Patient-reported experience with hypoglossal nerve stimulation in the treatment of obstructive sleep apnea.

BACKGROUND: Breathing-synchronized hypoglossal nerve stimulation (HNS) is routinely used as an alternative treatment for patients with obstructive sleep apnea (OSA). Significant and clinically relevant improvements in disease severity and OSA symptoms such as daytime sleepiness as well as overall quality of life have been reported in randomized-controlled trials and large real-world cohort studies. However, so far, few data exist on patient-reported experience with the treatment. METHODS: A structured survey with 22 questions was constructed using five-level Likert scales (1 = no agreement, 5 = complete agreement) to evaluate patient experience with HNS and perception of the treatment in the domains "Overall experience with therapy," "Experience with treatment process," and "Side-effects from treatment." Additional data were collected on current symptom status, measured with Epworth sleepiness scale (ESS) questionnaire, and OSA disease history. Multiple linear regression analysis was conducted to test associations of medical variables and response behavior. Correlations between variables and domains, as well as individual items, were assessed using Spearman rank test. RESULTS: A total of 75 patients from Germany who were treated with breathing-synchronized HNS were enrolled (mean age 57.3 years, 78% male), and 71 questionnaires with complete data were included for analysis. Two-thirds of participants (67%) had a history of OSA history for 5 years or longer. Of all patients, 76% had normalized OSA symptoms at time of the study (ESS: 6.4 ± 5.0) and 98% reported using stimulation therapy every night. Regression analysis revealed an association of current symptoms measured with ESS and response behavior. Hence, patients with normalized daytime sleepiness reported significantly more positive experience across all domains assessed, compared to patients with residual daytime sleepiness. Overall, only 2% of participants reported side effects that made them reduce or discontinue stimulation therapy. The rate of reported side effects was associated with current symptom control under therapy. CONCLUSIONS: Overall patient-reported experience with breathing-synchronized HNS therapy was positive and high satisfaction with the treatment process was observed. Side effects occurred, but rarely affected subjective use of the therapy or satisfaction. Subjective experience and perception are influenced by residual daytime sleepiness with stimulation therapy.

Tailoring the escape rate of a Brownian particle by combining a vortex flow with a magnetic field.

The probability per unit time for a thermally activated Brownian particle to escape over a potential well is, in general, well-described by Kramers's theory. Kramers showed that the escape time decreases exponentially with increasing barrier height. The dynamics slow down when the particle is charged and subjected to a Lorentz force due to an external magnetic field. This is evident via a rescaling of the diffusion coefficient entering as a prefactor in the Kramers's escape rate without any impact on the barrier-height-dependent exponent. Here, we show that the barrier height can be effectively changed when the charged particle is subjected to a vortex flow. While the vortex alone does not affect the mean escape time of the particle, when combined with a magnetic field, it effectively pushes the fluctuating particle either radially outside or inside depending on its sign relative to that of the magnetic field. In particular, the effective potential over which the particle escapes can be changed to a flat, a stable, and an unstable potential by tuning the signs and magnitudes of the vortex and the applied magnetic field. Notably, the last case corresponds to enhanced escape dynamics.

Theory of chain walking catalysis: From disordered dendrimers to dendritic bottle-brushes.

The chain walking (CW) polymerization technique has the unique property of a movable catalyst synthesizing its own path by creating branch-on-branch structures. By successive attachment of monomers, the resulting architecture ranges from dendritic to linear growth depending on the walking rate, which is defined by the ratio of walking steps and reaction events of the catalyst. The transition regime is characterized by local dendritic sub-structures (dendritic blobs) and a global linear chain feature forming a dendritic bottle-brush. A scaling model for structures obtained by CW catalysis is presented and validated by computer simulation relating the extensions of CW structures to the catalyst's walking ability. The limiting case of linear (low walking rate) and dendritic growth (high walking rate) is recovered, and the latter is shown to bear analogies to the Barabási-Albert graph and Bernoulli growth random walk. We could quantify the size of the dendritic blob as a function of the walking rate by using spectral properties of the connectivity matrix of the simulated macromolecules. This allows us to fit the numerical constants in the scaling approach. We predict that independent of the underlying chemical process, all CW polymerization syntheses involving a highly mobile catalyst ultimately result in bottle-brush structures whose properties depend on a unique parameter: the walking rate.

Effects of tranexamic acid on human nasal ciliary beat frequency.

BACKGROUND: Patients with recurrent epistaxis, particularly due to hereditary hemorrhagic telangiectasia (HHT) are recommended to apply topical tranexamic acid (TXA) to reduce bleeding events. Those patients may suffer ciliary dysfunction due to TXA's effects on ciliary beating frequency (CBF) and their consequences. METHODOLOGY/PRINCIPAL: Human nasal epithelial cells were harvested with a nasal brush in 30 healthy subjects. We investigated the CBF in RPMI medium using high-frequency video microscopy. TXA was added to the cells in various concentrations ranging from 2 to 5%, including the therapeutic concentration (2%) and a control (0%). RESULTS: CBF in the control condition was 6.1 ± 1.6 Hz. TXA reduces CBF in a time and concentration dependent manner, to, e.g. 4.3 ± 1.2 Hz with 2% TXA and 3.3 ± 0.9 Hz with 5% TXA after 16-20 min. The differences in CBF were statistically significant for all concentrations of TXA. CONCLUSIONS: TXA has the potential to significantly impair nasal epithelial function. Therefore, frequent or regular topical nasal application of TXA should be done under close monitoring of nasal function, especially in patients with co-morbidities like chronic rhinosinusitis.

Diagnosis and treatment of isolated snoring-open questions and areas for future research.

STUDY OBJECTIVES: Snoring is a common phenomenon which is generated by vibration of soft tissue of the upper airway during sleep. Due to the high incidence of isolated snoring and the substantial burden for the patient and the bed partner, a thorough examination and appropriate therapy are required. Many recommendations for the treatment of isolated snoring are either not evidence-based or are derived from recommendations for the management of obstructive sleep apnea. Therefore, the aim of this study is the identification and description of open questions in the diagnosis and treatment of isolated snoring and the illustration of areas for further research. METHODS: In the context of the development of the new version of the German guideline "Diagnosis and treatment of isolated snoring in adults," a multidisciplinary team of experts performed a systematic literature search on the relevant medical data and rated the current evidence regarding the key diagnostic and therapeutic measures for snoring. RESULTS: The systematic literature review identified 2293 articles. As a major inclusion criterion, only studies on primary snoring based on objective sleep medical assessment were selected. After screening and evaluation, 33 full-text articles remained for further analysis. Based on these articles, open questions and areas for future research were identified for this review. CONCLUSION: Several major gaps in the literature on the diagnosis and treatment of isolated snoring were identified. For the majority of diagnostic and therapeutic measures for snoring, high-level scientific evidence is still lacking.

Nondiffusive fluxes in a Brownian system with Lorentz force.

The Fokker-Planck equation provides a complete statistical description of a particle undergoing random motion in a solvent. In the presence of Lorentz force due to an external magnetic field, the Fokker-Planck equation picks up a tensorial coefficient, which reflects the anisotropy of the particle's motion. This tensor, however, cannot be interpreted as a diffusion tensor; there are antisymmetric terms which give rise to fluxes perpendicular to the density gradients. Here, we show that for an inhomogeneous magnetic field these nondiffusive fluxes have finite divergence and therefore affect the density evolution of the system. Only in the special cases of a uniform magnetic field or carefully chosen initial condition with the same full rotational symmetry as the magnetic field can these fluxes be ignored in the density evolution.

Patient-reported outcome: results of the multicenter German post-market study.

PURPOSE: Upper airway stimulation (UAS) is an alternative second-line treatment option for patients with obstructive sleep apnea (OSA). In our substudy of a previous multicentre study of patients implanted with UAS, we focused on patient-related outcomes like Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), snoring and personal satisfaction 6 and 12 months after the implantation. METHODS: 60 patients, who were initially non-adherent to CPAP and implanted with UAS, were included in a prospective multicentre study. Data were collected preoperative, 6 and 12 months after implantation regarding FOSQ, ESS, snoring, and their experience with the UAS device. RESULTS: Besides relevant Apnoea-Hypopnea Index (AHI) reduction, we saw significant improvements in ESS (p < 0.001), FOSQ (p < 0.001) and snoring under UAS therapy. A strong correlation between AHI results postoperative and the personal satisfaction of the patients after implantation was found as well as between usage results and AHI compared to the preoperative results. CONCLUSION: The more the patients benefit from UAS according to their self-reported outcome, the higher is the therapy use.

Influence of MP 29-02 on ciliary beat frequency in human epithelial cells in vitro.

PURPOSE: MP 29-02, which contains fluticasone propionate and azelastine hydrochloride, is used as a topical nasal application for the treatment of seasonal and perennial allergic rhinitis. Although a multitude of data is available on the clinical symptom reduction and treatment safety of MP 29-02, the effect of MP 29-02 on ciliary beat frequency (CBF) has not been evaluated thus far. METHODS: MP 29-02-containing solution was applied at concentrations of 2.5, 5, 10, and 20% to 14 healthy subjects, and nasal ciliated epithelial cells were then visualized using a phase-contrast microscope. CBF was measured after the application of MP 29-02. For a comparison, fluticasone propionate was used. CBF measurements were then performed for 15 min at 22 °C. Ringer's solution was applied as a negative control. RESULTS: MP 29-02 significantly reduced CBF at all the tested concentrations compared with that of the control group within the observation time. At a 2.5% concentration, MP 29-02 significantly reduced CBF from 6.81 Hz (SD ± 1.35 Hz) at baseline to 4.88 Hz (SD ± 1.52 Hz, p < 0.001) after 15 min. In contrast, for fluticasone propionate, a significant reduction was observed only with the 20% concentration after 5, 10, and 15 min. CONCLUSIONS: MP 29-09 significantly reduced CB, with an almost linear relationship between the MP 29-09 concentration and reduction in CBF. For fluticasone propionate, a significant reduction of CBF was observed only at the highest analyzed concentration. The findings have implications for the long-term use of the MP 29-02. Yet, further clinical studies are needed to confirm these results in vivo, especially in patients with seasonal or perennial allergic rhinits.

[Treatment of supine position-related obstructive sleep apnea with smartphone applications]. / Therapie rückenlagebezogener obstruktiver Schlafapnoe mittels Smartphone-App.

BACKGROUND: Positional obstructive sleep apnea (POSA) is common in mild and moderate forms of obstructive sleep apnea (OSA). Two smartphone applications (apps) professing to avoid the supine position (SP) are available: for Android the "Apnea Sleep Position Trainer" and for iOS the "SomnoPose-Sleep Position Monitor". The smartphone needs to be attached to the chest to recognize SP, which then triggers a vibration alarm. This is intended to encourage the patient to change position and the vibration stops as soon as SP is left. These apps, however, have not yet undergone a systematic evaluation. METHODS: Adult patients with polysomnographically diagnosed POSA were invited to participate in the study. POSA was defined as an apnea-hypopnea index (AHI) in SP >10, with AHI in a lateral position <10 and doubling of the AHI in SP. After 1 month, a control polysomnography (PSG) was performed and compliance (at least 4 h/night on 5 of 7 days) was evaluated after 6 months by phone. A sufficient therapy was defined as reduction in SP to <10% of the total sleep time and to an overall AHI <10. RESULTS: Although 57 patients entered the study, 24 did not appear to the PSG control; therefore, 33 patients finished the study, of whom 25 were treated successfully. The overall AHI in 33 patients was reduced from 14.5 ± 9.0 to 9.5 ± 12.6 and the time in SP decreased significantly from 71.1 ± 50.5 to 25.4 ± 65.0 min. Compliance among the 25 continuously treated patients after 6 months was 79.2%. CONCLUSION: Both smartphone apps have the capability to prevent PS in POSA patients and can potentially offer a cost-effective option in the treatment of POSA.

Dendrimer solutions: a Monte Carlo study.

We study the conformational properties of dendrimers with flexible spacers in solutions over a wide range of concentrations from dilute solutions to melts. By combining large scale computer simulations using the bond fluctuation model with scaling arguments we identify the semi-dilute regime of dendrimers which is controlled by the concentration behavior of the linear spacers. Associated with this observation we find that the decrease in the size of flexible dendrimers is accompanied by increasing interpenetration between the molecules with increasing concentration of the solution. In the melt state we show that the size of individual dendrimers follows the scaling prediction for isolated dendrimers at the θ-point rather than that of collapsed dendrimers. The pair correlation functions between the centers of dendrimers indicate that for short spacers dendrimer solutions retain the morphological characteristics of simple liquids. For long spacers the functions reveal high penetration of neighboring dendrimers in the melt state. Our studies show that flexible dendrimers in solution can be understood with arguments similar to those of linear polymers. The role of generation is to influence the particular form of the crossover-function.

Mupirocin reduces ciliary beat frequency of human nasal epithelial cells.

Mupirocin is used worldwide for topical treatment of infected skin lesions, impetigo, and especially for nasal decolonization of patients with carriage of Staphylococci, including methicillin-resistant Staphylococcus aureus. Nevertheless, data regarding the effects of mupirocin on the nasal mucosa, in particular on ciliary beat frequency (CBF), is lacking to date. We tested the CBF of ciliated nasal epithelial cells under the influence of Mupirocin-calcium dissolved in tert-butyl alcohol (TBA) containing media in different concentrations comparable to clinical use. Ringer's lactate solution and TBA served as negative control. Cells were visualized with a phase contrast microscope, and the CBF was measured with the SAVA system's region of interest method. Mupirocin-calcium dissolved in TBA led to a statistically significant time- and concentration-dependent decrease in CBF compared to the negative control. TBA addition without mupirocin also led to a significant decrease in CBF, although to a lesser extent than mupirocin/TBA. In conclusion, CBF of human nasal epithelia is significantly reduced by mupirocin-calcium-containing solutions in therapeutic concentrations. Due to our results in this study, mupirocin as a nasal decolonization agent should be used only with care, with a strictly set medical indication, and additional care measures should be considered.

Chemosensory stimulation during sleep - Arousal responses to gustatory stimulation.

The processing of nociceptive, visual, vibrotactile, thermal and acoustic stimuli during sleep has been extensively investigated in the past. Recently, interest has focused on the impact of olfactory stimulation on sleep. In contrast to all other sensory systems, olfactory stimulation does not lead to an increased arousal frequency, regardless of hedonicity and concentration. The impact of the second chemosensory system, gustation, on sleep however has not been investigated to date. Twenty-one normosmic and normogeusic volunteers of both genders, aged 19-33 years, participated in the trial. Stimulation was performed with a gustometer using the following aqueous solutions: saccharose 20% (sweet), sodium chloride (NaCl) 7.5% (salty), citrate 5% (sour), and quinine 0.02% (bitter). A tasteless solution was used as negative control. Capsaicin, a strong trigeminal stimulus, served as positive control. Primary outcome was arousal frequency per stimulus in each sleep stage, as assessed with polysomnography. The frequency of arousals decreased in deeper sleep stages (N1: 211 arousals of 333 stimuli=63%, N2: 676/2728=25%, N3: 43/1378=3%, REM: 57/1010=6%). Statistically significant differences in terms of arousal frequency were found in N2 between the negative control and NaCl 100 µl (p<0.001), saccharose 100 µl, citrate 50 µl & 100 µl, and quinine 100 µl (p<0.05). Capsaicin led to complete awakenings in 94% of stimuli (30/32). These results demonstrate that gustatory stimulation during sleep induces arousals depending on stimulus intensity and sleep stage, which is different to olfactory stimulation and may be related to differences in central processing of the two chemosensory systems.

Water around fullerene shape amphiphiles: A molecular dynamics simulation study of hydrophobic hydration.

Fullerene C60 sub-colloidal particle with diameter ∼1 nm represents a boundary case between small and large hydrophobic solutes on the length scale of hydrophobic hydration. In the present paper, a molecular dynamics simulation is performed to investigate this complex phenomenon for bare C60 fullerene and its amphiphilic/charged derivatives, so called shape amphiphiles. Since most of the unique properties of water originate from the pattern of hydrogen bond network and its dynamics, spatial, and orientational aspects of water in solvation shells around the solute surface having hydrophilic and hydrophobic regions are analyzed. Dynamical properties such as translational-rotational mobility, reorientational correlation and occupation time correlation functions of water molecules, and diffusion coefficients are also calculated. Slower dynamics of solvent molecules­water retardation­in the vicinity of the solutes is observed. Both the topological properties of hydrogen bond pattern and the "dangling" -OH groups that represent surface defects in water network are monitored. The fraction of such defect structures is increased near the hydrophobic cap of fullerenes. Some "dry" regions of C60 are observed which can be considered as signatures of surface dewetting. In an effort to provide molecular level insight into the thermodynamics of hydration, the free energy of solvation is determined for a family of fullerene particles using thermodynamic integration technique.

The formation and structure of Olympic gels.

Different methods for creating Olympic gels are analyzed using computer simulations. First ideal reference samples are obtained from freely interpenetrating semi-dilute solutions and melts of cyclic polymers. The distribution of pairwise concatenations per cyclic molecule is given by a Poisson-distribution and can be used to describe the elastic structure of the gels. Several batches of linear chains decorated with different selectively binding groups at their ends are mixed in the "DNA Origami" technique and network formation is realized. While the formation of cyclic molecules follows mean field predictions below overlap of the precursor molecules, an enhanced ring formation above overlap is found that is not explained by mean field arguments. The "progressive construction" method allows to create Olympic gels with a single reaction step from a concentrated mixture of large compressed rings with a low weight fraction of short chains that are below overlap concentration. This method, however, is limited by the difficulty to obtain a sufficiently high degree of polymerization of the large rings.

Polyhexanide-containing solution reduces ciliary beat frequency of human nasal epithelial cells in vitro.

In ENT, polyhexanide-containing solutions are used to treat nasal infections caused by multiresistant bacteria like methicillin-resistant Staphylococcus aureus. Many forms of commercial nasal solutions containing polyhexanide exist, such as gels or solutions for topical use. Data regarding the influence of polyhexanide on ciliary beat frequency (CBF) are lacking to date. We tested the CBF of nasal ciliated epithelial cells under the influence of a commercially available polyhexanide-containing solution (Lavasept(®) Concentrate) in a therapeutic concentration (0.04, 0.02%). In addition, we tested the concentrations of 0.1 and 0.01%. Cells were visualized with a phase contrast microscope, and the CBF was measured with the SAVA system's region of interest method. Ringer's solution and macrogol served as negative controls. A therapeutic concentration of Lavasept significantly reduced CBF in a time- and concentration-dependent manner. After 1 min, the CBF was reduced from 8.90 ± 1.64 to 5.00 ± 3.72 Hz with a concentration of 0.04% (p value = 0.001). After 10 min, all cilia stopped beating. After 5 min, a 0.02% solution of Lavasept concentrate decreased CBF significantly from 8.64 ± 1.71 to 3.30 ± 3.27 Hz (p value < 0.001). In conclusion, CBF of human nasal epithelia is significantly reduced with the use of the polyhexanide-containing solution Lavasept in some therapeutic concentrations. Due to our findings in this study, Lavasept should be used on ciliated mucosa only with caution and in a concentration of 0.02%.

C60-dyad aggregates: self-organized structures in aqueous solutions.

Extensive full-atomistic molecular dynamics simulations are performed to study the self-organization of C60-fullerene dyad molecules in water, namely phenyl-C61-butyric acid methyl ester and fulleropyrrolidines, which have two elements of ordering, the hydrophobic fullerene cage and the hydrophilic/ionic group. While pristine fullerene or phenyl-C61-butyric acid methyl ester forms spherical droplets in order to minimize the surface tension, the amphiphilic nature of charged solute molecules leads to the formation of supramolecular assemblies having cylindrical shape driven by charge repulsion between the ionic groups located on the surface of the aggregates. We show that formation of non-spherical micelles is the geometrical consequence if the fullerene derivatives are considered as surfactants where the ionized groups are only hydrophilic unit. The agglomeration behavior of fullerenes is evaluated by determining sizes of the clusters, solvent accessible surface areas, and shape parameters. By changing the size of the counterions from chloride over iodide to perchlorate we find a thickening of the cylinder-like structures which can be explained by stronger condensation of larger ions and thus partial screening of the charge repulsion on the cluster surface. The reason for the size dependence of counterion condensation is the formation of a stronger hydration shell in case of small ions which in turn are repelled from the fullerene aggregates. Simulations are also in good agreement with the experimentally observed morphologies of decorated C60-nanoparticles.

Swelling of Olympic gels.

The swelling equilibrium of Olympic gels, which are composed of entangled cyclic polymers, is studied by Monte Carlo simulations. In contrast to chemically cross-linked polymer networks, we observe that Olympic gels made of chains with a larger degree of polymerization, N, exhibit a smaller equilibrium swelling degree, Q ∝ N(-0.28)ϕ(0)(-0.72), at the same polymer volume fraction ϕ(0) at network preparation. This observation is explained by a desinterspersion (reorganization with release of nontrapped entanglements) process of overlapping nonconcatenated rings upon swelling.

Two universality classes for random hyperbranched polymers.

We grow AB2 random hyperbranched polymer structures in different ways and using different simulation methods. In particular we use a method of ad hoc construction of the connectivity matrix and the bond fluctuation model on a 3D lattice. We show that hyperbranched polymers split into two universality classes depending on the growth process. For a "slow growth" (SG) process where monomers are added sequentially to an existing molecule which strictly avoids cluster-cluster aggregation the resulting structures share all characteristic features with regular dendrimers. For a "quick growth" (QG) process which allows for cluster-cluster aggregation we obtain structures which can be identified as random fractals. Without excluded volume interactions the SG model displays a logarithmic growth of the radius of gyration with respect to the degree of polymerization while the QG model displays a power law behavior with an exponent of 1/4. By analyzing the spectral properties of the connectivity matrix we confirm the behavior of dendritic structures for the SG model and the corresponding fractal properties in the QG case. A mean field model is developed which explains the extension of the hyperbranched polymers in an athermal solvent for both cases. While the radius of gyration of the QG model shows a power-law behavior with the exponent value close to 4/5, the corresponding result for the SG model is a mixed logarithmic-power-law behavior. These different behaviors are confirmed by simulations using the bond fluctuation model. Our studies indicate that random sequential growth according to our SG model can be an alternative to the synthesis of perfect dendrimers.

[Position paper "Chemosensory testing for expert opinion in smell disorders"]. / Positionspapier "Die chemosensorische Testung bei der gutachterlichen Abklärung von Riechstörungen"

Providing expert opinion in the context of smell disorders is often challenging, not only with regard to general aspects of providing an expert opinion but particularly with regard to chemosensory testing. Currently there is no consensus which chemosensory test should be selected and how they should be executed. This positions paper from Committee on Olfaction and Gustation of the German Society of Otorhinolaryngology, Head and Neck Surgery aims to give concrete recommendations for chemosensory testing for providing expert opinion for smell disorders with regard to the selection and execution of these test.