Automated surgery planning for an obstructed nose by combining computational fluid dynamics with reinforcement learning.

Septoplasty and turbinectomy are among the most common interventions in the field of rhinology. Their constantly debated success rates and the lack of quantitative flow data of the entire nasal airway for planning the surgery necessitate methodological improvement. Thus, physics-based surgery planning is highly desirable. In this work, a novel and accurate method is developed to enhance surgery planning by physical aspects of respiration, i.e., to plan anti-obstructive surgery, for the first time a reinforcement learning algorithm is combined with large-scale computational fluid dynamics simulations. The method is integrated into an automated pipeline based on computed tomography imaging. The proposed surgical intervention is compared to a surgeon's initial plan, or the maximum possible intervention, which allows the quantitative evaluation of the intended surgery. Two criteria are considered: (i) the capability to supply the nasal airway with air expressed by the pressure loss and (ii) the capability to heat incoming air represented by the temperature increase. For a test patient suffering from a deviated septum near the nostrils and a bony spur further downstream, the method recommends surgical interventions exactly at these locations. For equal weights on the two criteria (i) and (ii), the algorithm proposes a slightly weaker correction of the deviated septum at the first location, compared to the surgeon's plan. At the second location, the algorithm proposes to keep the bony spur. For a larger weight on criterion (i), the algorithm tends to widen the nasal passage by removing the bony spur. For a larger weight on criterion (ii), the algorithm's suggestion approaches the pre-surgical state with narrowed channels that favor heat transfer. A second patient is investigated that suffers from enlarged turbinates in the left nasal passage. For equal weights on the two criteria (i) and (ii), the algorithm proposes a nearly complete removal of the inferior turbinate, and a moderate reduction of the middle turbinate. An increased weight on criterion (i) leads to an additional reduction of the middle turbinate, and a larger weight on criterion (ii) yields a solution with only slight reductions of both turbinates, i.e., focusing on a sufficient heat exchange between incoming air and the air-nose interface. The proposed method has the potential to improve the success rates of the aforementioned surgeries and can be extended to further biomedical flows.

Elastometry - The biomechanical analysis of the lateral nasal wall.

'Elastometry' is a novel technique that allows for the quantitative assessment of elastic properties of the nasal tissues, providing valuable insights into the dynamic behavior of the external, soft lateral nasal wall. This study aimed to explore the application of 'elastometry' in understanding the biomechanics of the lateral nasal wall and its implications for nasal function in 'elastometry' measurements. After validation of safety and reliability of this method, we investigated mechanical properties of the lateral nasal wall by 'elastometry' using specifically developed measurement forceps with end pieces including sensors applied on 30 healthy volunteers, aged 18 to 82 without a history of severe trauma or surgery. By measuring normal stress and path length between the end pieces the modulus of elasticity was calculated. Among 360 measurements, the mean value determined for healthy female volunteers was E = 0.135 [N/mm2] and for healthy males E = 0.169 [N/mm2], fitting the range reported in the literature. A tendency of an age-related degree of elastic behavior of the lateral nasal wall was observed, whereby a decrease in elasticity with age in female and a slight increase in elasticity with age in male was detected. Our research showed that 'elastometry' is a cost and time-efficient method to calculate the modulus of elasticity, and could be used in conjunction with 4-phase rhinomanometry (4 PR) to extend diagnostic yield.

Measurement of Nasal Obstruction: Rhinomanometry as Basic Method in Functional Rhinology.

Measuring nasal obstruction should be mandatory before every nasal surgery to determine the necessary surgical steps and to separate mucosal congestion from skeletal deformity. Rhinomanometry is considered the "golden standard" for measuring nasal airway resistance. An extension of the diagnostic power was achieved by the introduction of the four-phase rhinomanometry (4PR), which provides additional information about the influence of the elasticity of the nasal wall. Also, a high correlation to the subjective sensing of obstruction could be achieved by the introduction of logarithmic parameters. The parameters of 4PR could be classified by evaluating 36,500 measurements. The International Standardization Committee on the Objective Assessment of the Upper Airway (ISCOANA) determined it as the new standard. Adding a visual analog scale (VAS) to every measurement is a documentation of the feeling of obstruction at the moment of measurement. Practical hints for 4PR are given. The determination of obstruction for both nasal sides or the calculation of the total nasal resistance should be followed by a second analysis of the detailed obstruction anatomy. In the future, pressure losses or temperature gradients can be determined by computational fluid dynamics (CFD). A reliable way to simulate the success of single surgical steps with a high didactical meaning is the three-dimensional (3D) print of sliced nose models and to measure the effect of stepwise mechanical corrections.

An effective simulation- and measurement-based workflow for enhanced diagnostics in rhinology.

Physics-based analyses have the potential to consolidate and substantiate medical diagnoses in rhinology. Such methods are frequently subject to intense investigations in research. However, they are not used in clinical applications, yet. One issue preventing their direct integration is that these methods are commonly developed as isolated solutions which do not consider the whole chain of data processing from initial medical to higher valued data. This manuscript presents a workflow that incorporates the whole data processing pipeline based on a Jupyter environment. Therefore, medical image data are fully automatically pre-processed by machine learning algorithms. The resulting geometries employed for the simulations on high-performance computing systems reach an accuracy of up to 99.5% compared to manually segmented geometries. Additionally, the user is enabled to upload and visualize 4-phase rhinomanometry data. Subsequent analysis and visualization of the simulation outcome extend the results of standardized diagnostic methods by a physically sound interpretation. Along with a detailed presentation of the methodologies, the capabilities of the workflow are demonstrated by evaluating an exemplary medical case. The pipeline output is compared to 4-phase rhinomanometry data. The comparison underlines the functionality of the pipeline. However, it also illustrates the influence of mucosa swelling on the simulation. Graphical Abstract Workflow for enhanced diagnostics in rhinology.

Four-phase rhinomanometry: a multicentric retrospective analysis of 36,563 clinical measurements.

Rhinomanometry can still be considered as the standard technique for the objective assessment of the ventilatory function of the nose. Reliable technical requirements are given by fast digital sensors and modern information technology. However, the xyimaging of the pressure-flow relation typically shows loops as a sign of hysteresis, with the need for resolution of the breath in four phases. The three pillars of 4-phase rhinomanometry (4PR) are the replacement of estimations by measurements, the introduction of parameters related to the subjective sensing of obstruction, and the graphical information regarding the disturbed function of the nasal valve. In a meta-analysis of 36,563 clinical measurements, we analyze the errors of the "classic" parameters (flow in 150 Pa) and reject the further use of these parameters as obsolete, because they correspond to an inaccurate estimation rather than proper measurement. In a pre-study of 1580 measurements, the logarithmic effective resistance (Reff) was found to have the highest correlation with values obtained from a visual analog scale. Next, we classify the inspiratory effective resistance in 20,069 measurements without treatment and 16,494 measurements after decongestion with xylometazoline 0.1 % spray in 20 % percentiles. The gradation of obstruction delivers not only "normal" values but also indications for the severity of the obstruction in adult Caucasian noses. Adoption of the distribution for the growing nose and analysis of the total nasal resistance is addressed, and typical findings of nasal valve phenomena are outlined.

Reaching movement onset- and end-related characteristics of EEG spectral power modulations.

The spectral power of intracranial field potentials shows movement-related modulations during reaching movements to different target positions that in frequencies up to the high-γ range (approximately 50 to above 200 Hz) can be reliably used for single-trial inference of movement parameters. However, identifying spectral power modulations suitable for single-trial analysis for non-invasive approaches remains a challenge. We recorded non-invasive electroencephalography (EEG) during a self-paced center-out and center-in arm movement task, resulting in eight reaching movement classes (four center-out, four center-in). We found distinct slow (≤5 Hz), µ (7.5-10 Hz), ß (12.5-25 Hz), low-γ (approximately 27.5-50 Hz), and high-γ (above 50 Hz) movement onset- and end-related responses. Movement class-specific spectral power modulations were restricted to the ß band at approximately 1 s after movement end and could be explained by the sensitivity of this response to different static, post-movement electromyography (EMG) levels. Based on the ß band, significant single-trial inference of reaching movement endpoints was possible. The findings of the present study support the idea that single-trial decoding of different reaching movements from non-invasive EEG spectral power modulations is possible, but also suggest that the informative time window is after movement end and that the informative frequency range is restricted to the ß band.

Airway assessment by four-phase rhinomanometry in septal surgery.

PURPOSE OF REVIEW: This article updates the state of the art in functional ventilation tests of the nasal airway. Multidisciplinary international cooperation has led within the last years to the development of four-phase rhinomanometry (4PR) by eradicating the errors of the 'classic' rhinomanometry. RECENT FINDINGS: Physical experiments, mathematical models and comprehensive statistical analyses implicate that the nasal breath consists of four phases of different diagnostic importance. Presuming the motility of the nasal entrance, it is necessary to depict the elastic behavior within the rhinomanometric curve, as well as to use new parameters for the clinical evaluation of the nasal obstruction. The parameters logarithmic vertex resistance and logarithmic effective resistance are related to the sensing of the patient. Their clinical importance was proved in studies of more than 12 000 patients. SUMMARY: The human eye is not able to estimate the degree of impairment in nasal breathing. Therefore, a functional diagnosis is mandatory to avoid unnecessary surgery and to control the results. 4PR is a substantial improvement over the currently used methods. It should be implemented in the standards of the international standardization committee for the objective assessment of the upper airway (ISOANA). Practical hints for correct measurements are given.

4-Phase-Rhinomanometry (4PR)--basics and practice 2010.

The last comprehensive publications about the theory and practice of rhinomanometry appeared more than 20 years ago. Since the 1980's, the general progress of sensor techniques, fluid physics and data processing was accompanied by the permanent work of the authors to analyze the errors of rhinomanometry and to create a fundament for a contemporary and practical method that can be used in functional diagnostics of the nasal air stream. In this special document, the objectives and measurement principles, as well as the history of rhinomanometry are described in the first three chapters. It is pointed out, that the key parameters are not only intranasal pressure and flow, but also the factor time. The technical requirements as following from the dynamics of breathing are described. The process of averaging of rhinomanometric data lead to a separate and time-dependent analysis of the changes of pressure and flow and implicated the introduction of the 4 breathing phases (ascending and descending curve part in inspiration and expiration) into rhinomanometry and is therefore called 4-Phase-Rhinomanometry (4PR). Chapter 4 is containing a comprehensive analysis of the practical errors, which may follow neglecting the 4 breathing phases. The in chapter 5 described mathematical-physical concept of 4PR is based on the introduction of the terms "steady" and "unsteady" flow, in addition to the up to now used terms of laminarity and turbulence. After the derivation of the HOFFRICHTER-equation as explaining the loops around the intersection point of the x-axis and y-axis, a clinical classification of the rhinomanometric findings is given and confirmed by physical experiments with "artificial noses". Finally, testing the rhinomanometric method by CFD (Computational Fluid Dynamics), lead to the same conclusions as to the importance of 4 phases of the breathing cycle. The precondition for the worldwide introduction of new parameters into the 4PR is a comprehensive statistical analysis. The disadvantages of the present recommended standard values are described in chapter 6. Following previous studies in 5800 cases, the parameters Vertex Resistance (VR), Effective Resistance (Reff) and their logarithmic transformations have been investigated in 1580 rhinograms of different degrees of obstructions, also including the correlations to a VAS. It could be confirmed, that the parameters VR and Reff after logarithmic transformation, have a significant and high correlation to the sensation of obstruction. The new clinical classification of obstruction and conductance of the nose is proposed in Table 1 for Caucasian noses. Table 1. Clinical classification of obstruction and conductance for Causcasian noses. [see text for table]. Chapter 7 is dedicated to the advantages of 4PR in the functional diagnosis of nasal valve problems. Graphical as well as numerical solutions are available by the fact, that the motions of the nasal entrance as caused by the breathing process are now visible from the shape of the 4PR-curve. Discussing practical aspects in chapter 8, the start point of proposals and discussions are the standard recommendations of the ISOANA and the results of its consensus conference in 2003. In particular the calibration processes, hygiene, the correct attachment of the pressure tube at the nostril ("tape method") and the different measurement procedures (AAR, APR), decongestion and provocation tests are extensively described. Both the final chapters are clinical contributions from mainland China, which are of high importance because of the racial differences in nasal respiratory function. In chapter 9, tests of the assessment of normal nasal airway in adult Chinese by 4PR, rhinomanometry and acoustic rhinometry are presented. This investigation lead to the conclusion that 4PR is an important supplement to classic rhinomanometry and acoustic rhinometry, if the classification of obstruction is adapted to the higher basic resistance of the Chinese population. Chapter 10 is dealing with 4PR and acoustic rhinometry in the functional evaluation of septal deviations and concludes, that both methods are valuable objective instruments for the evaluation of nasal obstruction.

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide.

In animals, successful production of the visual chromophore (11-cis-retinal or derivatives thereof such as 11-cis-3-hydroxy-retinal) is essential for photoreceptor cell function and survival. These carotenoid-derived compounds must combine with a protein moiety (the opsin) to establish functional visual pigments. Evidence from cell culture systems has implicated that the retinal pigment epithelium protein of 65 kDa (RPE65) is the long-sought all-trans to 11-cis retinoid isomerase. RPE65 is structurally related to nonheme iron oxygenases that catalyze the conversion of carotenoids into retinoids. In vertebrate genomes, two carotenoid oxygenases and RPE65 are encoded, whereas in insect genomes only a single representative of this protein family, named NinaB (denoting neither inactivation nor afterpotential mutant B), is encoded. We here cloned and functionally characterized the ninaB gene from the great wax moth Galleria mellonella. We show that the recombinant purified enzyme combines isomerase and oxygenase (isomerooxygenase) activity in a single polypeptide. From kinetics and isomeric composition of cleavage products of asymmetrical carotenoid substrates, we propose a model for the spatial arrangement between substrate and enzyme. In Drosophila, we show that carotenoid-isomerooxygenase activity of NinaB is more generally found in insects, and we provide physiological evidence that carotenoids such as 11-cis-retinal can promote visual pigment biogenesis in the dark. Our study demonstrates that trans/cis isomerase activity can be intrinsic to this class of proteins and establishes these enzymes as key components for both invertebrate and vertebrate vision.

Movement related activity in the high gamma range of the human EEG.

Electrocorticographic (ECoG) recordings obtained using intracranially implanted electrodes in epilepsy patients indicate that high gamma band (HGB) activity of sensorimotor cortex is focally increased during voluntary movement. These movement related HGB modulations may play an important role in sensorimotor cortex function. It is however currently not clear to what extent this type of neural activity can be detected using non-invasive electroencephalography (EEG) and how similar HGB responses in healthy human subjects are to those observed in epilepsy patients. Using the same arm reaching task, we have investigated spectral power changes both in intracranial ECoG recordings in epilepsy patients and in non-invasive EEG recordings optimized for detecting HGB activity in healthy subjects. Our results show a common HGB response pattern both in ECoG and EEG recorded above the sensorimotor cortex contralateral to the side of arm movement. In both cases, HGB activity increased around movement onset in the 60-90 Hz range and became most pronounced at reaching movement end. Additionally, we found EEG HGB activity above the frontal midline possibly generated by the anterior supplementary motor area (SMA), a region that was however not covered by the intracranial electrodes used in the present study. In summary, our findings show that HGB activity from human sensorimotor cortex can be non-invasively detected in healthy subjects using EEG, opening a new perspective for investigating the role of high gamma range neuronal activity both in function and dysfunction of the human cortical sensorimotor network.

The Drosophila class B scavenger receptor NinaD-I is a cell surface receptor mediating carotenoid transport for visual chromophore synthesis.

The blind Drosophila mutant ninaD lacks the visual chromophore. Genetic evidence that the molecular basis is a defect in carotenoid uptake which causes vitamin A deficiency exists. The ninaD gene encodes a scavenger receptor that is significantly homologous in sequence with the mammalian scavenger receptors SR-BI (scavenger receptor class B type I) and CD36 (cluster determinant 36), yet NinaD has not been characterized in functional detail. Therefore, we established a Drosophila S2 cell culture system for biochemically characterizing the ninaD gene products. We show that the two splice variant isoforms encoded by ninaD exhibit different subcellular localizations. NinaD-I, the long protein variant, is localized at the plasma membrane, whereas the short variant, NinaD-II, is localized at intracellular membranes. Only NinaD-I could mediate the cellular uptake of carotenoids from micelles in this cell culture system. Carotenoid uptake was concentration-dependent and saturable. By in vivo analyses of different mutant and transgenic fly strains, we provide evidence of an essential role of NinaD-I in the absorption of dietary carotenoids to support visual chromophore synthesis. Moreover, our analyses suggest a role of NinaD-I in tocopherol metabolism. Even though Drosophila is a sterol auxotroph, we found no evidence of a contribution of NinaD-I to the uptake of these compounds. Together, our study establishes an evolutionarily conserved connection between class B scavenger receptors and the numerous functions of fat soluble vitamins in animal physiology.

Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial.

BACKGROUND: Desloratadine reduces symptoms and maintains nasal airflow in patients with seasonal allergic rhinitis (SAR) during experimental allergen exposure. OBJECTIVE: To compare the effects of desloratadine and placebo on symptom scores, quality of life (QOL), and nasal airway patency in patients with SAR during the allergy season. METHODS: Adults with symptomatic SAR were randomized in a double-blind manner to receive desloratadine, 5 mg, or placebo for 14 days. Patient-rated SAR symptoms were recorded twice daily (morning and evening). On days 1 and 15, SAR symptoms were scored jointly (investigator and patient), nasal airflow was measured using 4-phase rhinomanometry, and QOL and the overall condition of SAR were rated. Overall treatment response was scored on day 15. Adverse events were recorded. RESULTS: At day 15, total symptom (P = .03) and total nasal symptom (P = .02) scores and patient morning-rated individual nasal symptom scores (except nasal stuffiness) (P < or = .04) decreased significantly from baseline with desloratadine vs placebo. Flow in the descending expiratory nasal airflow phase was significantly greater (P = .046) and the percentage increase in total inspiratory nasal airway resistance was less (P = .03) in the desloratadine group vs the placebo group. The overall condition of SAR was less severe (P = .045), the therapeutic response was greater (P = .004), and the nasal symptom domain of the QOL score was significantly better (P = .03) in the desloratadine group. Adverse event rates were similar in both groups. CONCLUSION: Desloratadine treatment for 14 days improved nasal airflow and resistance as well as symptom and QOL scores in patients with symptomatic SAR during the allergy season.

Towards a better understanding of carotenoid metabolism in animals.

Vitamin A derivatives (retinoids) are essential components in vision; they contribute to pattern formation during development and exert multiple effects on cell differentiation with important clinical implications. All naturally occurring vitamin A derives by enzymatic oxidative cleavage from carotenoids with pro-vitamin A activity. To become biologically active, these plant-derived compounds must first be absorbed, then delivered to the site of action in the body, and metabolically converted to the real vitamin. Recently, molecular players of this pathway were identified by the analysis of blind Drosophila mutants. Similar genome sequences were found in vertebrates. Subsequently, these homologous genes were cloned and their gene products were functionally characterized. This review will summarize the advanced state of knowledge about the vitamin A biosynthetic pathway and will discuss biochemical, physiological, developmental and medical aspects of carotenoids and their numerous derivatives.

Vitamin A formation in animals: molecular identification and functional characterization of carotene cleaving enzymes.

Vitamin A and its derivatives (retinoids) are essential components in vision; they contribute to pattern formation during development and exert multiple effects on cell differentiation. It has been known for 70 y that the key step in vitamin A biosynthesis is the oxidative cleavage of a carotenoid with provitamin A activity. While a detailed biochemical characterization of the respective enzymes could be achieved in cell-free homogenates, their molecular nature has remained elusive for a long time. Recent research led to the identification of genes encoding two different types of carotene oxygenases from animal species. The molecular cloning of these different types of animal carotene oxygenases establishes the existence of a family of carotenoid metabolizing enzymes in animals heretofore described in plants. With these tools in hands, old questions in vitamin A research can be definitively addressed on the molecular levels contributing to a mechanistic understanding of the regulation of vitamin A homeostasis or tissue specificity of vitamin A formation, with impact on animal physiology and human health.

Provitamin A conversion to retinal via the beta,beta-carotene-15,15'-oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis.

The egg yolk of vertebrates contains carotenoids, which account for its characteristic yellow color in some species. Such plant-derived compounds, e.g. beta-carotene, serve as the natural precursors (provitamins) of vitamin A, which is indispensable for chordate development. As egg yolk also contains stored vitamin A, carotenoids have so far been solely discussed as pigments for the coloration of the offspring. Based on our recent molecular identification of the enzyme catalyzing provitamin A conversion to vitamin A, we address a possible role of provitamin A during zebrafish (Danio rerio) development. We cloned the zebrafish gene encoding the vitamin A-forming enzyme, a beta,beta-carotene-15,15'-oxygenase. Analysis of its mRNA expression revealed that it is under complex spatial and temporal control during development. Targeted gene knockdown using the morpholino antisense oligonucleotide technique indicated a vital role of the provitamin A-converting enzyme. Morpholino-injected embryos developed a morphological phenotype that included severe malformation of the eyes, the craniofacial skeleton and pectoral fins, as well as reduced pigmentation. Analyses of gene expression changes in the morphants revealed that distinct retinoic acid-dependent developmental processes are impaired, such as patterning of the hindbrain and differentiation of hindbrain neurons, differentiation of neural crest derivatives (including the craniofacial skeleton), and the establishment of the ventral retina. Our data provide strong evidence that, for several developmental processes, retinoic acid generation depends on local de novo formation of retinal from provitamin A via the carotene oxygenase, revealing an unexpected, essential role for carotenoids in embryonic development.