We theoretically study the effects of isotropic dissipation in a topological mechanical system which is an analogue of Chern insulator in mechanical vibrational lattice. The global gauge invariance is still conserved in this system albeit it is destroyed by the dissipation in the quantum counterpart. The chiral edge states in this system are therefore robust against strong dissipation. The dissipation also causes a dispersion of damping for the eigenstates. It will modify the equation of motion of a wave packet by an extra effective force. After taking into account the Berry curvature in the wave vector space, the trace of a free wave packet in the real space should be curved, feinting to break the Newton’s first law. Since the discovery of quantum Hall effect124589It will be plausible to find similar topological phenomena in systems “cleaner” than the electronic ones. There are both theoretical and experimental works to extend the theory to photonic crystallines1112131415161820222425262727However the effect of unavoidable dissipations in the classical models has not been systematically investigated yet. In this paper, we try to solve this problem based on a 2-dimensional (2D) topological mechanical lattice. This investigation extends our understanding on these systems in two aspects. The first one is that our discussions are not based on a Hamiltonian representation because in fact there is no Hamiltonian for such systems. So it is impossible to borrow the discussions on the language of Hamiltonian from its quantum counterpart directly. The second one is that the symmetry which protects edge states should be reexamined in the presence of the dissipation. It is believed that the dissipation will induce decoherence and dephasing in quantum systems303132333435q is still good quantum number. Effectively, this variance can be expressed as an extra force acting on the wave packet, Furthermore, we find that the dissipation will induce a damping spectrum. Such damping dispersion can generate an effective force for a free moving wave packet, which seems to break the Newton’s first law at the first glance. We can understand this effect by considering a free wave packet whose profile in the wave vector space is a Gaussian function, The paper is organized as the following: In section 2, we present a topological mechanical system on a rotating square lattice. All our arguments will base on this model. In section 3, we introduce how to calculate the Chern number by the evolution of the centers of the Wannier functions. The gauge invariance that protecting the chiral edge states is discussed. We further illustrate that such gauge argument is still available in a disordered lattice. In section 4, we derive the equation of motion for a free wave packet. The dissipation induced force is discussed. Section 5 is for the conclusions and outlooks.Rx and Ry in the plane. After Fourier transformation to the wave vector space We first consider a square lattice shown in x and y directions for the Bloch wave. The three terms on the right hand side stand for the restoring forces, the Coriolis forces and the dissipative forces, respectively.Here M isThe matrix m1 and m2 are the masses of the two MPs in each unit cell. The restoring force matrix K readswith k1 and k2 are the spring constants shown in qx, qy are the wave vectors of the phonon modes along x and y directions,respectively. It is derived from the harmonic potential: i and j label the positions of a unit cell in the x and y directions.where G is the matrix describing the Coriolis force acting on the lattice,2. For the dissipation term, we take isotropic dissipative forces with Γ = γI, where I is a 4 × 4 unit matrix.where Ω is the angular velocity of the plane with the positive direction defined in Such second order differential equations can be solved as an eigenvalue problem by introducing new variables, eiωt for an eigenstate, the phonon dispersion will be obtained by solving the eigenvalue problem: det(iωI − A) = 0, where A is the matrix on the right hand side of As m1 = m2 = m, k2 = 0.2k1 and γ = 0. Throughout this paper, all physical quantities are taken as dimensionless. It is easy to recast the unit at the end of the calculations  of the Wannier functions for the ath band. Yu et al. have developed a numerical method to calculate Xaath band when changing kx by one reciprocal vector in the BZ. One can divide such variation into M pieces, and each piece is a nonzero matrix only for where the summation is over all the occupied bands and the closed path integration is along the boundaries of the first Brillouin zone (BZ). As x direction) for the studied phonon bands as changing qy by one reciprocal vector. But the inner product for |uaq〉 and 〈uaq| must take the form of the new definition. As a result, the project operator inserted into the pieces qy) for the interesting n phonon bands is βa is the eigenvalues of the n × n matrix In our classical system, the Chern number can still be considered as the total displacement of the Wannier functions k1, (1 + D/2)k1]. Other parameters are fixed and are the same as those in D = 0.9. When the gap is not closed, the gauge argument is performed on an ensemble of cylinders with different disordered configurations. The number of pumped bulk states can still be investigated by the evolution of the centers of the Wannier functions. Similar to that in the electronic systemN × N disordered samples are taken as the unit cell. In this case, the first and the second bands split into totally 2N2 bands and the total phase Φ is calculated for these bands. We find that the Chern number C, which characterizes the evolution of the Wannier functions, is fixed at 2 in the ensemble. It will fluctuate from sample to sample only when the gap is closed by the disorder for D > 0.9. So from this gauge investigation, it is concluded that the chiral edge states in the topological mechanical system are robust against disorder and dissipation. This provides further support for the conclusions of At the end of this section, we show that the above gauge argument can be extended to the disordered case. In ath phonon band. Its profile at the initial time t = 0 is Supposed that there is a free wave packet composed by the states in the t easily,As there is no external force, ath eigenstate |ua,q〉 at the wave vector ua,q〉 to the first order of the derivation of where t is within a small time interval, the wave packet becomesOne can simplify So the motion of wave packet satisfies the following equations of motion for its centers where ω and κ, of the eigen-frequencies for the dissipative model. It seems that the damping rate is strongly dispersed in this topological system. This dispersion comes partially from the finite value of Ω. It is also caused by the fact that the damping of a vibrational mode is proportional to its velocity. As the time derivation of the displacement of an eigen-mode will generate a multiplier, the eigen-frequency ω, to the velocity, the eigen-modes with different eigen-frequencies will suffer different damping rates.In κ, κ is not varying rapidly for this band. It is shown that for the 2nd and the 3rd bands, there is a cirque in the BZ, in which both In The chiral edge states in the topological mechanical system are robust against dissipation and disorder. We also find that the dissipation can induce a dispersion of damping for the eigenstates. As a result, an extra force appears in describing the motion of free wave packet. After taking into account the non-zero Berry curvature in such system, we find that the free wave packet will swerve even through there is no external force acting on the packet. One should be aware that the Coriolis forces and dissipative forces have been taken into account during the calculation of bands so that they should not be considered as external forces again during the calculation for the wave packet. We also suggest that such effect should also exist in dissipative photonic system. Besides this, a general method to calculate the Chern numbers in such systems is developed and we believe that it is also applicable in non-hermitian quantum systems.How to cite this article: Xiong, Y. et al. The effects of dissipation on topological mechanical systems. Sci. Rep.6, 32572; doi: 10.1038/srep32572 (2016).


Biobetters are new drugs designed from existing peptide or protein-based therapeutics by improving their properties such as affinity and selectivity for the target epitope, and stability against degradation. Computational methods can play a key role in such design problems—by predicting the changes that are most likely to succeed, they can drastically reduce the number of experiments to be performed. Here we discuss the computational and experimental methods commonly used in drug design problems, focusing on the inverse relationship between the two, namely, the more accurate the computational predictions means the less experimental effort is needed for testing. Examples discussed include efforts to design selective analogs from toxin peptides targeting ion channels for treatment of autoimmune diseases and monoclonal antibodies which are the fastest growing class of therapeutic agents particularly for cancers and autoimmune diseases. Using a docking program, one could identify the binding region on the ligand, which will reduce the number of mutations, e.g., if there are 4 residues in the hot spot, the number of single and double mutations will be reduced to 76 and 2166, respectively. While this is a drastic reduction, the experimental effort required is still substantial. As a next step, one could refine the binding poses obtained from docking using molecular dynamics (MD) simulations and obtain an accurate structure for the protein-ligand complex. Now one has a precise map of the inter-molecular interactions and can predict with some certainty which single and double mutations will yield the best outcome for reducing the affinity of the ligand for the off-target protein.Most of the drug leads that have high affinity for the target receptor ultimately fail because of problems with side effects, cytotoxicity or degradation. In fact, such problems are present in existing drugs but at a tolerable level. Improving the properties of existing biologics (protein or peptide-based drugs or drug leads) against such shortcomings is dubbed biobetters. Because the chemical space is very large, design of biobetters through trial and error methods is unlikely to succeed. One needs to make use of all the available information about the problems faced by a drug in order to facilitate the design of a biobetter. In fact, the experimental effort will be inversely proportional to the amount and accuracy of the information provided. As an example, consider solving the selectivity problem of a peptide ligand which binds to an off-target protein with a high affinity. If no information is available, one has to examine various mutations on the ligand which could be a very large experimental undertaking, e.g., for an average ligand with 30 amino acids, there are 30 × 19 = 570 single mutations and (30 × 29/2)× 19As illustrated in the above example, obtaining an accurate model of the protein-ligand complex holds the key for designing biobetters with minimal experimental effort. The most common method used for complex structure prediction is docking, which is fast but not very accurate. On the other extreme is MD, which can provide the desired accuracy but it is very slow. Combining the two methods by refining the binding poses obtained from docking in MD simulations offers a compromise solution that has been successfully applied to numerous protein-ligand complexes in the past decade Determination of validated complex structures is the most important step in design of biobetters because inspection of the binding mode will readily indicate the most promising mutations to achieve the desired improvement in affinity or selectivity. In fact, one can go beyond that and turn qualitative predictions into quantitative ones by calculating the effect of the mutation on the binding free energy from MD simulations. Such computational mutagenesis studies have the potential to eliminate guesswork completely and deliver the optimal biobetter for a given target with minimal side effects. In the following, we review the computational and experimental methods that will help to optimize design of biobetters while reducing the experimental efforts. Applications discussed include construction of selective analogs from toxin peptides targeting ion channels and design of biobetters from monoclonal antibodies with improved affinity and aggregation resistance.22.1Determination of crystal structures for protein-ligand complexes is extremely difficult and very rare. Therefore, construction of an accurate complex structure from a given pair of protein and ligand structures is the most critical step in the design of a biobetter. Here we stress accuracy of the complex model in particular because an incorrect binding mode will predict misleading mutation sites for improvements, resulting in wasted experimental effort. Assuming crystal or NMR structures (or good homology models) of the protein and ligand are available, one can use a docking program to find a set of initial poses for the complex Accuracy of docking programs is limited due to neglect of water molecules and lack of adequate sampling Several programs are available for performing MD simulations such as AMBER, CHARMM, GROMACS, and NAMD. The NAMD program In the final stage, trajectory data obtained from the equilibrated system are used for visualization of the complex structure and analysis of the binding mode. The binding mode can be characterized quantitatively by calculating the average distances between the interacting residues. The strong ones include charge interactions, where the N—O distance between the charged residues is about 3 Å, and hydrophobic interactions involving aromatic side chains . Intermediate strength interactions include hydrogen bonds and charge interactions at larger distances . The binding mode results can be compared directly to alanine scanning mutagenesis data, which provides a detailed validation for a complex model. Unfortunately alanine scanning experiments are available only in a few cases, and one has to rely on binding free energies for validation in most cases.2.2Free energy calculations can contribute to design problems in two ways: validation of complex models as alluded above and prediction of free energy changes due to mutations. Binding constants of ligands are routinely available for most complexes and thus provide a standard test for a complex model. Several methods can be used for this purpose, from docking and scoring Keq (inverse of the dissociation constant KD) of a ligand is obtained from the integration of the PMF, which is related to the standard binding free energy via Gb = − kT ln(KeqC0), where C0 is the standard concentration of 1 M. Umbrella sampling MD simulations is the most common method used in PMF calculations. The problem with sampling at high-energy positions is overcome by introducing harmonic biasing potentials along the reaction coordinate The PMF provides the free energy profile of a ligand along a chosen reaction coordinate. The binding constant H(λ) = (1 − λ)H0 + λH1, where H0 represents the Hamiltonian in the initial state (wild-type ligand) and H1 in the final state (mutant ligand). The alchemical transformation is performed by changing the parameter λ from 0 to 1 in small steps, which ensures that the change in the free energy in each step is small enough to enable sufficient sampling of the system. In the FEP method, the interval  is divided into n subintervals, and for each subinterval the free energy difference ΔGi is calculate from the ensemble average. The free energy difference between the initial and final states is obtained from the sum of all ΔGi. In the TI method, the ensemble average of the derivative ∂ H(λ)/∂λ is obtained at several λ values, and the free energy difference is calculated from the integral of this quantity from 0 to 1.Binding mode of a complex structure gives important clues on how to improve affinity and/or selectivity of a peptide ligand. By calculating the free energy change due to each suggested mutation, one can predict which one will be the most effective. Again chemical accuracy is essential in such calculations to retain predictive power, which is provided only by the MD-based methods. The two most common methods used for this purpose are free energy perturbation (FEP) and thermodynamic integration (TI) Gb = ΔΔG(K → K0) + ΔΔG (K0 → A0) + ΔΔG (A0 → A). The thermodynamic cycle that combines these procedures in the FEP/TI calculations is illustrated in Charged residues have the strongest interactions, hence mutation of a neutral residue to a charged one for improving affinity (or vice versa for improving selectivity) is a common situation. This is a challenging problem that has been resolved only recently. FEP/TI calculations for mutations are usually performed separately in the binding site and bulk. This causes problems for charge mutations because the system needs to be kept neutral and also errors arise when solvation energies are calculated in different systems. In fact, such errors can be avoided by performing the binding site and bulk calculations simultaneously in the same system. That is, while a charged residue on the peptide is mutated to a neutral one in the binding site, the reverse transformation is applied simultaneously to the mutant peptide in bulk, which is well separated from the binding pocket. It is also necessary to separate the Coulomb and Lennard-Jones interactions to avoid stability and convergence problems. This can be achieved by introducing residues with uncharged side chains (denoted with a superscript 0) as intermediate steps. For example, the free energy change due to a Lys to Ala (K → A) mutation can be expressed as ΔΔ3There are many biophysical and biochemical techniques used for affinity measurements and aggregation studies of biologics. In the following, we briefly discuss some of the widely used methods.3.1KD = koff/kon) of proteins using a variety of biophysical or biochemical techniques. The binding affinity is related to KD inversely, thus a lower KD value means a higher affinity. Using bioassays in measurement of the binding kinetics is among the most common methods. However, recording of the binding rate constants is not a trivial task, and sensitivity of the assay and reproducibility of the data need to be considered. Existing experimental methods to measure the KD of biotherapeutics include enzyme-linked immunosorbent assay (ELISA) based methods, spectroscopy-based assays, calorimetric methods such as isothermal titration calorimetry, and a diverse range of biochemical methods.Affinity measurements involve detecting the equilibrium dissociation constant (ELISA-based methods are used for detecting and determining the amount of biomolecule under study in a quantitative manner Another widely used method is surface plasmon resonance spectroscopy (SPR) Many different fluorescence properties can also be used to study molecular interactions including protein affinities. The sample is labeled with a fluorescence tag unless intrinsic tryptophan (tryp) fluorescence is used. One of the fluorescence properties  is used to probe the interactions. A fluorimeter, lifetime instrument or a confocal microscope can be utilized for the detection of fluorescence intensity and lifetime. Depending on the interactions, a change in the fluorescence signal is expected upon binding to the target. This could be an increase or decrease in the emission maximum, a concurrent shift in the emission wavelength, a change in fluorescence lifetime or a change in polarization leading to change in anisotropy.Flow cytometers are mainly used for cell sorting and detection but they can also be used in affinity studies. The sample flows through a steady stream created via hydrodynamic focusing in a narrow tubing and the scattered light as well as a fluorescence signal is detected from a fluorescent dye that is bound to the biomolecule of interest 3.2Methods to study the structural stability and aggregation profiles of proteins can be roughly categorized into three groups Intrinsic tryp fluorescence is probably the most used method for studying conformational changes in proteins, but it is also very helpful for probing protein-protein interactions Light-scattering spectroscopy is used extensively to check aggregate formation in biotherapeutic formulations HPLC is the main method used in aggregation studies of proteins 4As emphasized in Methods, accurate determination of the protein-ligand complex is the most crucial step in design of biobetters whether it is for improving their affinity, selectivity or stability. Thus a proper validation of a complex structure using a variety of experimental checks is essential before proposing any mutations on a ligand. The applications discussed below are successful examples of this approach but there are many other complex structure predictions, which lack proper validation and therefore cannot be trusted for design purposes.4.1Potassium channels are targeted by many toxins, which could be utilized as therapeutics in treatment of diseases caused by their dysfunction The scorpion toxin HsTx1 has a similarly high affinity for Kv1.3 and also exhibits 700-fold selectivity for Kv1.3 over Kv1.1 4.2Monoclonal antibodies (mAbs) are the leading molecules in the biotech industry Thus the first step in a computational study of protein aggregation is to find the partially unfolded conformations. Most of the existing approaches for predicting aggregation-prone regions of proteins are based on bioinformatics methods that search for hydrophobic regions in the amino acid sequence and use static protein structures 5Thanks to the continuing increase in computing power and developments in computational methods, we now have the ability to determine the structure of protein–ligand complexes and their binding free energies accurately. Such methods will be very useful in rational drug design in general and will facilitate development of biobetters from existing peptide and protein- based drugs. The possibility of constructing accurate complex models means that one can make rational choices for mutations to improve the affinity/selectivity profile or stability of a peptide drug lead. The effect of the chosen mutations on the binding free energy of a ligand can be determined from free energy calculations, which will minimize the experimental efforts. Although we have used peptide toxins targeting potassium channels for illustration purposes, the computational methods described here are quite general and can be applied to any receptor–ligand system, as long as their individual structures are available. In particular, developing biobetters from mAbs will greatly benefit from the computation-driven approach espoused here.


The aim of this retrospective cohort study was to assess the accuracy of the completely customized lingual appliance WIN  employing a three-dimensional (3D) comparison between the setup and the final result.t test for unpaired samples, Kruskal–Wallis tests, U tests, and ANOVA with Duncan post hoc test were applied statistically.The setup and final models of 20 consecutively debonded patients  with various malocclusions of a private practice specialized in orthodontics were digitalized using a 3D scanner. The 3D models of the setup and the final model of each jaw were then digitally matched using the best fit algorithm and segmented into single teeth. After placing individual coordinate systems, the homologous teeth of the setup and the final model were matched to be able to calculate the exact deviations of all rotational and translational components. The Regarding the incisors, the angle discrepancies between the setup and the final result appeared to be less than 3° . The translations showed mean values less than 0.3 mm . Slightly higher values could be measured in the lateral segments regarding rotations  as well as regarding translations .Using the completely customized lingual appliance WIN, it is possible to achieve the final result predicted by the setup with a high accuracy. Since the late 20th century, as a result of the rising demand on the part of patients for an esthetic alternative to conventional labial brackets , many orIn order to produce the desired outcome in the patient’s dentition, not only the accuracy of brackets and archwires, the positioning and transfer system, but also the rebonding procedure have to be as good as possible. For the completely customized lingual appliance (CCLA) WIN , as well as models made at different points in time using the same coordinate system , 4. NumeUntil now, no evaluation of the accuracy of the CCLA WIN has been made. The aim of the present study was to assess to which degree the completely customized lingual appliance WIN can realize the tooth positions planned by the setup using a three-dimensional (3D) analysis of all rotations and translations of each individual tooth.To compare the therapeutic accuracy of the CCLA WIN, in this retrospective study, the setup models, which were regularly made from a silicone impression of the malocclusion before beginning the treatment for the appliance’s production process, and final plaster casts made directly after removal of the appliance were compared three-dimensionally.The study population comprised 40 jaws  from 20 consecutively debonded patients , whose mean age at the beginning of treatment was 15.76 ± 4.45 years. In 6 jaws of 4 patients, none of the second molars were erupted at the time of impression taking, resulting in a total of 548 examined teeth. At the beginning of the treatment 5 patients had an Angle Class I malocclusion (25%), whereas 13 patients presented an Angle Class II (65%), and 2 an Angle Class III (10%). No extractions were performed in any patient of the study group. The patients were included in this study by the first author without any further selection. The initial malocclusion was not a selection criterion. Patients with general diseases, clefts, or other syndromes affecting the cranial complex or bone remodeling, as well as cases in which surgical assistance was foreseen by the treatment plan were excluded. Patients with periodontal problems were also excluded. Steps were taken to ensure that no additional appliances had been used, such as Herbst and other fixed functional appliances, mini-implants, or extra-oral appliances, like headgear, so that it was possible to measure only the effect induced by the lingual bracket system itself. In most of the cases, elastics were utilized for finishing. In addition, only patients in whom no manual finishing bends by the clinician were necessary were chosen, thus, enabling us to analyze the tooth positions related to the appliance alone.All patients were treated with the CCLA WIN and the same archwire sequence at the orthodontic practice of Prof. Dr. Wiechmann and partners in Bad Essen, Germany. The treatment was undertaken by different clinicians who all followed the same treatment procedures. In all patients, the treatment could be performed according to the treatment plan and none of the patients required their therapy to be discontinued. Treatment was commenced between June 2012 and June 2013. The debonding was undertaken between August 2014 and October 2014, resulting in a mean treatment time of 1.62 ± 0.30 years. If stripping was scheduled in the treatment plan, during setup manufacturing, the exact amount of stripping for each affected tooth surface was noted, and exactly transferred to the patient during treatment by the clinician. Neither the person who assessed the data nor the statistical expert were involved in the treatment of the patients. They both were blinded.For the matching process of the teeth, it was essential that the plaster casts did not contain a bonded lingual retainer, buttons, or other attachments. In addition, patients were only included in the study in whom no restorations or fillings were carried out between commencement and end of treatment. Casts were inspected to exclude the possibility of them having any plaster beads or other flaws, such as broken or incomplete teeth.No patients had to be excluded because of incomplete records. Four of the initial 24 patients had to be excluded because they did not meet all the inclusion criteria, resulting in a total of 20 patients being enrolled in the study. Two of these were excluded because a finishing bend was made by the practitioner, as the setup position of one particular tooth was not satisfactory. Since consecutively debonded patients were investigated, no selection was performed.The setup model was made during the production process of the completely customized lingual appliance WIN (setup model).The final plaster casts were made immediately after the debonding of the lingual appliance .The models were examined for plaster beads or other flaws which were then carefully removed if necessary. For each jaw, two models were scanned using a 3D scanner :http://www.gom.com). The 3D data were saved in standard triangulation language (STL) format. These files were imported into the program Geomagic Studio 2014 , together with a custom-made square plane and attached single coordinate systems for each tooth. Each of the 3D models was trimmed in a way that only the teeth were left—all gingival parts, as well as the alveolar crest, or possible scan artefacts, were removed. Then, the two models were segmented into individual teeth.The 3D scanner used is equipped with cameras with a resolution of 2 × 5,000,000 pixels and a point spacing of 0.02–0.79 mm , as well as for the rotation around the three axes, in degrees .For the matching process, homologous teeth, e.g., left central incisor of both the setup and the final model, were matched using the software’s automated best fit registration routine with the setup tooth being moved Fig. . ConsequThe accuracy of the best fit method was automatically calculated by the software after each matching process and transferred to an Excel sheet.n-point registration was carried out. Accordingly, three corresponding points of the two teeth were manually chosen. Using this information, the software registered the two teeth. Subsequently, the automated registration could always be successfully completed. The movements of the n-point registration were added by the software to those of the automated registration in order to calculate the full extent of the deviations of the teeth.If a corresponding pair of teeth could not be successfully matched automatically by the software, a manual The variables for every of the 40 jaws were then transferred to an Excel sheet .This study has been approved by the ethics committee of the Hannover Medical School (No. 3151-2016).Ten randomly selected jaws were re-examined 4 weeks after completion of the measurements by the same examiner to assess the reproducibility of the measurements and the accuracy of the method used. The double measurements revealed no single discrepancy. Because of the computed algorithm, for every single tooth, the best fit matching showed the exact same result as that measured at first. This result indicates the high level of reproducibility of the method used in this study.t test for unpaired samples was chosen for data analysis. For the evaluation of discrepancies between the different types of teeth , Kruskal–Wallis tests and U tests were applied, because of an absence of a normal distribution. The level of significance of the single U tests following a Bonferroni correction was p < 0.007. When comparing the different types of tooth movement, normal distributions were found. Therefore, statistical tests comprising an analysis of variance (ANOVA) with Duncan post hoc test were implemented.Statistical analysis was carried out using SPSS . All data were examined for normal distribution employing the Shapiro–Wilk test. When comparing upper versus lower jaw, a normal distribution was found. Therefore, the p < 0.05, whereby p values <0.001 were regarded as being highly statistically significant.The level of significance was set to The mean discrepancy of the matching of homologous teeth appeared to be 0.029 ± 0.009 mm. The mean values of the discrepancies between the setup and the final result are shown in Table In every angle and translational measurement, the incisors presented fewer deviations than the lateral teeth, with mean values for the rotations between 2.00° (rotation) and 2.96° (torque) and for the translations between 0.16 mm  and 0.29 mm . For the posterior teeth, the largest discrepancies were found for the torque and the buccolingual dimension  than in the setup; for the mesiodistal translation, there was again no tendency to either side.p < 0.001) and significant differences for rotation (p = 0.021) and buccolingual position (p = 0.021) of the teeth (Table p < 0.000) and for translations (p < 0.000). The Duncan post hoc test revealed significant differences between torque (rot x) and tip (rot y), as well as for torque and rotation (rot z). For translational movements, all types differed significantly  and translation in the mesiodistal dimension (p = 0.74), no significant differences were detected between the various tooth types. In the lower jaw, all rotations and translations were significantly different. The second molars differed significantly from all other teeth regarding tip in the upper jaw and torque in the lower jaw. The incisors showed no significant differences in any rotation or translation to each other.In addition, we examined whether there were significant differences between the various types of teeth. The central and lateral incisors, canines, first and second premolars, and first and second molars of the upper, as well as of the lower jaw, were investigated in terms of all rotations and translations. For the upper jaw, in relation to torque (The accuracy of a different lingual bracket system has already been evaluated using similar methodology , 11. In For the matching process, it is also important to remove all elements not belonging to the dental crowns before using the best fit algorithm. Therefore, the gingival parts were thoroughly removed and the teeth were segmented. We also made sure that no additional elements, such as bonded lingual retainers or buttons were present in the plaster casts before scanning was carried out. The small mean discrepancy in the matching process below 0.03 mm could be explained by tooth wear due to ingestion and possible bruxism, as well as by possible alterations in the surface which the lingual appliance was bonded to. When removing the composite from the bonding surface, there is the possibility of remnants or a slight removal of enamel. Therefore, not only the lingual surface was used for the matching process, but also the whole dental crown, in order to provide the largest possible surface for this process and to reduce the effect of possible surface alterations. In all patients evaluated in this study, no fillings or restorations were made or changed by the dentist throughout the treatment period.It must be critically mentioned that the initial matching of the whole jaws could lead to small discrepancies because the differences are averaged by the algorithm. There are no stable structures in the upper or lower jaw that remain exactly the same before treatment, when the setup is made, and after treatment, when the final models are produced. In most cases—as can be seen in Fig. x- and y-axis of all coordinate systems were located. The plane was placed in a manner such that the dental crowns of all teeth were crossed at the approximate height of the bracket slots representing the level of force application. With regard to the rotations, each coordinate system was positioned manually onto the mesiodistal center of the crown of the incisors and canines, and onto the center of the crown of the premolars and molars. With regard to the position of the coordinate systems, the tooth of the setup was always chosen because this was the tooth to be moved later during the best fit matching process. It must be mentioned that the translational and angular discrepancies influence each other. The values calculated always indicate the differences in the position of the homologous teeth in the center of the chosen coordinate system. However, the resulting translations or rotations of any other point of the dental crown can be computed with the values if necessary. The direction of discrepancies, e.g., if the torque is more positive or more negative in the final situation compared to the setup, could be influenced by the initial position of the teeth in the malocclusion.Because the tooth axis cannot be identified exactly using a model of the teeth without information on root positions and root morphology, a plane was chosen in which the By investigating the data of consecutively debonded patients, there was no bias in relation to treatment complexity, treatment duration, and type of malocclusion. Certain additional appliances, such as the Herbst appliance or forms of treatment, such as a surgical correction of a malocclusion, were excluded, as were interventions by the orthodontist using manually made finishing bends. In addition, patients with periodontal diseases were excluded because of biomechanical differences caused by the different position of the center of resistance of the teeth. This should provide the opportunity for measuring only the effects induced by the completely customized lingual brackets and archwires. Interproximal reduction was not an exclusion criterion because the amount of reduction planned on the setup and in the dentition were the same. It should be mentioned that in some cases class II elastics were used which could have affected rotations or translations. These effects are supposed to be quite small because the elastics were only used on 0.016 × 0.024″ stainless steel or 0.018 × 0.018″ slot-filling β-titanium archwires with tight steel ligatures in place.The largest translational discrepancies between the setup and the final situation occurred in the buccolingual position of the second molars. The mean values for each second molar were slightly more than 1 mm with the setup being mostly transversally wider than the final result. It was also possible to show that the further distal, the more transversal discrepancies occurred. Also, all other translational discrepancies were mostly higher for the second molars than for the other teeth. This result is in accord with previous studies , 11 and We know from the literature that the completely customized lingual appliance WIN differs from other lingual appliances , 5, 9. TThese superior values could be explained by the various changes implemented in the WIN system, as well as by the high precision of bracket slots and archwire dimensions . The greSince this study only assessed whether the planned tooth movements could be achieved by the appliance, the amount of movement of each tooth is not relevant to make a statement in this regard and could be the subject of further studies.Finally, it should be noted that a fixed appliance can only position teeth in the respective jaw. The coordination of the two jaws must be optimized by using additional features, such as elastics. Moving teeth with a multibracket appliance always results in a multi-indeterminate system of forces affecting each other, which may impose a need for a compliance-dependent finishing stage at the end of treatment. Because of the uncertainty of patient cooperation, it is not valid to examine occlusion in a study concerned with the accuracy of such an appliance.It is possible to plan the final result of orthodontic treatment using a setup and to realize these tooth movements with a high degree of accuracy.The best fit algorithm used in this study seems to be a very accurate and highly reproducible method for matching homologous teeth.


LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.The 5‐lipoxygenase (5 From a pathologic point of view, AD is characterized by the progressive accumulation of insoluble intra‐ and extracellular Aβ peptides and intracellular aggregates of highly phosphorylated microtubule‐associated protein tau  is a pro‐inflammatory enzyme that by oxidizing free and esterified fatty acids produces potent bioactive lipids, most of which are grouped under the name of leukotrienes (LTs)  mice were administered with zileuton or vehicle for 7 months, after which they were assessed in two behavioral paradigms: the Y‐maze and the Morris water maze. No differences were observed between the four groups of mice  in regard to their general motor activity which was assessed by the total number of arm entries in the arms of the maze  levels, the major metabolic product of 5LO enzymatic activation  that have been suggested to play a functional role in this aspect of tau metabolism. Among the different kinases investigated, we observed that only the cdk5 kinase pathway was significantly changed following the pharmacologic blockade of 5LO activation, suggesting a specific involvement for this kinase in the biological effect.It is known that the development of tau pathology results in biochemical and functional manifestations of synaptic deficits, which are typically represented by altered levels of pre‐ and postsynaptic protein markers . This amount of the drug was selected based on our previous work where we showed that it significantly reduced 5LO activation  express human mutant microtubule‐associated protein tau, MAPT, driven by the mouse prion protein promoter . Testing was always performed in the same room and at the same time to ensure environmental consistency as previously described , we used a white circular plastic tank , filled with water maintained at 22°±2°C, and made opaque by the addition of a nontoxic white paint, as previously described  extracts from mouse brain homogenates were used for Western blot analyses as previously described  and following the instructions of the manufacturer , and Bonferroni multiple comparison tests were performed using prism 5.0 . All data are presented as mean ± standard error of the mean. Significance was set at p < .05.One‐way analysis of variance (ANOVA), unpaired Student's This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were approved by the Institutional Animal Care and Use Committee.The authors have no conflicting financial interest to disclose.PFG and DP designed the study. PFG and JC carried out the experiments, performed the measurement, and analyzed the data. PFG and DP drafted the manuscript. All authors read and approved the final manuscript.


The expanded disability status scale (EDSS) is a validated and reliable tool to assess the extent of disabilities in patients with multiple sclerosis (MS). However, the use of this tool has been found to be limited in assessing various symptoms of MS that are important. Our study aimed at evaluating the efficacy of a new scoring system, reverse nutech functional score (RNFS) as compared to EDSS in assessing patients with MS treated with human embryonic stem cell (hESC) therapy.The MS patients were treated with hESC therapy for one treatment period. All the patients were evaluated with EDSS and RNFS at baseline and after the hESC therapy.The study included a total of 24 MS patients with mean age of 45 year. The patients showed an improvement in parameters  associated with MS when evaluated with RNFS. This improvement went unnoticed when the patients were assessed with EDSS.RNFS can efficiently assess the effectiveness of hESC therapy in treating patients with MS. It could be a suitable scoring system for patients with MS as it can assess the slightest improvements in the patients. Use in other settings would be helpful in assessing its utility. Multiple sclerosis (MS) is an autoimmune, chronic inflammatory demyelinating disease of the central nervous system (CNS) with genetic and environmental effects, among young and middle-aged adults , 2. It aThe rate of growth of the disease is extremely mutable and uncertain, with an unclear etiology. Presently there is no cure, and only symptomatic therapy is available. Generally, oral or intravenous corticosteroids like methylprednisolone is used at a high dose in the routine therapy for acute attacks which results in a faster recovery from the disability within a duration of three to five days of course . HoweverBasically, EDSS quantifies disability in eight functional systems (FS) and allows neurologists to assign a functional systems scores (FSS) in each of these systems. It consists of ordinal rating system ranging from 0  to 10 (death due to MS) in 0.5 increments interval (when reaching EDSS 1) . EDSS alWe have previously published a case study of a patient with MS, who was treated with human embryonic stem cell therapy (hESC) and was assessed with EDSS before and after the therapy . We haveThe RNFS scoring system assesses a symptom based on five ordinal grades that runs in a direction of GOOD → BAD. The RNFS system is also useful in conducting probability based studies as these scores have been converted into numeric values. It is a numeric scale that scores all the known symptoms for patients with MS. RNFS for MS is a 36-point positional  and directional  scoring system that can be used to assess or validate the diagnosis of patients with MS  whereas The establishment and characterization of hESCs were explained in our previous paper . All theIn this study, the patients with MS were assessed with RNFS and EDSS. The RNFS/EDSS scores before and after the therapy were compared to assess which scoring system is better in evaluating the patients treated with hESC therapy. All the patients provided written informed consent prior to start of the study. The study was conducted in accordance with Declaration of Helsinki and approved by an independent Institutional Ethics Committee (IEC).A total of 24 patients with a mean age of 45 year were enrolled in the current study. The days of treatment in T1 varied from 42 to 84 days with a gap phase of 120–240 days.Out of 24 patients, only one patient reached the BPG at ET and 21 patients showed change in grade after the treatment  parameters improved by at least one grade Table The scores for cases have also been categorized based on the affected parameters. Muscle weakness, an important symptom of MS, was scored to be as <BPG in all the cases at BL. At ET, 3 (12.5 %) patients reached BPG. Fatigue was scored as <BPG in 22 cases at BL, 8 36.4 %) of them reached BPG at ET. The scores of all other parameters are presented in Table  % of theIn this study, an improvement in condition of the patients was evaluated more efficiently with RNFS system by highlighting even the slightest improvement. The levels in RNFS run in direction 1 (Good) → 5 (Bad) and patients could be placed in these levels on the basis of their symptoms and functional limitations.Gray and Butzkueven stated that EDSS is subjective in certain areas . It is also insensitive to small changes. Further, it does not present an accurate picture of the patient’s cognitive abilities and functional abilities in performing ADLs. It is nonlinear in terms of the time spent at various ranges of the scale . MoreoveSchwid et al. reported in the study for comparing limitations of walking ability in MS patients, the EDSS and ambulation index (AI) were less sensitive to change than the D max (the maximum distance that a person can go) and T8  . SimilarUse of hESC therapy has generally led to a concern because of clinical non-viability in culturing of cells in a xeno-free environment. However, our institution uses a patented methodology  for the The RNFS is a solitary classification system for the patients of all ages with diminished complexity of the assessment system for the practitioners. So, we conclude that the newly developed RNFS is a unique tool can be used to gauge the betterment of patients receiving hESC therapy. Thus, this newly developed classification, functional and evaluation system can be used globally to help the patients with MS.


The artichoke by‐products from the canning industry are mainly used for silage, being minimally revaluated. The ways of extraction of by‐products of artichoke into fiber‐rich powders modify their industrial applications in biscuits, as the sensory evaluation may change compared with the reference fiber  used with commercial biscuit. In this sensory study biscuits enriched with fiber‐rich powders of artichoke  are compared with biscuits with the same percentage of the reference fiber (P) and control biscuits without fiber (B). For most of the sensory attributes of the biscuits enriched with artichoke fiber‐rich powders were perceived similar to the biscuits with the commercial reference fiber (P). The good sensory behavior of the biscuits with artichoke fiber‐rich powders during two storage conditions applied may confirm that the artichoke by‐products would be a suitable substitute for pea fiber in oven‐baked products, like wholemeal biscuits with high‐fiber content. Consumer trends demand more natural products with better nutritional characteristics which can complement nutritional deficiencies, like the low fiber ingestion , Raftilose® (chicory) with less functional qualities.From an environmental perspective, the revaluation of vegetable by‐products is also critical, since it increases the economic viability of waste minimization processes. Usually, those by‐products (70% by weight are by‐products of artichoke) are only used as animal feed, being minimum their economic revaluation. Assuming that the by‐products have a composition similar to the edible part of the artichokes, these by‐products can be a promising source of new value‐added compounds such as phytochemicals and fiber  and control biscuits without fiber. The shelf‐life study of the biscuits was carried out by investigating the evolution of the sensorial qualities during storage at ambient (25°C) and accelerated (45°C) temperature.22.12.5H2O (pH 6.5) (Ca). In the control biscuits, the 4% (w/w) of fiber was replaced by wheat flour.The biscuits were formulated in triplicate following the recipe of Whitley  with sliThe dough was kneaded with a pilot mixer during 10 min at minimum speed. Subsequently, the dough was laminated to a thickness of 5 mm, using a manual sheet pasta machine. The round form of the biscuits was obtained manually, using a cutting cylinder (die) of 60 mm in diameter. After making eight evaporation holes in the dough with a fork, the biscuits were baked in an electrical convection oven at a temperature of 180 ± 10°C during 17 min  and wrapped in heat‐sealed bags of high‐density polyethylene. The biscuits were divided into two groups as a function of the storage conditions. As the control for each group of biscuits, the values were taken at time 0, which was the day after preparation.2.2The wrapped biscuits were stored in two incubation chambers (Incudigit Selecta Spain), where temperature and humidity were kept constant.One of the chambers simulated storage at room temperature , while the other simulated conditions of accelerated storage  .Appearance is related to the geometry and the structure of the biscuits, and the outer ends of appearance went from an irregular biscuit with an irregular surface produced by evaporation bubbles, to a very compact biscuit with a smooth surface.Overall acceptability is a mixture of all of the sensory attributes and therefore the outer ends of the scale go from: very little like the commercial standard biscuit, with a very light color, little flavor and taste of biscuit, a very crumbly and soft biscuit, to a very dark biscuit, with a strong taste of toasted, a very hard and compact biscuit, at the upper end. In order to be able to describe the possible sensory defects, like the appearance of strange flavors and odors caused by the accelerated storage, the consensus on the sensory variables taste and flavor was differentiated. For the attributes characteristic flavor and taste, the freshness of the sample was rated as the point in the middle of the non‐structured scale. Thus, the absence of characteristic flavor and taste was rated below the standard value, like loss of characteristic flavor or taste when tastes or smells related to oxidative processes were detected, being a strong flavor and taste of rancidity the lower end of the scale. This nuance in the description of the sensory outer ends of flavor and taste caused the redefinition of the overall acceptability of the biscuits, in the lower end of the scale of overall acceptability, where the biscuits have a very light color, a strong taste and smell of rancidity, and are very soft and crumbly Figure .The presentation of the biscuit samples was performed in a blind fashion, coding each sample with a random numeric code of three digits. The order of presentation of the biscuits was balanced using all of the presentation combinations possible on the tasting sheet. The characterization of the products was carried out under daylight lighting and in portable cabins within the sensory laboratory. The ration of consumption was one whole biscuit of each reference, maintained at a temperature of 25°C. Water was served to the evaluators for cleaning of the mouth between the different samples. The samples were judged without replicate. With the aim of testing the reliability of the results, the control biscuit was introduced two times in the evaluations, randomly between other samples.2.4The samples tested during the sensory analysis were samples randomly selected from each of the three pilot plant batches. The three session of each replica of samples were performed with a time lapse of 2 days. Before the sensory analysis sessions, the samples were tempered for 30 min, at a temperature of the sensory analysis room (25°C). The presentation of the sample to the panelist was as follows: using white light, the four hold biscuits were presented together on a piece of white paper divided into four equal parts, in which the codes of the biscuit were printed randomly. The panelists were instructed to taste the samples clockwise starting from the upright quarter.2.5Statistical analysis of the sensorial measurements was carried out with the sensory analysis software Panel Check. The data were expressed as Mean ± Coefficient of variation (CV). Two‐way ANOVA (1 rep) sample means and LSD, and principal component analysis (PCA‐statis) were applied. The PCA decomposes the viability of a group of data in principal components and tracks the panelist in the principal component space according to their valuations of the samples together with the average classifications of the samples or attributes.33.1p < .001). With respect to color, as was expected, the biscuits without fiber (B) had a lighter color than the rest, followed by the pea biscuits (P), while the biscuits formulated with artichoke fiber‐rich powders  were significantly darker, mainly due to the darker color of the artichoke fiber‐rich powders . When comparing the biscuits with artichoke fiber‐rich powders  with the biscuits formulated with pea fiber, it was observed that their taste was similar.With respect to the overall acceptability, biscuits B were more similar to the standard biscuit, because of their more neutral taste and color. Similar results were found by other authors for wholemeal wheat biscuits in which part of the flour was replaced by another functional ingredient  explained 75.5% and the second component (PC2) 14.3%  explained 65.2% and the second (PC2) 17.2%  cookies are separated vertically cookies control (0). Feel this differentiation greater in them cookies of a color clearer, as the biscuits B and P, where small changes in color are more perceptible to the panelists.The sensory variables overall acceptability, taste and flavor were correlated with the biscuits enriched with artichoke fiber‐rich powder at the beginning of the accelerated test . On the contrary, the variables appearance and texture are not explained well by the model, since they are close to the centre of both principal components.In conclusion, the evolution of the sensory qualities of the biscuits formulated with artichoke fiber‐rich powders  was similar to that of the biscuits formulated with pea commercial reference fiber (P), and thus that its better sensory appreciation would be maintained throughout the accelerated storage.4The sensory description of the biscuits with fiber showed that the variables taste and color were the sensory qualities that significantly differentiate them from the biscuits without fiber (B).The taste of all biscuits enriched with fiber was appreciated as similar by the panelist. With respect to color, the use of both artichoke fiber‐rich powders  modifies the color of the biscuits, making them darker than the biscuits formulated with pea fiber, due to its more neutral color. However, initially, the overall acceptability of the biscuits formulated with both artichoke fiber‐rich powders was similar to that of the biscuits formulated with pea fiber (P).When the biscuits were subjected to accelerate storage, significant changes in taste and color were produced in the biscuits without fiber (B), since color and taste in these biscuits are more neutral, and therefore small variations are more easily detected by the panelist. It was also demonstrated that the biscuits formulated with artichoke fiber‐rich powders  had a similar behavior during storage to that of the biscuits formulated with the commercial reference fiber (P).These results conclude that the utilization of fiber‐rich powders from artichoke by‐products  can be a viable alternative for the enrichment of biscuits as well as other oven‐baked products and that it could be a suitable substitute for commercial pea fiber.


The data presented here were originally collected for the article “Frontiers of Urbanization: Identifying and Explaining Urbanization Hot Spots in the South of Mexico City Using Human and Remote Sensing”   Specifications TableValue of the Data•As the frontiers of urbanization are spaces with a high potential for conflict, these new data and combination of data types present a methodology with the capacity for replication of studies in many cities.•A combination of human (VGI) and remote sensing is relevant for a more reliable and validated analysis of urban growth.•Due to the decreasing costs of satellite imagery and the increasing availability of VGI, this type of analysis has been proven to be cost effective for future urban growth research.•Other socio-economic variables can be easily integrated into the analysis for further investigation.1For the urban change data, two tiles (IDs 1447913 and 1447914) of RapidEye 3A level products (5 m per pixel) covering the south of Mexico City in November 2009 and August 2014 were classified using E-cognition 2We investigated the growth of illegal settlements on the frontiers of urbanization in Mexico City using a combination of human observation (VGI) and remote sensing see . A graphIn order to compare data from both human and remote sensing, it was necessary to work with the same data type. Vector data were favorable for most parts of the analysis. As the ecological complaints were already available as point data, the urbanization class from the change detection based on RapidEye imagery had to be extracted and converted to points. Each pixel classified as non-urban in 2009 and urban in 2014 was converted into one point. In the next step, we conducted the optimized hot spot analysis using ArcGIS 10.3. Within the analysis, statistically significant hot and cold spots were identified with the Getis-Ord Gi* statistic An optimized hot spot analysis was executed for the ecological complaints and for the remote sensing data. However, a key limitation of this approach using ArcGIS is the cost associated with software licensing. The Python script allows for a more transparent presentation of the analysis with this software. A file with the detailed code has been added here. A particular note is that the names of the folders and paths should be adjusted to run this file. We recommend using a file geodatabase for data storage.2, the biggest area was 7.25 km2. The mean size was 0.4 km2 with a standard deviation of 0.504 km2. To minimize the loss of accuracy and ensure the consistency of our analysis, we chose a grid size of 0.143 km2. To transfer the data to the target grid (378 m), we made a spatial join using the mean value as the merge rule and intersect as the match option. Although the fishnet was smaller, both the fishnet and AGEBs were comparable because the difference was acceptable, with a loss of accuracy. Both layers are shown in For the integration of socio-economic drivers, population and unemployment data from Mexico City, AGEB data was used from the National Census 2010


Some 600 rotation-vibration lines are illustrated in 20 spectrograms and wavenumbers are listed in companion tables with considerable intercomparison with worthy data obtained in other laboratories. The absorpotion bands were remeasured or calibrated by using either a precisely graduated grating circle or standard atomic lines with the fringe system formed by a Fabry-Perot interferometer. Characteristic features of the individual bands are discussed briefly and references to other publications are given. The substances used for calibration include H2O, CO2, CO, HCl, HBr, NH3, C2H2, CH4, N2O, and polystyrene film.Suitable bands of common gases have been tabulated and remeasured wherever necessary from 2 to 16 microns to obtain an accuracy of about 0.03 cm In the case of prism instruments, the use of appropriate atomic lines for calibration is rather limited to the visible and near infrared regions and the need for single order coverage throughout is apparent. Present day commercial instruments are more easily calibrated in absorption than in emission and the molecular band method obviates the need for a full battery of atomic line equipment as well as personnel capable of using it. In addition, only available or easily obtainable substances have been used in this work so that laboratories should experience little difficulty in using this method. Most of the gases are available in typical chemistry laboratories and it will be mentioned that work in this laboratory has indicated that, in general, natural gas from commercial lines and acetylene drawn from the welder’s tank are suitable for calibration purposes. Should impurity peaks arise in these bands, use can still be made of the lines which are clearly those tabulated and illustrated in the following sections.Although in several cases  the lead telluride detector was replaced with a thermocouple detector. When this instrument was used in the 2- to 4-μ region, the thermocouple detector was purposefully used so that resolution could be lowered and made comparable to that of small grating instruments. A KBr foreprism arrangement with fixed foreprism slits and a manually adjustable prism was used for order separation throughout this work. Under these stated conditions the instrument was capable of resolving lines separated by 0.3 cm−1 in the 7- to 16-μ region and up to about 1 cm−1 in the 2.5- to 6.5-μ region.The previously described  grating −1. By making frequent settings of the foreprism (about every 2 deg of grating angle) so that the energy would be maximized and hence placed symmetrically on the entrance slit, these effects could be ignored. Such considerations were, of course, of greater importance in regions where wide spectrometer slits were required or at long wavelengths where the dispersion of KBr is greatest.  In the course of any complete run (standards plus spectrum to be measured) no changes were made in instrumental conditions  unless absolutely necessary.With a microscope attachment, angles were read off the inscribed circle, centered with respect to the spindle of the cone which rotates the grating, and fiducial marks recorded on the chart. During measuring runs, readings were taken every 5 min of arc and a slow drive speed (~23 min per deg) was used. It was found that proper positioning of the foreprism energy upon the entrance slit of the spectrometer proper was necessary in the sense that for extreme settings, where the maximum of energy being admitted to the spectrometer would come about 5 grating degrees away from the point of interest, the frequencies of measured lines would be in error by several hundredths of a cmnλ=K sin θ, where an “effective” grating constant, Kair, incorporating spectrometer characteristics, could be calculated by measuring about 15 CO lines and the physical central image. This was done with the grating being turned first in one direction then in the reverse direction. If slightly different, the K’s obtained separately for each direction would be averaged. Once a good value of K had been determined for a grating, the central image was always calculated from the 10 (or so) standard lines recorded either before or immediately following a measuring run. Using this procedure, the frequency of standard CO lines could always be recalculated from chart measurements to within about ±0.01 cm−1 of the accepted value. With good spectrometer and grating alinement, it was felt that CO standards could be used to calibrate NH3, CH4, and H2O lines even though the grating angle for the standards differed appreciably from that of the lines in question. In calibrating the lines, both standards and runs to be measured would be recorded with the grating being turned in the same direction. As is often the case, it was found that slightly different values would be obtained for the two directions. Final values represented the average of an equal number of measurements in each direction. It is believed that the tabulated values are accurate to ±0.02 cm−1 in this region.At the start of the work, it was decided that the precisely measured CO fundamental lines (see ref. ) table  be used Wherever possible single lines were picked out for measuring, but in some instances certain complex lines were measured since they are particularly suited for direct prism observation. It is advisable to record spectra on ruled chart paper where the ruled lines are reproducible perpendicular to the chart edge. The determined center point of the line to be measured can then be easily projected to a suitable measuring base line on the chart by using a pair of dividers and the nearest ruled line. The center of the line should be determined with a pair of stiff dividers at about the 2/3 absorption point and not at the peak or apparent maximum of absorption. If the spectrum is particularly noisy the center should be determined at a number of places from the 2/3 to 3/4 point of the maximum of absorption and the average taken. Fractional distances between “pip” marks should be measured to within 0.005 in. using a steel rule and visual enlarger if necessary. For the majority of measuring runs, 5 min of grating are corresponded to 2 in. on the chart.−1 has been described [−1 and the absolute to ±0.01 cm−1. With scanning at a medium rate, absolute values are probably in error by ±0.03 cm−1. The accuracy of measurement of this instrument is increased by the lines being very narrow (0.03 cm−1). Measurements made under lower resolution (about 1 cm−1) with the other instrument in this region agreed with these to about ±0.05 cm−1. This indicates that low resolution spectrometers can measure with an error of about 1/10 of the resolution.The instrument, which uses the double-pass system and is capable of resolving about 0.03 cmescribed  and onlyescribed ) were usIn this laboratory measurements on both instruments are carried out with the grating in air so that reported frequencies were corrected to vacuum by using refractive index tables, and temperature and pressure corrections given by Penndorf .For the present-day molecular spectroscopist who wishes to carry out precise measurements, useful points on measurement technique, whether on standard or unknown lines, have already been mentioned in previous sections on method of calibration, instrument performance, chart reduction and also in reference . Concern−1) relations by fitting a straight line to two end points and an extended deviation curve plotted. In view of extremely precise data for certain bands  the utility of using these standard lines in higher orders for the same grating angle should not be overlooked. In terms of precision measurement, it would appear that the R branch  of the μ/2 NH3 band might also be classified in this category. This higher order procedure, of course, requires refractive index considerations for conversion to vacuum and each spectral region must be handled independently.It is advisable to record both spectra and standards for each direction of grating turn if the driving mechanism is equally accurate in both directions. Provisions or modifications should be made on commercial or laboratory instruments so that the grating can be used in both directions with near equal accuracy and the results averaged. Undoubtedly, in most laboratories the standards will be used in conjunction with reproducible pip marks. Data will be extracted from simple pip or drum number versus frequency  the lines are single and suitably spaced throughout, even ripple peaks observed with a prism instrument would serve as satisfactory calibration points. Whereas, in many other bands proper usage under lower resolution may require judicious use of sufficiently low pressures and slow scanning speeds to assure the proper development of lines and eliminate “pulling” by strong neighboring absorption.In general, the runs made on white chart paper for illustration purposes were made at somewhat faster speeds and with much more chart concentration than was the case for the measuring runs. On some of the illustrations, sloping or bowing backgrounds are due either to foreprism effects or the joining of separate sections.2 used in a vapor cell. The spectrum is illustrated in Some 20 lines in this band were remeasured and comparison is made with the work of Rossman, Rao, and Nielsen , 21–B anμ CO2 band and the ammonia band. On the low-frequency end, our values are in excellent agreement with the recently published values of Rao, Ryan, and Nielsen [This band was included in order to provide useful calibration points between the end of the strong 15- Nielsen  and tabl Nielsen . The agr−1 exclusion conditions). The average values are probably better than individual determinations, and it is estimated that they are good to within ±0.01-cm−1 absolute on the average. The region from 1,000 to 1,200 cm−1 is particularly good. We have cause for suspicioning some of our low-frequency lines  due to the fact that the grating was being used at exceedingly high angle. As more experimental and theoretical data become available for ammonia, a good set of calculated values may ultimately replace the average value column. The spectrum is shown in −1 absolute. The spectrum is shown in This band serves the purpose of providing connection between the ammonia and water bands and is included mainly because workers with small instruments may have difficulty in observing weak water lines in this region. We are unable to compare these numbers with others, as there are no other precision measurements available but our results see  would ap−1 lower than those reported by Dalby and Nielsen [−1. Our results, when compared with Dalby and Nielsen’s values, would indicate that this is the case throughout the band. Wherever possible, mild flushing or pumping down of the spectrometer housing is to be recommended for cleaner development of the lines but our results indicate that good calibration measurements can be made even on saturated lines provided the line is not a complex one. This band is illustrated in Some 50 good lines of varying intensity were picked out for measurement. See . Whereve Nielsen  for the μ was measured accurately by Plyler, Blaine, and Connor (see ref. [μ), it was possible to calculate the position of the fundamental band. This has been done by Rank and his colleagues  in 1955see ref. ) and a v13O2 band is excellent for calibration from 2,240 to 2,280 cm−1 and connects with the v3 band of C12O2. This spectrum was measured in 1955 by Plyler, Blaine, and Tidwell [J values were incorrectly listed in J of the P branch should be reduced by 2; that is, P 44 should be P 42, etc. The work with a small grating spectrometer of Mizushima and his colleagues  −1 absolute. Since the band consists of a collection of no less than four overlapped bands, results are subject to being extremely resolution sensitive and workers should not use lines exhibiting pronounced overlap. (The R branch is comparatively free of such difficulties.)The only precision work for this band is the work which was done at the NBS. The frequencies were first published in 1955 (see ref. ) and sin79 and HBr81 were being resolved out. This was done intentionally to see whether, when measured as a single peak, the frequency agreed with the average determined for each component under resolution approaching 0.05 cm−1. The low resolution single-peak frequency agreed with the high resolution average value to within 0.05 cm−1 on the average , its frequency is given well enough by the component average. In −1 absolute.As shown in rage See . This re−1 absolute. (Future precision measurements are contemplated for this band.)The spectrum illustrated in R branch of this band and some of the lower-J lines of the P branch are fairly suitable for providing calibration points in this region. However, care should be exercised to the extent of staying within the bounds of the resolution illustrated in P 4, for example, shows four components within 0.37 cm−1 and frequency allocation becomes difficult. The values are listed in The The spectrogram of The spectrogram , illustr−1. The two bands are illustrated in 2 in a cell. Plyler and Tidwell (see ref. ) report P branch of the CO harmonic to the beginning of the μ3 water vapor band there is a gap of about 100 cm−1. There is a band of acetylene of medium intensity that falls in this region . This band is overlapped by four weaker bands and when measured with low pressure and high resolution many lines are observed [P and R branches of the band stand out clearly. A number of the strong lines were measured under both high and low pressures and the values agreed closely. The numbers listed in From the end of the μ has been measured very accurately by Rank and his colleagues  and alssee ref. ). This bv1 band of N2O has been measured in the region from 2,520 to 2,580 cm−1 and the results are shown in −1 of the values in this work. There is a small shift in the direction of lower frequency of all the values of the present measurements. An average of the two sets of values would probably be correct to ±0.03 cm−1, which should be entirely adequate for calibrating medium resolution instruments.The 2μ water band and should prove of some use to workers who wish to flush their instruments or use double-beam operation to study samples contained in cells. Dr. W. S. Benedict, of the Johns Hopkins University, has picked out of the band  measuresee ref. ) in 1957μ was not used in this work because of its resolution sensitiveness and also because of temperature and pressure effects. For example, there are 12 components in the P 8 “line” extending over 1.5 cm−1. Under low resolution  the Q bμ coverage may be appropriately extended by making use of frequency values reported by Lakshmi, Rao, and Nielsen [2O. In this work, we have checked Rao’s measurements on the 15-μ CO2 band and feel that if the same techniques were used on the N2O measurements, then these numbers may be used. Considering the lower resolution used by the Japanese workers (see ref. [The 16- Nielsen  for N2O.see ref. ) on thissee ref.  above is2O vapor at 1.9 μ and on CH4 at 2.2 μ as given in reference [At the high frequency end, we have already given reference to the work of Rank and coworkers on HCN (see ref. ) and wiseference .μ. As further measurements are carried out in other laboratories, there will be more values for intercomparison and it should be possible to obtain calculated values for certain bands which would be more accurate than the observed values from any one laboratory. No recommended frequencies representing properly weighted averages of the work of several laboratories have been given, but this may be done at a later date when more data are available. It is hoped that spectroscopists will send new data of this type to the authors for wavelength standards so that it may be incorporated in a future report. It is also requested that any corrections or suggested changes be communicated to the authors.The calibrating values given in this report should make it easier for infrared spectroscopists to obtain accurate measurements in the region from 2 to 16


To design and pilot a survey to be used at the population level to estimate the frequency of patient-perceived potentially harmful preventable problems occurring in UK primary care. To explore the nature of the problems, patient-suggested strategies for prevention and opinions of clinicians and the public regarding the potential for harm.A survey was codesigned by three members of the public and one researcher and piloted through public and patient involvement and engagement networks.Self-selected sample of the UK population.977 members of the public accessed the online survey during October and November 2015.Respondent feedback about the ease of completion of the survey, quality of responses in terms of review by clinicians and members of the public, preliminary estimates of the frequency and nature of patient-perceived potentially harmful problems occurring in the last 12 months.638 (65%) members of the public completed the survey and few respondents reported any difficulty in understanding or completing the survey. 132 (21%) respondents reported experiencing a potentially harmful preventable problem during the past 12 months and 108 (82%) of these respondents provided a description that was adequate for at least one clinician to form an opinion about the potentially harmful problem. Respondents were older than the UK generally, more likely to work or volunteer in the healthcare sector and tended to use primary care more frequently but their confidence and trust in their own general practitioner (GP) was similar to that of the UK population as measured by the annual English GP patient survey.The survey was acceptable to patients and mostly provided data of sufficient quality for review by clinicians and members of the public. It is now ready to use at a population level to estimate the frequency and nature of potentially harmful preventable problems in primary care from a patient’s perspective. We have designed and tested a survey to measure the frequency and nature of potentially harmful preventable problems in primary care from the patient’s perspective.The survey was codesigned by three members of the public and piloted through extensive public and patient involvement (PPI).The patient-described scenarios were reviewed by primary care clinicians.The study respondents were self-selected through PPI and engagement groups.The survey is ready to be administered to a representative sample of the general population.Patients are thought to take a different view of patient safety to healthcare professionals.Studies that quantify patient safety problems in primary care are uncommon and incidence estimates from record review or incident reporting by clinicians range from less than 1 to 24 per 100 consultations or record review.21 22codesign (with PPI partners) and test a survey asking about problems occurring in primary care that caused, or had the potential to cause, preventable harm as perceived by patients;pilot the survey to examine the usefulness and overall quality of the information collected with respect to describing the patient-perceived problems, the primary care service involved, how the problem was discussed (if it was) and how it might have been prevented;compare the opinions of the survey respondents, members of the public and primary care clinicians as to the likelihood the patient-reported scenario describes a potentially harmful preventable problem.Although it is acknowledged that patients tend to take a different view to professionals,Our main aim was to design a survey asking about problems occurring in primary care that caused, or had the potential to cause, preventable harm as perceived by patients that was easily understood and free from jargon. Currently, there is no well-established terminology for asking such a question.10.1136/bmjopen-2017-017786.supp1Supplementary file 1The first question Q1,  was takeThe nature of the problem in each described scenario was coded at face value, that is, as the patient described without further interpretation, by one author (SJS) and checked by a second author . A bottom-up (inductive) approach was used to identify similar topics which were coded then cross-matched to an existing taxonomy for errors in general practiceHigher threshold: Median score of 5 (‘very likely or certain’) or 4 (‘probably’) or at least one score of 5 (‘very likely or certain’).Lower threshold: Median score of 3 (‘possibly’) or at least one score of 4 (‘probably’ or higher).All other scenarios: Median score below 3 (‘possibly’) and zero scores above 3 (‘possibly’).Five GPs, one general dental practitioner and seven members of the public estimated the likelihood that, in their opinion, each patient-described scenario was a potentially harmful preventable problem. Brief biographies of the coders are provided in online 10.1136/bmjopen-2017-017786.supp2Supplementary file 22 test. All analyses were done using Stata V.14.Simple cross-tabulations were used to describe the data and a binary logistic regression model was used to explore whether particular types of patient were more likely to perceive potentially harmful preventable problems, for example, by demographics or their opinions. Comparisons between demographics and outcomes for the respondents and the UK (or England) population were made using a χPPI was central to this codesign study and was provided through the GMPSTRC RUGThe involvement of the PPI partners in the survey design had a profound impact on the piloted version of the survey. Professional researchers may have focused more on asking questions in a way that forces the responses into categories but the PPI partners were more concerned that respondents should have the freedom to express themselves and the categorisation should occur during the analysis. They themselves had often completed surveys where there was no appropriate option in the categorical responses. We did not find any of the previous approachesOver 250 respondents provided free text feedback on the survey, 200 comments reported that the questionnaire was easy to complete and understand and just one comment described the survey as complex. Most of the remaining comments expressed the desire to be able to provide more information, for example, more than one event or report for a relative or as a carer  and 13 comments actually provided this unrequested information. Nobody used the ‘Do not understand the question’ option as their response to Q2 of In total, 977 members of the public accessed the online pilot survey and 638 (65%) completed the survey during October and November 2015. The majority of respondents were recruited through the Help Beat Diabetes group .BoxDid you have confidence and trust in the GP you saw or spoke to at your last appointment? (benchmarking question)When using primary care, have you ever felt concerned that your health might be worsened, or actually was made worse, because of a mistake or a problem that could have been prevented?If no to Q10, if yes to Q3How long ago did the mistake or preventable problem happen?How did this affect your health?Which primary care service were you using when the mistake or preventable problem occurred?Briefly describe the mistake or problem and how it happened.Could the mistake or problem have been avoided? If so, how?Were you able to talk about the mistake or problem with anybody working in the primary care service? If not, why not?If you discussed the mistake or problem with somebody working in primary care, please describe their job or role.In the list below are some examples of preventable problems* that might happen when using primary care. Has anything similar happened to you in the last 12 months? If yes, go to Q4.*See Q10 in online The majority of respondents  had confidence and trust in the GP seen at their last appointment similar to the 2016 England proportion of 92% Q1, . RespondThe types of patient-reported scenarios and their categorisation following clinician review are shown in Around half the respondents had not discussed their problem with anybody working in primary care 51%, . The mos2=0.01) and higher threshold . Examples of the patient-reported scenarios with higher clinician rankings are shown in boxes 1–15, online Generally, the members of the public assigned a higher probability to the likelihood that the patient-described scenario was a potentially harmful preventable problem compared with clinicians , table 5We have designed and tested a survey to measure the frequency of occurrence of potentially harmful preventable problems in primary care and found it to be well understood and acceptable to patients. The open-ended questions Q6–Q9,  led to pWe believe that our survey captures the true patient perspective due to the involvement of members of the public as research partners through data acquisition to analysis and reporting in a codesigned study. By the use of a simple non-leading screening question, we encouraged respondents to express their own perspective on what constituted a potentially harmful preventable problem rather than directing them towards existing definitions. To ensure that we did not miss any problems, we followed up with a prompt that encouraged respondents to think in terms of the traditional view of patient safety problems. Furthermore, our survey goes further than describing and counting the frequency of occurrence of potentially harmful preventable problems and provides information about how patients dealt with the problem and how it could have been prevented that offers insight into ways to reduce the frequency of their occurrence. The absence of a link between practices and the patients allows for responses that might not occur if this survey were administered through the individual’s practice. The main weakness of the study is the self-selection of the respondents who were older and tended to use primary care more frequently. More frequent users of primary care were more likely to report a problem, but age was not associated with the likelihood of reporting a problem. Our benchmarking question Q1,  showed tOur finding that 35% of respondents perceived that they had experienced a potentially harmful problem in their lifetime is consistent with a European survey .Our finding that 21% of respondents perceived that they had experienced a potentially harmful problem in the last 12 months, and the corresponding proportion following clinician review of 3% (higher threshold) to 11% (lower threshold) may well reflect the self-selected nature of the study population and needs to be validated in a large population level survey. We anticipate that a population-level survey would be fruitful since this approach yielded a number of patient-described scenarios that were amenable to further analysis including coding by clinicians. The high response to this pilot survey by healthcare professionals and volunteers probably reflects the population invited to complete the survey as well as an interest in this topic. It is likely that these respondents are better at articulating their potentially harmful problem given the higher ranking given by clinicians to scenarios originating from healthcare professionals. Healthcare professionals are an educated and accessible group with the expectations of a patient and with an understanding of the healthcare system who could provide a valuable resource for learning about preventable problems in primary care. Further work is also needed to understand and reconcile the differences between members of the public and clinicians’ perceptions of a potentially harmful problem. In 1997, Professor Berwick stated ‘The ultimate measure by which to judge the quality of a medical effort is whether it helps patients (and their families) as they see it. Anything done in healthcare that does not help a patient or family is, by definition, waste, whether or not the professions and their associations traditionally hallow it.’ If this tenet still holds, then we suggest there is a real need to influence patient’s expectations and beliefs about primary care.


In this paper, we propose two proximal-gradient algorithms for fractional programming problems in real Hilbert spaces, where the numerator is a proper, convex and lower semicontinuous function and the denominator is a smooth function, either concave or convex. In the iterative schemes, we perform a proximal step with respect to the nonsmooth numerator and a gradient step with respect to the smooth denominator. The algorithm in case of a concave denominator has the particularity that it generates sequences which approach both the  optimal solutions set and the optimal objective value of the underlying fractional programming problem. In case of a convex denominator the numerical scheme approaches the set of critical points of the objective function, provided the latter satisfies the Kurdyka-ᴌojasiewicz property. One of the classical methods to handle  an it an it5])while ution of . Howeverution of  can be aution of .g and a proximal step with respect to f. In this way, the functions f and g are processed separately in each iteration. A further advantage of the algorithm investigated in case g is concave comes from the fact that it generates sequences that concomitantly approach the set of optimal solutions and the optimal objective value of  is the Opial Lemma, which we recall in the following.Lemma 1:C be a nonempty set of (a)for every (b)C;every weak sequential cluster point of Then C.[Opial] Let When proving the first part of the Opial Lemma, one usually tries to show that for every Lemma 2:Let The following summability result will be useful in Section 2.2.Lemma 3:Let Finally, the descent lemma which we recall next is a helpful tool in the convergence analysis of the algorithms proposed in this manuscript.Lemma 4:L-Lipschitz continuous gradient. Then Let the following inequality holdsh satisfies the KL property at each point in h is called a KL function.If The origins of this notion go back to the pioneering work of ᴌojasiewicz , where i Kurdyka  extended Kurdyka ,18–20.One of the remarkable properties of KL functions is their ubiquity in applications, according to . To thisAn important role in our convergence analysis will be played by the following uniformized KL property given in , Lemma 6Lemma 11:h is constant on h satisfies the KL property at each point of x in the intersectionLet the following inequality holdsThe techniques used below are well-known in the community dealing with algorithms for optimization problems involving functions with the Kurdyka-ᴌojasiewicz property (b)(c)(d)is satisfied. Assume that Remark 13:Suppose that Then the sequence We give now the main result concerning the convergence of the whole sequence Theorem 14:L-Lipschitz continuous, and consider the sequences generated by Algorithm under the additional conditions (a)(b)there exists In the setting of Problem 7, let (a)(I)There exists By using , we dedu(II)For all  In virtue of Lemma 12(c) and (d) and Lemma 11, the KL property of g, the fact that Consider the sequences generated by Algorithm . According to Lemma 12 we can choose an element t for all one has one has Let  be ows from . Furtherows from  and [11,er, from  we obtai(b)It follows from (a) that  3.(1)f and S is addressed in the algorithm by means of its projection operator?Is it possible to evaluate in each iteration the functions (2)How to incorporate in Algorithm some extrapolation terms in the sense of Nesterov in order to improve its speed of convergence?(3)f is smooth and g is nonsmooth, or even the more general case where both functions are nonsmooth?Can one consider also other situations, for instance when  We point out some open questions to be followed in the future related to the solving of the fractional programming problem under investigation: