jamming), which is often observed at high-volume fractions, is of practical and fundamental importance. Yet, manufacture of these products and their subsequent dispensing often involves flow geometries substantially different from that of simple shear flow experiments. In this study, we show that the elongation and breakage of a filament of a colloidal fluid under tensile loading is closely related to the jamming transition seen in its shear rheology. However, the modified flow geometry reveals important additional effects. Using a model system with nearly hard-core interactions, we provide evidence of surprisingly strong viscoelasticity in such a colloidal fluid under tension. With high-speed photography, we also directly observe dilatancy and granulation effects, which lead to fracture above a critical elongation rate.

Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature.

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.

Shear banding and flow-concentration coupling in colloidal glasses.

We report experiments on hard-sphere colloidal glasses that show a type of shear banding hitherto unobserved in soft glasses. We present a scenario that relates this to an instability due to shear-concentration coupling, a mechanism previously thought unimportant in these materials. Below a characteristic shear rate γ(c) we observe increasingly nonlinear and localized velocity profiles. We attribute this to very slight concentration gradients in the unstable flow regime. A simple model accounts for both the observed increase of γ(c) with concentration, and the fluctuations in the flow.

Speckle-initialized dynamic segmentation of the prostate.

Echography is a commonly used modality for prostate imaging. Prostate segmentation is the first step in analyzing echographic prostate images. Because of the nature of these images, traditional local image processing operators are inadequate for finding the prostate boundary. Most automated segmentations described in literature require user interaction for contour initializing or editing. Also shape templates are applied as prior knowledge. In this paper, an automatic segmentation method is presented, based on prostate specific image granulation and image intensity. First, a granulation detector is used to extract granulation. Subsequently, the Hessian is adopted to evaluate granulation shape and intensity for the extraction of the prostate-specific dot pattern. This dot pattern is used to construct the contour initialization. A smooth contour model (discrete dynamic contour; DDC) is evolved from this initialization to the final contour. The guiding vector field for the DDC deformation is the gradient vector flow field calculated from an edge map of the original image. The scale of the relevant edges (large compared to granulation) is estimated from the prostate-specific dot pattern. Comparison of automated segmentations with clinical expert manual segmentations reveals a mean sensitivity and accuracy of 0.90 and 0.93, respectively.

Slip and flow of hard-sphere colloidal glasses.

We study the flow of concentrated hard-sphere colloidal suspensions along smooth, nonstick walls using cone-plate rheometry and simultaneous confocal microscopy. In the glass regime, the global flow shows a transition from Herschel-Bulkley behavior at large shear rate to a characteristic Bingham slip response at small rates, absent for ergodic colloidal fluids. Imaging reveals both the "solid" microstructure during full slip and the local nature of the "slip to shear" transition. Both the local and global flow are described by a phenomenological model, and the associated Bingham slip parameters exhibit characteristic scaling with size and concentration of the hard spheres.

Three-dimensional imaging of colloidal glasses under steady shear.

Using fast confocal microscopy we image the three-dimensional dynamics of particles in a yielded hard-sphere colloidal glass under steady shear. The structural relaxation, observed in regions with uniform shear, is nearly isotropic but is distinctly different from that of quiescent metastable colloidal fluids. The inverse relaxation time tau(alpha)(-1) and diffusion constant D, as functions of the local shear rate gamma*, show marked shear thinning with tau(alpha)(-1) proportional to D proportional to gamma*(0.8) over more than two decades in gamma*. In contrast, the global rheology of the system displays Herschel-Bulkley behavior. We discuss the possible role of large scale shear localization and other mechanisms in generating this difference.

Dynamic melting of confined vortex matter.

We study dynamic melting of confined vortex matter moving in disordered, mesoscopic channels by mode-locking experiments. The dynamic melting transition, characterized by a collapse of the mode-locking effect, strongly depends on the frequency, i.e., on the average velocity of the vortices. The associated dynamic ordering velocity diverges upon approaching the equilibrium melting line T(m,e)(B) as v(c) approximately (T(m,e)-T)(-1). The data provide the first direct evidence for velocity dependent melting and show that the phenomenon also takes place in a system under disordered confinement.

Intraoperative scrape cytology of the sentinel lymph node in patients with breast cancer.

BACKGROUND: Intraoperative examination of the sentinel lymph node (SLN) may detect metastatic disease, allowing immediate axillary lymph node dissection and therefore avoiding the need for reoperation. The aim of this study was to evaluate the accuracy of scrape cytology of the SLN in patients with early breast cancer. METHODS: Sentinel node biopsy was performed in 148 patients with clinical T1-2 N0 breast cancer. After harvesting, the SLN was bisected and cells from both halves were scraped with a scalpel blade on to a slide and stained with a Papanicolaou and Giemsa stain. Scrape cytology results were compared with the results of paraffin sections stained with haematoxylin and eosin and with immunohistochemistry. RESULTS: The intraoperative diagnosis was correct in 126 patients (85 per cent). Sensitivity and specificity were 67 and 98 per cent respectively; positive and negative predictive values were 95 and 81 per cent. CONCLUSION: Scrape cytology is a useful method for intraoperative evaluation of the SLN in patients with breast cancer.

Mode locking of vortex matter driven through mesoscopic channels.

We investigated the driven dynamics of vortices confined to mesoscopic flow channels by means of a dc-rf interference technique. The observed mode-locking steps in the IV curves provide detailed information on how both the number of vortex rows and the lattice structure in each flow channel change with magnetic field. Minima in flow stress occur when an integer number of rows is moving coherently, while maxima appear when the incoherent motion of mixed n and n+/-1 row configurations is predominant. Simulations show that the enhanced pinning at mismatch originates from quasistatic fault zones with misoriented edge dislocations induced by disorder in the channel edges.

Histologic processing of microbiopsies from cervical smears is diagnostically useful in selected cases.

We analyzed the value in cervical cytology of a recently developed technique by which it is possible to remove thick tissue specimens, called microbiopsies, from cervical smears and to process them for histologic examination. In 12 (48%) of 25 cervical smears in which microbiopsies were found, the histologic sections from them confirmed the cytologic diagnosis. Most cases involved classification of lesions diagnosed as cervical intraepithelial neoplasia. In 13 (52%) of 25 smears, processing the microbiopsy allowed considerable modification of the cytologic diagnosis. In six of these cases, microbiopsies consisted of groups of columnar cells that were incorrectly classified as atypical on the basis of cytologic criteria. After histologic processing, the microbiopsies revealed nonatypical columnar cells in four cases and only mildly atypical columnar cells in two cases. In 3 of 13 smears, there were insufficient dispersed atypical cells for a conclusive diagnosis. Processing the microbiopsies in these cases allowed classification into one of the cervical intraepithelial neoplasia categories.