The Role of Mobility in the Dynamics of the COVID-19 Epidemic in Andalusia.

Metapopulation models have been a popular tool for the study of epidemic spread over a network of highly populated nodes (cities, provinces, countries) and have been extensively used in the context of the ongoing COVID-19 pandemic. In the present work, we revisit such a model, bearing a particular case example in mind, namely that of the region of Andalusia in Spain during the period of the summer-fall of 2020 (i.e., between the first and second pandemic waves). Our aim is to consider the possibility of incorporation of mobility across the province nodes focusing on mobile-phone time-dependent data, but also discussing the comparison for our case example with a gravity model, as well as with the dynamics in the absence of mobility. Our main finding is that mobility is key toward a quantitative understanding of the emergence of the second wave of the pandemic and that the most accurate way to capture it involves dynamic (rather than static) inclusion of time-dependent mobility matrices based on cell-phone data. Alternatives bearing no mobility are unable to capture the trends revealed by the data in the context of the metapopulation model considered herein.

Backcasting COVID-19: a physics-informed estimate for early case incidence.

It is widely accepted that the number of reported cases during the first stages of the COVID-19 pandemic severely underestimates the number of actual cases. We leverage delay embedding theorems of Whitney and Takens and use Gaussian process regression to estimate the number of cases during the first 2020 wave based on the second wave of the epidemic in several European countries, South Korea and Brazil. We assume that the second wave was more accurately monitored, even though we acknowledge that behavioural changes occurred during the pandemic and region- (or country-) specific monitoring protocols evolved. We then construct a manifold diffeomorphic to that of the implied original dynamical system, using fatalities or hospitalizations only. Finally, we restrict the diffeomorphism to the reported cases coordinate of the dynamical system. Our main finding is that in the European countries studied, the actual cases are under-reported by as much as 50%. On the other hand, in South Korea-which had a proactive mitigation approach-a far smaller discrepancy between the actual and reported cases is predicted, with an approximately 18% predicted underestimation. We believe that our backcasting framework is applicable to other epidemic outbreaks where (due to limited or poor quality data) there is uncertainty around the actual cases.

[Perioperative risk management of patients with obstructive sleep apnea]. / Perioperative Risikobetreuung bei Patienten mit obstruktiver Schlafapnoe.

Obstructive sleep apnea (OSA) has a relatively high prevalence of 3-7% in the general population in western industrialized countries. The prevalence is higher in older patients and in patients with cardiac or metabolic disorders. In the general surgical population patients with OSA are often unrecognized prior to surgery so that unexpected problems can occur due to the higher risk of airway collapse. Severe apnea can result even hours later and especially after surgery of the upper airway. Anesthesists and ear nose and throat surgeons are equally responsible for the perioperative surveillance. The article will show the importance of the preoperative identification of OSA patients and the perioperative risk management in the different risk phases apart from surgery. Although the importance of guidelines is very high there are no mandatory guidelines in Germany in contrast to the USA and the implementation should be given priority.

[Midfacial fractures. Diagnosis and treatment]. / Mittelgesichtsfrakturen. Diagnostik und Therapie.

The clinical diagnosis and treatment of midfacial fractures have been optimized by modern computer tomography and the development of plate osteosynthesis. Even complex fractures involving the orbit and scull base can be accurately reconstructed and stabilized. The use of titanium mini- and micro-plates as well as resorbable materials allows customized treatment of this esthetically and functionally important area. The preservation of basic functions such as vision, scent, speech, occlusion and swallowing, in addition to aesthetic aspects, should be the primary goals of surgical treatment. In general, reconstruction is not required immediately and polytrauma patients will need interdisciplinary care. Conservative treatment of midfacial fractures should be the exception.

[Therapeutic options after the accidental application of cyanacrylate into the outer ear canal]. / Therapieoptionen bei akzidenteller Applikation von Cyanacrylat in den äusseren Gehörgang.

BACKGROUND: The accidental application of cyanacrylate (superglue) into the outer ear canal requires different treatments depending on location and extent. METHODS: Two case studies are presented. Treatment included surgical removal, with or without prior conservative treatment, for complete canal obstruction, as well as conservative treatment for partial ear canal obstruction. RESULTS: Because of its unique anatomy, treatment of accidentally applied superglue into the outer ear canal differs from treatment in other locations. Conservative treatment was ineffective for complete obstruction, making secondary surgical removal necessary. Partial obstruction was successfully treated conservatively. No complications were observed after the surgical removal of superglue obstructing the complete outer ear canal. CONCLUSIONS: Conservative treatment is adequate for cases of partial obstruction of the outer ear canal with superglue. In cases of complete obstruction or inclusion of the ear drum, surgical treatment is recommended.

[Extramedullary manifestation of plasmocytoma in ENT]. / Dreifachmanifestation eines extramedullären Plasmozytoms im HNO-Bereich - Ein Fallbericht.

Plasmocytomas are non-Hodgkin's tumors which occur with an incidence of 4/100,000. Malignant plasma cells in bone marrow produce monoclonal antibodies which are typically found in urine and blood samples. In rare instances plasmocytoma occur exclusively in extramedullary locations preferring head and neck region. We report about two patients with extramedullary plasmocytoma, one of them with an extremely rare triple manifestation in the upper airway.

[Therapy for sleep-related breathing disorders using positive airway pressure. Data from an HNO sleep laboratory]. / Therapie schlafbezogener Atmungsstörungen mit positivem Atemwegsdruck. Datenanalyse eines HNO-Schlaflabors.

BACKGROUND: Computer-assisted cardiopulmonary polysomnography is generally required to differentiate common snoring from serious sleep-related breathing disorders (SRBD) such as sleep apnea. METHODS: This study investigates data from 2,683 diagnostic and therapeutic cardiopulmonary polysomnographies of 1,087 patients over the period 2003-2004. Indications and efficacy of therapy using positive airway pressure (PAP) in SRBD are analyzed as well as alternative procedures. RESULTS: Of the 1,087 patients, 260 (23.9%) needed PAP therapy. In 61% of the patients CPAP-therapy was applied, 19% needed Bi-PAP-ST and 10% Bi-PAP-S-therapy. A total of 91 patients (8.4%) were treated with alternative procedures, partially combined with positive airway pressure. In 760 patients (69.9%) PAP-therapy was controlled or SRBD was excluded. CONCLUSION: There are no generally accepted guidelines for the therapy of SRBD. Indications for conservative and/or surgical procedures in the treatment have to be determined individually, depending on polysomnographic findings, subjective discomfort and physical comorbidities of the patients.

[IMOLA -- a new larynx model for surgical training. Education in transoral laser microsurgery of the upper airways]. / IMOLA -- ein interventionsfähiges Larynxmodell. Ausbildung in der transoralen Lasermikrochirurgie der oberen Atemwege.

BACKGROUND: Education in laser microsurgery is generally acquired under the supervision of an experienced surgeon. During training phases, however, increased complication rates may occur. Viable models for training are therefore important. METHODS: Larynx models should be anatomically accurate in size, form and texture, and be able to simulate normal as well as pathological findings. RESULTS: The main component is gelatin. Elasticity and thermal qualities can be modified by additives. We have been able to develop a synthetic larynx model for CO(2)-laser surgery that closely resembles the physical and tactile qualities of human tissue. Further modification of the material produced cutting characteristics for CO(2)-laser similar to human tissue. CONCLUSION: The new larynx model allows the simulation of typical surgical situations. Surgeons in training can practice even difficult surgical procedures at low costs and without putting patients at risk, before carrying out the procedure on patients.

[Diagnostic and therapeutic endoscopy in ENT. Possibilities and limits]. / Diagnostische und interventionelle HNO-Endoskopie. Möglichkeiten und Grenzen.

Both flexible and rigid endoscopy have become very common in ENT in the last decade. This has led to an increase in the diagnostic and therapeutic spectrum, and, in particular, quality control. Because the purchasing price of optical systems, as well as their maintenance, can be quite expensive, the expected spectrum of applications should be taken into account in choosing endoscopic equipment. This review provides aid in choosing the right system without defining legally binding parameters.

On the organization of self-assembled actin networks in giant vesicles.

We studied the formation of actin scaffolds in giant vesicles of dimyristoylphosphatidylcholine (DMPC). Polymerization of actin was induced at low ionic strength through ionophore-mediated influx of Mg2+ (2 mM). The spatial organization of the filamentous actin was visualized by confocal and epifluorescence microscopy as a function of the filaments length and membrane composition, by including various amounts of cholesterol or lipids with neutral and positively charged polyethyleneglycol headgroups (PEG lipopolymers). In vesicles of pure DMPC, the newly polymerized actin adsorbs to the membrane and forms a thin shell. In the presence of 2.5 mol% lipopolymers or of cholesterol at a molar fraction x=0.37, formation of a thin adsorbed film is impeded. A fuzzy cortex is predominantly formed in vesicles of diameter d smaller than the filament persistence length (d< or =15 microm) while for larger vesicles a homogeneous network formation is favoured in the bulk of the vesicle. The fuzzy-cortex formation is interpreted as a consequence of the reduction of the bending energy if the actin filaments accumulate close to the vesicle wall.

Shape instability of a biomembrane driven by a local softening of the underlying actin cortex.

We present a theory showing that local shape instabilities of composite biological membranes, consisting of a lipid bilayer and an underlying actin cortex, can be triggered by a local softening of the membrane-associated cytoskeleton. A membrane containing such cortical defects can form blisters or invaginations, depending on external conditions. The theoretical predictions agree with observations provided by two sets of experiments: (i) microscopic observations of shape changes of giant vesicles with underlying shells of a thin actin network show the formation of local blisters and (ii) micropipet aspiration experiments of Dictyostelium discoideum cells in which we observed the formation of blisters in the aspirated cell part. In the latter experiments, the existence of a hole in the underlying cortex is confirmed by observation of the entrance of cell organelles into the blister. Our model may also be applied to the formation of lobopodia, fast-growing cell protrusions that play an important role in the locomotion and spreading of biological cells.

Intervesicle cross-linking with integrin alpha IIb beta 3 and cyclic-RGD-lipopeptide. A model of cell-adhesion processes.

We report the synthesis of a new integrin alpha(IIb)beta(3)-specific cyclic hexapeptide that contains an Arg-Gly-Asp (RGD) sequence and is coupled to a dimyristoylthioglyceryl anchor. We demonstrate that this ligand is useful to study specific integrin binding to membrane surfaces. With the help of biotinylated analogues of the peptide, a spacer of optimal length between the peptide and lipid moieties was searched for by evaluating the binding strength with an enzyme-coupled immunosorbent assay (ELISA) and by surface plasmon resonance (SPR). It was found to be strongly dependent on the length of the spacer introduced between the biotin and peptide moieties of the ligands, which consisted either of epsilon-aminohexanoic acid (epsilonAhx) or of epsilonAhx with two additional glycine units. Best results were obtained with c[Arg-Gly-Asp-D-Phe-Lys(Biot-Ahx-Gly-Gly)-Gly-] with dissociation constants of K(D) = 0.158 microM from ELISA and K(D) = 1.1 microM from SPR measurements. The analogous lipopeptide, c[Arg-Gly-Asp-D-Phe-Lys([dimyristoyl-3-thioglyceryl-succinimido -propanoyl]Ahx-Gly-Gly)-Gly], was used as a membrane-anchored integrin ligand. It is shown by fluorescence microscopy and cryo electron microscopy that integrin reconstituted into phospholipid vesicles binds to vesicles decorated with the lipopeptide, forming regularly spaced bridges between the two kinds of vesicles. The novel integrin-specific ligand allows establishment of new model systems for systematic studies of the self-organization of integrin clusters and focal adhesion complexes.

Energy filtered electron tomography of ice-embedded actin and vesicles.

Semiautomatic single-axis tilt electron tomography has been used to visualize the three-dimensional organization of actin filaments in "phantom cells," i.e. lipid vesicles. The instrumentation consisted of a 120-kV electron microscope equipped with a postcolumn energy filter, which was used in the zero-loss imaging mode. Apart from changing the tilt angle, all steps required for automated tomography, such as recentering the image area, refocusing, and centering the energy-selecting slit, were performed by external computer control. This setup permitted imaging of ice-embedded samples up to a thickness of 800 nm with improved image contrast compared with that produced by tomography with a conventional electron microscope. In spite of the missing-wedge effect that is especially obvious in the study of membrane-filament interaction, single-axis tilt tomography was found to be an appropriate (in fact the only available) method for this kind of investigation. In contrast to random actin networks found in actin gels, actin filaments in and on vesicles with a bending radius of less than approximately 2 microns tend to be arranged in single layers of parallel filaments and often induce an elongated shape of the vesicles. Actin filaments located on the outside usually associate with the vesicle membrane.

Determination of the inelastic mean free path in ice by examination of tilted vesicles and automated most probable loss imaging.

Using electron microscopy, the thickness of ice-embedded vesicles is estimated examining tilted and untilted views and assuming an ellipsoidal shape of the vesicles that appear to be circular in the untilted view. Another thickness measure is obtained from the ratio of the unfiltered and zero-loss-filtered image intensities of the vesicle. From these two measurements, the mean free path A for inelastic scattering of electrons in ice is calculated as 203 +/- 33 nm for 120 kV acceleration voltage. It is found that vesicles in thin ice films (< or = 1.5 lambda) significantly protrude out of the ice film. Due to surface tension the shape becomes an oblate ellipsoid. In holes covered with a thick ice film (> or = 3 lambda) and strong thickness gradients, vesicles are predominantly found in regions where the ice thickness is appropriate for their size. Also, a way of imaging the most probable loss under low-dose conditions involving thickness measurement is proposed. Even at large ice thicknesses zero-loss filtering always gives better image contrast. Most probable loss imaging can only help where there is no intensity in the zero-loss image, at very large thicknesses (lambda > 8).

Actin binding to lipid-inserted alpha-actinin.

The interaction of alpha-actinin with lipid films and actin filaments was investigated. First alpha-actinin was incorporated in lipid films at the air/water interface. Injection of alpha-actinin into the subphase of a lipid monolayer led to a significant increase of the surface pressure only for lipid films consisting of a mixture of a negatively charged lipid with a high proportion of diacylglycerol. These alpha-actinin-containing films were transferred onto silanized quartz slides. Photobleaching experiments in the evanescent field allowed quantification of the lateral number density of the lipid-bound alpha-actinin. In combination with the area increase from the monolayer experiments, the photobleaching measurements suggest that alpha-actinin is incorporated into the lipid film in such a way that actin binding sites are accessible from the bulk phase. Binding experiments confirmed that the alpha-actinin selectively binds actin filaments in this configuration. We also showed that, in contrast to actin filaments which are adsorbed directly onto planar surfaces, the alpha-actinin-bound actin filaments are recognized and cleaved by the actin-severing protein gelsolin. Thus we have constructed an in vitro system which opens new ways for investigations of membrane-associated actin-binding proteins and of the physical behavior of actin filaments in the close neighborhood to membranes.

Talin binds to actin and promotes filament nucleation.

Platelet talin binds to actin in vitro and hence is an actin binding protein. By four different non-interfering assay conditions (fluorescence, fluorescence recovery after photobleaching, (FRAP), dynamic light scattering and DNase-I inhibition) we show that talin promotes filament nucleation, raises the filament number concentration and increases the net rate of actin polymerization but has no inhibitory effect on filament elongation. Binding of talin to actin occurs at a maximal molar ratio of 1:3 as determined by fluorescencetitration under G-buffer conditions. The overall binding constant was approximately 0.25 microM.

Botulinum C2 toxin treatment increases the G-actin pool in intact chicken cells: a model for the cytopathic action of actin-ADP-ribosylating toxins.

Botulinum C2 toxin ADP-ribosylates actin in intact chicken embryo cells in a concentration-dependent manner. This effect correlates with an enhancement in the inhibitory potency of the respective cell lysates on DNAse I activity, indicating an increase in the cellular G-actin content of toxin-treated cells. The data support our view, that ADP-ribosylation of cellular actin with subsequent depolymerization of cytoskeleton-associated F-actin to monomeric G-actin is involved in the cytotoxic effects of botulinum C2 toxin. A model of the cytopathic action of actin-ADP-ribosylating toxins is presented.

Botulinum C2 toxin ADP-ribosylates cytoplasmic beta/gamma-actin in arginine 177.

Isolated cytoplasmic actin of human platelet and pig liver actin, but not rabbit skeletal muscle actin, was ADP-ribosylated by botulinum C2 toxin in the presence of [32P]NAD. Tryptic digestion of the [32P]ADP-ribosylated platelet actin generated two labeled peptides: a soluble peptide covering residues 174-183 and an insoluble fragment containing residues 148-183. Further digestion of these two peptides with thermolysin yielded the same radioactive peptide, which was in both cases peptide 175-177. Amino acid sequence analysis of peptides 174-183 and 175-177 located the ADP-ribosylation on Arg177.

ADP-ribosylation of skeletal muscle and non-muscle actin by Clostridium perfringens iota toxin.

The enzymatically active component ia of Clostridium perfringens iota toxin ADP-ribosylated actin in human platelet cytosol and purified platelet beta/gamma-actin, in a similar way to that been reported for component I of botulinum C2 toxin. ADP-ribosylation of cytosolic and purified actin by either toxin was inhibited by 0.1 mM phalloidin indicating that monomeric G-actin but not polymerized F-actin was the toxin substrate. Perfringens iota toxin and botulinum C2 toxin were not additive in ADP-ribosylation of platelet actin. Treatment of intact chicken embryo cells with botulinum C2 toxin decreased subsequent ADP-ribosylation of actin in cell lysates by perfringens iota or botulinum C2 toxin. In contrast to botulinum C2 toxin, perfringens iota toxin ADP-ribosylated skeletal muscle alpha-actin with a potency and efficiency similar to non-muscle actin. ADP-ribosylation of purified skeletal muscle and non-muscle actin by perfringens iota toxin led to a dose-dependent impairment of the ability of actin to polymerize.

Clostridium perfringens iota toxin ADP-ribosylates skeletal muscle actin in Arg-177.

Clostridium perfringens iota toxin ADP-ribosylates actin. Substrates of C. perfringens toxin are both non-muscle beta/gamma-actin and skeletal muscle actin. This finding suggests that C. perfringens iota ADP-ribosylates the same amino acid in skeletal muscle and non-muscle actin as does C. botulinum C2 toxin in non-muscle actin. Protein chemical analysis involving thermolysin cleavage on [32P]ADP-ribosylated actin or tryptic digestion followed by a secondary thermolysin cleavage of the radiolabelled fragments showed one major site of ADP-ribosylation. From its amino acid composition and sequence, the radiolabelled peptide was identified as peptide 175-177, locating the acceptor ADP-ribosyl amino acid as Arg-177.